Anilino-pyrazole derivatives, compositions and methods thereof

Abstract

The invention provides novel anilino-pyrazole derivatives as modulators (e.g., agonists) of cannabinoid type 2 receptor (CB2R). The invention also provides pharmaceutical compositions comprising the compounds and methods thereof for treating various diseases or conditions associated with or related to CB2R activities (e.g., pain, inflammation, cancer, cardiovascular, and metabolic and neurodegenerative diseases and conditions).

Description

ANILINO-PYRAZOLE DERIVATIVES, COMPOSITIONS AND METHODS THEREOFPriority Claims and Related Applications

[0001] This application claims the benefit of priority to Int'l Application No. PCT / CN2023 / 140167, filed December 20, 2023, the entire content of which is incorporated herein by reference for all purposes.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 modulators (e.g., agonists) of cannabinoid type 2 receptor (CB2R). The invention also provides pharmaceutical compositions comprising the compounds and methods thereof for treating various diseases or conditions associated with or related to CB2R activities (e.g., pain, inflammation, cancer, cardiovascular, and metabolic and neurodegenerative diseases and conditions).Background of the Invention

[0003] The CB2 receptor is a G protein-coupled receptor from the cannabinoid receptor family that in humans is encoded by the CNR2 gene. Cannabinoid receptors, located throughout the body, are part of the endocannabinoid system, which is involved in a variety of physiological processes. Changes in endocannabinoid levels and / or CB2R expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer. The CB2 receptor has been shown to have potential as a therapeutic target in models of diseases, such as neuropathic pain and neurodegenerative conditions. For example, CB2 receptors may play therapeutic roles in the treatment of neurodegenerative disorders such as Alzheimer's disease. Modulating CB2R activity by either selective CB2R agonists or inverse agomsts / antagonists depending on the disease and its progression holds unique therapeutic potential for these pathologies (Benito et al. 2023 The Journal of Neuroscience 23 (35): 11136-11141; Fernandez-Ruiz et al. 2008 Molecular and Cellular Endocrinology 286 (1-2 Suppl 1): S91-S96; Tolon et al. 2009 Brain Research 1283 (11): 148-154; Tiraboschi et al. 200 Neurology 62 (11): 1984-1989; Pacher 2011 Progress in Lipid Research 50 (2): 193-211; Bie, et al. 2018 Curr Opin Anae sthesiol. 31(4): 407-

[0004] There is an urgent need for safe and potent and CB2R modulators, in particular, CB2R selected agonists that are useful in treating diseases and conditions associated with CB2R.Summary of the Invention

[0005] The invention provides novel CB2R modulators (e.g., agonists) that have been shown to exhibit favorable potency and selectivity profiles over known CB2R modulators. The disclosed compounds selectively modulate the activity of CB2R. The compounds are also orally available with pharmacokinetic profiles suitable for development into an orally administered therapeutic agent for pain, inflammation, cancer, cardiovascular, and metabolic and neurodegenerative diseases and conditions.

[0001] In one aspect, the invention generally relates to a compound having the structural Formula (II):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or two R"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’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y3is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N; each of X1, X2and XJis selected from CHR7, O and NR, and X2additionally may be absent in which case X1and X3are joined by a single bond; provided that when X1is O or NR, X2is CHR7or if X2is absent X3is CHR7; each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted Ci- C-6 alkyl or Cs-Ce cycloalkyl, unsubstituted or substituted C1-4 alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’ ; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-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 C1-6 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, 4 or 5; j is 0, 1, 2 or 3; and k is 0, 1, 2 or 3.

[0002] In another aspect, the invention generally relates to a compound having the structural Formula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 R’ is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, N R’, 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’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y3is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N; each of X4and X5is independently CHR7, and X4additionally may be absent in which case X5and S(O)2are joined by a single bond; each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted Ci- C& alkyl or C3-C6 cycloalkyl, unsubstituted or substituted C alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted CM 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 CM 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; z is 0, 1, 2, 3, 4 or 5; j is 0, 1, 2 or 3; andA: is 0, 1, 2 or 3.

[0003] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound of formula (II) or formula (III) and a pharmaceutically acceptable excipient, carrier, or diluent.

[0004] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0005] In yet another aspect, the invention generally relates to a method for treating a CB2R- mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound of formula (II) or formula (III).

[0006] In yet another aspect, the invention generally relates to a method for modulating CB2R activities, comprising administer to a subject in need thereof a therapeutically effective amount of a compound of formula (II) or formula (HI).

[0007] In yet another aspect, the invention generally relates to use of a compound of formula (II) or formula (III), and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a CB2R-mediated disease or condition.

[0008] In yet another aspect, the invention generally relates to a method for making a compound of formula (II) or formula (III).

[0009] In yet another aspect, the invention generally relates to a method for treating a CB2R- mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or twoR3’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 Y ’ and 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 Ci-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-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 Ci-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, 4 or 5; andAfis O, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0010] In yet another aspect, the invention generally relates to a method for modulating the activity of CB2R, comprising administer to a subject in need thereof a therapeutically effective amount of a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-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 Y’ and 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 Ci-6 alkyl, and unsubstituted or substituted C1-4 alkoxy, or two R7’s, alongwith 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 Ci-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, 4 or 5; and k is 0, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0011] In yet another aspect, the invention generally relates to use of a compound in the manufacture of a medicament for the treatment of a CB2R-mediated disease or condition, wherein the compound has the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and Cs-Ce 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 Ci-6 alkyl, unsubstituted or substituted Ci-6 alkoxy, NO2, NRR’, or two R”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 Y’ and 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 Ci-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 C1-6 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, 4 or 5; and k is 0, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0012] In yet another aspect, the invention generally relates to a compound for use in treating a CB2R-mediated disease or condition, wherein the compound has the structural formula (1):or a pharmaceutically acceptable form or an isotope derivative thereof,whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and Cs-Ce 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 R' is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-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 Y ' and 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 C 1-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-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 Ci-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;7 is 0, 1, 2, 3, 4 or 5; andA; is 0, 1, 2, 3, 4 or 5;provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e g., greater than 200 nM, greater than 500 nM, greater than 1 pM).Definitions

[0013] 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.

[0014] As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

[0015] 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.

[0016] 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.

[0017] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0018] 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.

[0019] 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.

[0020] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0021] 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.

[0022] 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).

[0023] 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 is administered 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.

[0024] 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-C1-C6 alkyl, C1-C6 alkyl, -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.

[0025] 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.

[0026] 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 withinorganic 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-toluenesulfonate, 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.

[0027] 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.

[0028] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable ester. As used herein, the term "pharmaceutically acceptable ester" refers to esters thathydrolyze 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, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfinic acids, sulfonic acids and boronic acids. Examples of esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. The esters can be formed with a hydroxy or carboxylic acid group of the parent compound.

[0029] 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.

[0030] 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.

[0031] 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., "Prodrugs 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 prodrugcan 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.

[0032] As used herein, the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, 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.

[0033] 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.

[0034] 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 theeradication 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 physiological symptoms 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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 moleculesfurther include synthetically produced molecules. Additionally, vector molecules contained in recombinant host cells are also isolated. Thus, not all “isolated” molecules need be “purified.”

[0039] 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 facilitate the 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.

[0040] 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 sub-range within the range. By way of example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, C1-4, Ci- 3, C1-2, C2-5, C2-4, C3-6, C3.5 and C4-6 alkyl groups.

[0041] 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 C1-6 (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)2wherein 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 -hydroxy ethyl, 3- hydroxypropyl, benzyl, and phenethyl.

[0042] 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-C1-C6 alkyl, C1-C6 alkyl, -C1-C6 alkenyl, -OCi-Cg alkynyl, -C1-C6 alkenyl, -C1-C6 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.

[0043] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0044] 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 acndinyl, 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, thi enothiazolyl, 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.

[0045] Heteroaryl groups may be substituted with 0, 1, 2, 3, or 4 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxy carbonyl, 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 acetylmethylamino.

[0046] As used herein, the term “alkoxy” refers to an -O-alkyl radical.

[0047] 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 carbocyclyl groups 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 , -OR'1, -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.

[0048] 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 orcombinations 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.

[0049] 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 the heterocyclic 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., octahydroindohzinyl), azaspiroheptanyls, dihydro-lH,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro [cyclopropane- 1 ,2'-pyrrolizine] , hexahydro- 1 H-pyrrolizinyl, hexahydro- 1 H-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 -dioxi de.Detailed Description of the Invention

[0050] The invention is based in part on the discovery of novel CB2R modulator that selectively modulate the activity of CB2R. The disclosed compounds have been shown to exhibit favorable potency and selectivity profdes over known CB2R modulator. The compounds exhibit superior DMPK profiles suitable for development into an orally administered therapeutic agent for treating various diseases and conditions.

[0051] In one aspect, the invention generally relates to a compound having the structural Formula (II):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-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, Ci-4alkyl, CN, NRR’, or C(O)NRR’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y’ is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N; each of X1, X2and X3is selected from CHR7, O and NR, and X2additionally may be absent in which case X1and X3are joined by a single bond; provided that when X1is O or NR, X2is CHR7or if X2is absent XJis CHR7; each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted Ci- Ce alkyl or C3-C6 cycloalkyl, unsubstituted or substituted C1-4 alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’;each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-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 Ci-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;7 is 0, 1, 2, 3, 4 or 5; j is 0, 1, 2 or 3; and k is 0, 1, 2 or 3.

[0052] In certain embodiments of formula (II), Ring A has the below specified stereochemistry:

[0053] In certain embodiments of formula (II) or (IIa), Ring A is a substituted or unsubstituted cyclopentyl bivalent radical, having the structural formula:

[0054] In certain embodiments of formula (IIb), X2is present.

[0055] In certain embodiments of formula (IIb), X2is absent, having the structural formula:

[0056] In certain embodiments of formula (II)-(IF), XHS NR.

[0057] In certain embodiments of formula (II)-(IF), X1is CHR7, wherein R7is H or substituted or unsubstituted C1-C3 alkyl.

[0058] In certain embodiments of formula (II)-(IF), XJis CHR7, wherein R7is H or substituted or unsubstituted C1-C3 alkyl.

[0059] In certain embodiments of formula (II)-(IF), each of Y1, Y2and Y3is independently CR6.

[0060] In certain embodiments of formula (II)-(IF), each of Y1, Y2and Y’ is CH.

[0061] In certain embodiments of formula (II)-(IF), two of Y1, Y2and Y3is CH and the third isCR6, wherein R6is selected from halogen, unsubstituted or substituted Ci-Cg alkyl or C3-C6 cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’.

[0062] In certain embodiments of formula (II)-(IF), each of Y1and Y2is CH, and Y3is CR6

[0063] In certain embodiments of formula (II)-(IF), each of Y1and Y3is CH, and Y2is CR6.

[0064] In certain embodiments of formula (II)-(IF), each of Y2and Y3is CH, and Y1is CR6.

[0065] In certain embodiments of formula (II)-(IF), R6is F, Cl or C1-C3 alkyl.

[0066] In certain embodiments of formula (II)-(IF), one of Y1, Y2and Y3is N and each of the other two is CH.

[0067] In certain embodiments of formula (II)-(IF), Y1is N, and each of Y2and Y3is CH.

[0068] In certain embodiments of formula (II)-(IF), Y2is N, and each of Y1and Y3is CH.

[0069] In certain embodiments of formula (II)-(IF), Y3is N, and each of Y1and Y2is CH.

[0070] In another aspect, the invention generally relates to a compound having the structuralFormula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 R’ is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-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’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y3is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N; each of X4and X5is independently CHR7, and X4additionally may be absent in which case X5and S(O)2are joined by a single bond; each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted Ci- Ce alkyl or C3-C6 cycloalkyl, unsubstituted or substituted C1-4 alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted C1-4 alkoxy, or two R7’s, alongwith 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 Ci-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, 4 or 5; j is 0, 1, 2 or 3; and k is 0, 1, 2 or 3.

[0071] In certain embodiments of formula (III), Ring A has the below specified stereochemistry:

[0072] In certain embodiments of formula (III) or (IIP), Ring A is a substituted or unsubstituted cyclopentyl bivalent radical, having the structural formula:

[0073] In certain embodiments of formula (IIIb), X4is present.

[0074] In certain embodiments of formula (IIIb), X4is absent, having the structural formula:(III )

[0075] In certain embodiments of formula (III)-(IIIC), each of Y1, Y2and Y’ is independently CR6.

[0076] In certain embodiments of formula (III)-(IIIC), each of Y1, Y2and Y3is CH.

[0077] In certain embodiments of formula (III)-(IHC), two of Y1, Y2and Y3is CH and the third is CR6, wherein R6is selected from halogen, unsubstituted or substituted C1-C6 alkyl or C3-C6 cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’.

[0078] In certain embodiments of formula (IH)-(Iir), R6is F, Cl or C1-C3 alkyl.

[0079] In certain embodiments of formula (III)-(IHC), one of Y1, Y2and Y3is N and each of the other two is CH.

[0080] Compounds disclosed herein include deuterated versions of the disclosed compounds, for example, having one or more deuterium atoms in place of hydrogen.

[0081] In certain embodiments, the compound has one deuterium atom in place of a hydrogen atom.

[0082] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0083] In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0084] In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

[0085] In certain embodiments, is in the form of a tablet. In certain embodiments, is in the form of a capsule.

[0086] In yet another aspect, the invention generally relates to a method for treating a CB2R- mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound of formula (II) or (III).

[0087] In yet another aspect, the invention generally relates to a method for modulating the activity of CB2R, comprising administer to a subject in need thereof a therapeutically effective amount of a compound of formula (II) or (III).

[0088] In yet another aspect, the invention generally relates to use of a compound of formula (II) or (III), and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a CB2R-mediated disease or condition.

[0089] In certain embodiments of the use, the CB2R-mediated disease or condition is selected from pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g, trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age- related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemia-reperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fatty liver (NAFL),attention-deficit hyperactivity disorder (ADHD), anxiety, autistic spectrum disorder, depression, insomnia / sleep disorders, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

[0090] In certain embodiments of the use, the CB2R-mediated disease or condition is chronic pain.

[0091] In certain embodiments of the use, the CB2R-mediated disease or condition is osteoarthritis.

[0092] In certain embodiments of the use, the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

[0093] In certain embodiments of the use, the CB2R-mediated disease or condition is anxiety and / or depression.

[0094] In certain embodiments, a compound disclosed herein, e.g., of formula (II) or formula (III), pharmaceutical composition and unit dosages comprising the same, and method and use thereof, the compound(s) is characterized by binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0095] In yet another aspect, the invention generally relates to a method for making a compound of formula (II) or (III).

[0096] In yet another aspect, the invention generally relates to a method for treating a CB2R- mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring;each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted Ci-6 alkoxy, NO2, NRR’, or two R"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, Y’ and Y4is N, and either Y’ or 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 Ci-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 Ci-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; z is 0, 1, 2, 3, 4 or 5; and k is 0, 1, 2, 3, 4 or 5;provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0097] In yet another aspect, the invention generally relates to a method for modulating the activity of CB2R, comprising administer to a subject in need thereof a therapeutically effective amount of a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, N R’, or two R5’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 Y ' and 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 C 1-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-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 Ci-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;7 is 0, 1, 2, 3, 4 or 5; andA; is 0, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0098] In yet another aspect, the invention generally relates to use of a compound in the manufacture of a medicament for the treatment of a CB2R-mediated disease or condition, wherein the compound has the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and Cs-Ce 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 Ci-6 alkyl, unsubstituted or substituted Ci-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 Y ’ and 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 Ci-6 alkyl, and unsubstituted or substituted C 1-4 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 Ci-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;7 is 0, 1, 2, 3, 4 or 5; and k is 0, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0099] In yet another aspect, the invention generally relates to a compound for use in treating a CB2R-mediated disease or condition, wherein the compound has the structural formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted C1-6 alkoxy, NO2, NRR’, or two R”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 Y’ and 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 Ci-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 C1-6 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, 4 or 5; and k is 0, 1, 2, 3, 4 or 5; provided that the compound of formula (I) is characterized by a binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM (e.g., greater than 200 nM, greater than 500 nM, greater than 1 pM).

[0100] In certain embodiments of the method or use of compound of formula (I), the CB2R- mediated disease or condition is selected from pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g., trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemia-reperfusion injury, heart failure, stroke, myocardial ischemia,cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, nonalcoholic fatty liver (NAFL), attention-deficit hyperactivity disorder (ADHD), anxiety, autistic spectrum disorder, depression, insomnia / sleep disorders, obsessive compulsive disorder (OCD), post- traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

[0101] In certain embodiments, the CB2R-mediated disease or condition is chronic pain.

[0102] In certain embodiments, the CB2R-mediated disease or condition is osteoarthritis.

[0103] In certain embodiments, the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

[0104] In certain embodiments, the CB2R-mediated disease or condition is anxiety and / or depression.

[0105] In certain embodiments, the CB2R-mediated disease or condition is addiction.

[0106] With regard to compounds of formula (I), in certain embodiments, none of Y1, Y2, Y' and 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 R3may be bonded to the rest of the compound; and j is 0, 1, 2 or 3.

[0107] In certain embodiments, R5is connected to the rest of the compound at the p position:

[0108] In certain embodiments, R5is connected to the rest of the compound at the a position:

[0109] In certain embodiments of (I), at least one of Y1, Y2, Y3and Y4is N.

[0110] In certain embodiments of (I), only one of Y1, Y2, Y3and Y4is N.[0011 1] In certain embodiments of (I), Y’ is C and R5is connected to the rest of the compound at the Y3position:[001 12] In certain embodiments, R5is selected from:

[0113] In certain embodiments of (I), Y4is C and R5is connected to the rest of the compound at the Y4position:

[0114] In certain embodiments, R5is selected from:

[0115] Ring B may be selected from:wherein each of X1, X2, X3, X4and X3is 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, X\ X4or X5are not each selected from NH and O.

[0116] 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).

[0117] In certain embodiments, neither of Xi and X2 is S(O)2 or C(O); and one of X3, X4 and X5 is S(O)2or C(O).

[0118] 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.

[0119] In certain embodiments, R5is selected from:

[0120] In certain embodiments, R5is selected from:

[0121] In certain embodiments, R5is selected from:

[0122] In certain embodiments, R5is selected from:

[0123] In certain embodiments, R5is selected from:

[0124] In certain embodiments, R5is selected from:

[0125] In certain embodiments, R5is selected from:

[0126] In certain embodiments, R5is selected from:

[0127] In certain embodiments, R5is selected from:

[0128] In certain embodiments, R5is selected from:

[0129] In certain embodiments, two R7’s, along with the carbon atom they are bound to, form a3- to 6-membered (e.g., 3-, 4-, 5- or 6-membered) unsubstituted or substituted carbocyclic ring.

[0130] In certain embodiments, two R7’s, along with the carbon atom they are bound to, form a3- 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.

[0131] In certain embodiments, R5is selected from:Table 1

[0132] In certain embodiments, R5is selected from:Table 2

[0133] In certain embodiments, R5is selected from:Table 3

[0134] In certain embodiments of Tables 1-3, Y1is N, Y2is CH and Y4is CH.

[0135] In certain embodiments of Tables 1-3, Y1is CH, Y2is N and Y4is CH.

[0136] In certain embodiments of Tables 1-3, Y1is CH, Y2is CH and Y4is N.

[0137] In certain embodiments of Tables 1-3, each of Y1, Y2and Y4is CH.

[0138] In certain embodiments, R5is selected from:Table 4

[0139] In certain embodiments, R5is selected from:Table 5

[0140] In certain embodiments, R5is selected from:

[0141] In certain embodiments of Tables 4-6, Y1is N, Y2is CH and Y3is CH.

[0142] In certain embodiments of Tables 4-6, Y1is CH, Y2is N and Y3is CH.

[0143] In certain embodiments of Tables 4-6, Y1is CH, Y2is CH and Y3is N.

[0144] In certain embodiments of Tables 4-6, each of Y1, Y2and Y' is CH.

[0145] In certain embodiments of R5, R is H.

[0146] In certain embodiments of R5, R is an unsubstituted or substituted C1-6 alkyl.

[0147] In certain embodiments, R is methyl.

[0148] In certain embodiments, R1is H and R2is an unsubstituted or substituted linear or branched C1-C6 alkyl.

[0149] In certain embodiments, each of R1and R2is independently an unsubstituted or substituted linear or branched C1-C6 alkyl.

[0150] 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.

[0151] In certain embodiments, Ring A is a 4- to 7-membered (e.g., 4-, 5-, 6- or 7-membered) carbocyclic ring.

[0152] In certain embodiments, Ring A is selected from:

[0153] In certain embodiments, Ring A is selected from:

[0154] In certain embodiments, Ring A is a 5-membered carbocyclic ring.

[0155] In certain embodiments, Ring A is:

[0156] In certain embodiments, z is 0.

[0157] In certain embodiments, compounds of the invention have the structural formula:

[0158] In certain embodiments of (Ia), Y1is N, Y2is CH and Y4is CH.

[0159] In certain embodiments of (la), Y1is CH, Y2is N and Y4is CH.

[0160] In certain embodiments of (Ia), Y1is CH, Y2is CH and Y4is N.

[0161] In certain embodiments, compounds of the invention have the structural formula:

[0162] In certain embodiments of (Ib), Y1is N, Y2is CH and Y3is CH.

[0163] In certain embodiments of (Ib), Y1is CH, Y2is N and Y3is CH.

[0164] In certain embodiments of (Ib), Y1is CH, Y2is CH and YJis N.

[0165] In certain embodiments of (Ia) and (Ib), Ring B is 5 -membered carbocyclic ring.

[0166] In certain embodiments of (Ia) and (Ib), Ring B is 5 -membered heterocyclic ring.

[0167] In certain embodiments of (Ia) and (Ib), Ring B is 6-membered carbocyclic ring.

[0168] In certain embodiments of (Ia) and (Ib), Ring B is 6-membered heterocyclic ring.

[0169] In certain embodiments of (Ia) and (Ib), Ring B comprises a -S(O)2NH- group.

[0170] In certain embodiments of (Ia) and (Ib), Ring B comprises a -S(O)2- group.

[0171] In certain embodiments of (Ia) and (Ib), Ring B comprises a -C(O)NH- group.

[0172] In certain embodiments of (Ia) and (Ib), Ring B comprises a CH2 group.

[0173] In certain embodiments of (Ia) and (Ib), Ring B comprises a C(CN)R” group, wherein R” is H, OH, C1-4 alkyl or O-C1-4 alkyl.

[0174] In certain embodiments

[0175] In certain embodiments

[0176] In certain embodiments

[0177] In certain embodiments

[0178] In certain embodiments

[0179] In certain embodimentsunsubstituted or substituted C1-6 alkyl.

[0180] Exemplary compounds of the invention include:(00181] Exemplary compounds of the mvention mclude

[0183] Exemplary compounds of the invention include:

[0184] 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.

[0185] 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 certain embodiments, 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).

[0186] 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.

[0187] 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.

[0188] 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 germ oil, 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 compositioncan also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

[0189] 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.

[0190] 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.

[0191] 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 nonaqueous 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.

[0192] 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 of compounds 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.

[0193] 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.

[0194] 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.

[0195] 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 nonaqueous 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.

[0196] 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 glycende derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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 be topically 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.

[0201] Methods of treatment disclosed herein may be employed in combination with or in addition to other therapies.

[0202] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and tra -isomers, R- and 5-enantiomers, 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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 for their 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.

[0207] Further, substitution of normally abundant hydrogen ('H) 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.)

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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 injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0214] 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.

[0215] 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.

[0216] 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 understoodthat 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

[0217] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.

[0218] 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 DichloromethaneDMAP 4-DimethylaminopyridineDMSO 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 chromatographyTBS tert-ButyldimethylsilylTHF TetrahydrofuranTLC Thin-layer chromatographyXantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)LC-MS Method.

[0219] Shimadzu LCMS2020, Reverse-phase column (Shim-Pack Scepter C18, 33 x 3.0 mm,3 urn), elution with A: H2O / MeCN / FA = 90 / 10 / 0.05; B: MeCN; Detection: MS, ELS, UV (100 pLsplit to MS with in-line UV detector); MS ionization method: Electrospray (positive and negative ion). ES-API = electrospray-atmospheric pressure ionization.HPLC Purification Method.

[0220] Instrument = Shimadzu FRC-40; Shimadzu LH-40; Shimadzu LC-8A; GX-281. Column = YMC-Triart C18, 250*20 mm, 5um; Welch Ultimate XB-C18, 250*21.2 mm, 5um. Detection wavelength = 220, 254 nM. Flow rate = 15ml / min-20ml / min; Run time = 8 min; Column temperature = 25 °CCompound SynthesisGeneral Procedure 1Synthesis of common intermediate 1: l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldimethylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-amine

[0221] Step A. methyl l,4-dioxaspiro[4.4]nonane-7-carboxylate. To a stirred solution of methyl 3 -oxocyclopentane- 1 -carboxylate (70 g, 492.9 mmol) in toluene (600 mL) was added ethane- 1,2-diol (61.1 g, 985.8 mmol), molecular sieve (15 g) and TsOH (8.5 g, 49.3 mmol) at rt. After stirnng at 110 °C O / N, the cooled mixture was concentrated. The residue was purified by chromatography (silica gel, 0-20%, EtOAc in PE) to give methyl l,4-dioxaspiro[4.4]nonane-7- carboxylate (34.8 g, 187.1 mmol, 31 %) as a colorless oil.

[0222] Step B. 3-{l,4-dioxaspiro[4.4]nonan-7-yl}-3-oxopropanenitrile. To a stirred solution of w-BuLi (90 mL, 224.5 mmol, 2.5 M in hexane) in THF (200 mL) was added dropwise MeCN (15.3 g, 374.2 mmol) at -60 °C. After stirring at -70 °C for Ih. A solution of methyl 1,4- dioxaspiro[4.4]nonane-7-carboxylate (34.8 g, 187.1 mmol) in THF (50 mL) was added dropwise at - 60 °C. After stirring at -70 °C for 2h, the reaction mixture was quenched with water (100 mL), adjust pH = 7 with IN aqueous HC1, extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4 and concentrated under reduced pressure to give crude 3-{ l,4-dioxaspiro[4.4]nonan-7-yl]-3-oxopropanenitrile (32.8 g, 168.2 mmol, 90%) as a yellow oil which was used in the next step directly.

[0223] Step C. l-tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yI]-lH-pyrazol-5-amine. To a stirred solution of sodium hydroxide (13.5 g, 336.4 mmol) in EtOH (300 mL) was added tertbutylhydrazine (31.3 g, 252.3 mmol) at rt. After stirring at rt for Ih, 3-{l,4-dioxaspiro[4.4]nonan-7- yl} -3 -oxopropanenitrile (32.8 g, 168.2 mmol) was added. After stirring at 80 °C O / N, the mixture was filtered. The filtrate was poured into water, adjusted PH to 6~7 with IM aqueous HC1 and extracted with EtOAc (80 mLx2). The combined organic phase was washed by water and brine, driedover Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0- 50 %, EtOAc in PE) to give l-tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yl}-lH-pyrazol-5-amine (30 g, 113 mmol, 67%) as a yellow oil. LCMS: m / z 266 [M+H]+.

[0224] Step D. Benzyl N-(l-tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yl}-lH-pyrazol-5- yl)carbamate. To a stirred solution of l-tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yl]-lH-pyrazol-5- amine (30 g, 113 mmol) in MeCN (350 mL) was added NaHCCh (47.5 g, 565.3 mmol) and Cbz-Cl (29 g, 169.6 mmol) at 0 °C. After stirring at rt O / N, the mixture was filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-40%, EtOAc in PE) to give benzyl N-(l- tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yl}-lH-pyrazol-5-yl)carbamate (28 g, 70 mmol, 62 %) as a yellow oil. LCMS: m / z 400 [M+H]+.

[0225] Step E. Benzyl N-[l-tert-butyl-3-(3-oxocyclopentyl)-lH-pyrazol-5-yl]carbamate.To a stirred solution of benzyl N-(l-tert-butyl-3-{l,4-dioxaspiro[4.4]nonan-7-yl}-lH-pyrazol-5- yl)carbamate (28 g, 70 mmol) in acetone (150 mL) was added H2O (150 mL) and TsOH (6 g, 35 mmol) at rt. After stirred at 60 °C O / N, the cooled mixture was poured into water (150 ml) and extracted with EtOAc (50 mlx2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give benzyl N-[l-tert-butyl-3-(3-oxocyclopentyl)-lH-pyrazol-5-yl]carbamate (21 g, 59 mmol, 84 %) as a white solid. LCMS: m / z 356 [M+H]+. 1H NMR (400 MHz, DMSO) 59.07 (s, 1H), 7.36-7.25 (m, 5H), 5.97 (s, 1H), 5.06 (s, 2H), 3.30 - 3.23 (m, 1H), 2.43-2.33 (m, 1H), 2.27 - 2.20 (m, 1H), 2.19 - 2.10 (m, 3H), 1.90 - 1.81 (m, 1H), 1.42 (s, 9H).

[0226] Step F. Benzyl N- [ l-tert-butyl-3-(3-hydroxy cyclopen tyl)-lH- pyrazol-5- yl]carbamate. To a stirred solution of benzyl N-[l-tert-butyl-3-(3-oxocyclopentyl)-lH-pyrazol-5- yl] carbamate (10 g, 28.134 mmol) in THF (100 mL) was added slowly LiBH(Et)s (56 mL, 56 mmol, 1 M in THF) at -65 °C. After stirred at -65 °C for 1.5 h, NaHCO? (aq, 40 mL) was added to the mixture at -30 °C (the mixture turned slowly into a glassy solid), then H2O2 (19 g, 562 mmol) was slowly added to the mixture from -10 °C to rt (the glassy solid slowly backed into a normal mixture that can be easily stirred). After stirring at rt for further 1.5 h, the following mixture was poured slowly into saturated ^2826)3 (aq, 100 mL) and extracted with EtOAc (30 mLx2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. TLC (DCM: MeOH= 10: 1) showed a low polarity spot, which was the desired cis product. The residue was purified by chromatography (silica gel, 0-3%, MeOH in DCM) to give the cis isomer of benzyl N-[l-tert-butyl-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl]carbamate (6.6 g, 18.5 mmol, 65%, lesspolar spot) as a white solid. LCMS: m / z 358 [M+H]+. 1H NMR (400 MHz, DMSO) 8 9.07 (s, 1H), 7.49 - 7.21 (m, 5H), 5.93 (s, 1H), 5.12 (s, 2H), 4.59 (d, J = 4.4 Hz, 1H), 4.15 (dd, J = 10.4, 4.5 Hz, 1H), 2.96 - 2.77 (m, 1H), 2.30 - 2.10 (m, 1H), 1.90 - 1.81 (m, 1H), 1.78 - 1.65 (m, 2H), 1.63 - 1.55 (m, 1H), 1.48 (s, 9H).

[0227] Step G. Benzyl N-{l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5- yl]carbamate. Benzyl N-[l-tert-butyl-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl]carbamate (6.6 g, 18.5 mmol) was purified by prep-SFC to give benzyl N-{ l-tert-butyl-3-[(lS,3R)-3- hydroxycyclopentyl]-lH-pyrazol-5-yl}carbamate (3.1 g, 8.6mmol, 46.7 %) as a white solid. LCMS: m / z 358 [M+H]+.

[0228] Step H. Benzyl (l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldimethylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)carbamate. To a solution of benzyl N-{1- tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl]carbamate (6.2 g, 17.3 mmol) in DCM (100 mL) were added DMAP (0.21 g, 1.73 mmol), IH-Imidazol (2.36 g, 34.7 mmol), and TBSCl (2.61 g, 17.3 mmol) at rt. The reaction mixture was stirred at room temperature O / N. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-50%] to afford the title compound benzyl N-{l-tert-butyl-3-[(lS,3R)-3- [(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}carbamate (7 g, 14.8 mmol, 85.7%) as a colorless oil. LCMS: m / z 472 [M+H]+.

[0229] Step I. l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsiIyI)oxy)cydopentyl)-lH- pyrazol-5-amine. To a solution of benzyl N-{l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}carbamate (7 g, 14.8 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Pd / C 10% (0.20 g, 1.86 mmol) at rt. The reaction mixture was stirred at rt for 3 h under H2 using a H2 balloon. The reaction mixture was filtered and concentrated to afford the title compound l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH- pyrazol-5-amine (4.8 g, 14.2 mmol, 96%) as a colorless oil. LCMS: m / z 338 [M+H]1. 'll NMR (400 MHz, CDC13) 5 5.47 (s, 1H), 4.32 - 4.08 (m, 1H), 3.47 (s, 2H), 2.98 - 2.80 (m, 1H), 2.34 - 2.19 (m, 1H), 1.98 - 1.89 (m, 1H), 1.85 - 1.75 (m, 2H), 1.72 - 1.64 (m, 1H), 1.63 - 1.59 (m, 10H), 0.90 - 0.88 (m, 9H), 0.05 (d, J= 2 Hz, 6H).Synthesis common intermediate 2: (lR,3S)-3-[5-amino-l-(2-methylprop-2-yl)pyrazol-3- yl] cyclopentyl (prop-2-ylamino)methanoateCommon intermediate 2

[0230] Step A: benzyl {[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(prop-2- ylamino)carbonyl]oxy}cyclopentyl]pyrazoI-3-yl]amino}methanoate To a solution of benzyl ({5- [(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl]amino)methanoate (1.0 g, 2.8 mmol) in THF (20 mL) were added Z-BuOK (4.2 mL, IM in THF) at 0 °C and the reaction was stirred at 0 °C for 30 min. A solution of 2-lsocyanatopropane (290 mg, 3.6 mmol) in 5 mL THF was added dropwise into the reaction at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for Ih, TLC and LCMS indicated the reaction was over. The reaction was poured into ice-water and extracted with EA (30 mL*3). The combined organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with methanol in dichloromethane. (Gradient: 0~ 3%) to afford the title compound benzyl {[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(prop-2- ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}methanoate (1.2 g, 2.7 mmol, 96.9%) as a white solid. LCMS: m / z 443 [M+H]+. ‘H NMR (400 MHz, DMSO) 5 9.07 (s, IH), 7.45-7.33 (m, 5H), 6.92 (d, J = 7.6 Hz, IH), 5.93 (s, IH), 5.11 (s, 2H), 4.97 (s, IH), 3.60-3.50 (m, IH), 3.01 - 2.88 (m, IH), 2.40 - 2.29 (m, IH), 1.98 - 1.77 (m, 2H), 1.75 - 1.56 (m, 3H), 1.47 (s, 9H), 1.02 (d, J = 6.4 Hz, 6H).

[0231] Step B: (lR,3S)-3-[5-amino-l-(2-methylprop-2-yl)pyrazol-3-yI]cyclopentyl (prop-2- ylamino)methanoate A suspension of benzyl {[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(prop-2- ylamino)carbonyl]oxy}cyclopentyl]pyrazol-3-yl]amino}methanoate (1.2 g, 2.7 mmol) and Pd / C 10% (290 mg) in THF (10 mL) and EA (10 mL) was stirred at room temperature under H2 atmosphere using a balloon for 18 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography eluting with methanol in dichloroform (gradient: 0~ 6%) to afford the title compound (lR,3S)-3-[5-amino-l-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl (prop-2-ylamino)methanoate (700 mg, 2.2 mmol, 83.7%) as syrupy solid. LCMS: m / z 309 [M+H]+. 'H NMR (400 MHz, DMSO) 56.88 (d, J = 7.6 Hz, IH), 5.22 (s, IH), 4.94 (s, IH), 4.70 (s, 2H), 3.62 - 3.53 (m, IH), 2.84-2.75 (m, IH), 2.34 - 2.24 (m, IH), 1.86-1.76 (m, 2H), 1.68 - 1.53 (m, 3H), 1.48 (s, 9H), 1.03 (d, J = 6.4 Hz, 6H).Synthesis common intermediate 3: l-(tert-butyl)-3-((ls,4s)-4-((tert- butyldiphenylsilyl)oxy)cyclohexyl)-lH-pyrazol-5-amine

[0232] Step A: methyl (ls,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-l-carboxylate To a solution of methyl (ls,4s)-4-hydroxycyclohexane-l -carboxylate (5 g, 31.6 mmol) in DCM (30 mL) were added DMAP (0.39 g, 3.16 mmol), Imidazole (6.46 g, 94.8 mmol), and TBDPSC1 (9.83 mL, 37.9 mmol), and the reaction was stirred at room temperature for overnight. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-50%] to afford the title compound methyl (ls,4s)-4-[(tert- butyldiphenylsilyl)oxy] cyclohexane- 1 -carboxylate (10.1 g, 25.4 mmol, 80.4%) as a colorless oil. LCMS: ESI m / z 397 [M + H]+

[0233] Step B: 3-((ls,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile A solution of w-BuLi (20.0 mL, 50.0 mmol) in THF (60 mL) was cooled to -65 °C. ACN (1.48 g, 31.5 mmol) was added dropwise at -65 °C. The reaction mixture was stirred at -65 °C for 1 hr. A solution of methyl (ls,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-l -carboxylate (5.00 g, 12.6 mmol) in THF (10 mL) was added dropwise at -65 °C. The resulting mixture was stirred at -65 °C for 1 hr. After TLC showed completion, the reaction mixture was quenched with water (50 mL), adjust pH = 7 with IN HC1, extracted with EA (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SC>4 and concentrated under reduced pressure to give 3-((ls,4s)-4-((tert- butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (5.10 g, 12.6 mmol, 99.8%) as an oil which was used for next step directly.

[0234] Step C: l-(tert-butyl)-3-((ls,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyI)-lH- pyrazol-5-amine To a solution of N-tert-butylhydroxylamine (1.91 g, 21.4 mmol) in EtOH (50 mL) was added NaOH (0.6 g, 15.1 mmol). The reaction mixture was stirred at room temperature for Ihr, then 3-((ls,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (5.10 g, 12.6 mmol) was added. The following mixture was stirred at 80 °C overnight. LCMS showed the reaction was complete. The cooled reaction mixture was filtered and concentrated. The residue was purified via a FC on silica gel eluting with PE / EA 1:1 as a yellow solid l-(tert-butyl)-3-((ls,4s)-4-((tert- butyldiphenylsilyl)oxy)cyclohexyl)-lH-pyrazol-5-amine (4.20 g, 8.83 mmol, 70%). LC-MS: ESI m / z476.75 [M+H]+. 'H NMR (400 MHz, DMSO) 57.65-7.57 (m, 4H), 7.48 - 7.39 (m, 6H), 5.25 (s, 1H), 4.71 (s, 2H), 4.00 (brs, 1H), 2.40 - 2.31 (m, 1H), 1.89 - 1.78 (m, 2H), 1.67-1.59 (m, 2H), 1.58-1.49 (m, 2H), 1.49 (s, 9H), 1.45 - 1.37 (m, 2H), 1.04 (s, 9H).Synthesis common intermediate 4: (ls,3s)-3-(5-amino-l-(tert-butyl)-lH-pyrazol-3-yl)cyclobutyl isopropylcarbamate

[0235] Step A: methyl (Is, 3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutane-l-carboxylate To a solution of methyl (Is, 3 s)-3-hydroxycyclobutane-l -carboxylate (5 g, 31.6 mmol) in DCM (30 mL) were added DMAP (0.39 g, 3.16 mmol), Imidazole (6.46 g, 94.8 mmol), and TBDPSC1 (9.83 mL, 37.9 mmol), and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-50%] to afford the title compound methyl (ls,3s)-3-((tert- butyldiphenylsilyl)oxy)cyclobutane-l -carboxylate (14 g, 25.4 mmol, 80.4%) as a colorless oil. LCMS: ESI m / z 369.35 [M + H]+

[0236] Step B: 3-((ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropanenitriIe To a stirred slurry of w-BuLi (10.0 mL, 25.2 mmol) in dry THF (150 mL) containing CH3CN (1.98 mL, 37.8 mmol), at -45 °C under N2, was added methyl methyl (ls,3s)-3-((tert- butyldiphenylsilyl)oxy)cyclobutane- 1 -carboxylate (5 g, 12.6 mmol) The reaction mixture was stirred at -45 °C for 2 h. The reaction was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by Na2SC>4, filtered and concentrated in vacuo. The compound 3-((ls,3s)-3-((tert- butyldiphenylsilyl)oxy)cyclobutyl)-3-oxopropanenitrile (5 g, 8.62 mmol, 68%) was obtained as a yellow solid and used into next step without further purification. LCMS: ESI m / z 378.20 [M + H]+

[0237] Step C: l-(tert-butyl)-3-((ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-lH- pyrazol-5-amine To a solution of 3-((l s,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-3- oxopropanenitrile (5 g, 12.3 mmol) in EtOH (100 mL) was added tert-butylhydrazine (2.17 g, 24.6 mmol) and NaHCCL (2.07 g, 24.6 mmol), the reaction mixture was stirred at 80 °C for 18 hours.The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0- 50%] to afford l-(tert-butyl)-3-((ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-lH-pyrazol-5- amine (2.1 g, 3.73 mmol, 30%) as white solid . LCMS: ESI m / z 448.3 [M + H]

[0238] Step D: benzyl (l-(tert-butyl)-3-((ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)- lH-pyrazol-5-yl)carbamate To a solution of l-(tert-butyl)-3-((ls,3s)-3-((tert- butyldiphenylsilyl)oxy)cyclobutyl)-lH-pyrazol-5 -amine (1.50 g, 3.35 mmol) in ACN (15 mL) was added CbzCl (0.57 g, 3.35 mmol) and NaHCCh (0.28 g, 3.35 mmol) at 0 °C for 30 min. The mixture was stirred at room temperature overnight. TLC (PE / EA=5: 1) showed starting material was consumed and new spot was observed. The reaction mixture was diluted with water 50 mL, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0 - 20% EtOAc / hexane to afford benzyl (l-(tert-butyl)-3-((ls,3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)- lH-pyrazol-5-yl)carbamate (1.2 g, 2.06 mmol, 61%) as a yellow oil. LCMS: 582 [M+H]+.

[0239] Step E : benzyl (l-(tert-butyl)-3-((ls,3s)-3-hydroxycyclobutyl)-lH-pyrazol-5- yl)carbamate A solution of benzyl (l-(tert-butyl)-3-((ls,3s)-3-((tert- butyldiphenylsilyl)oxy)cyclobutyl)-lH-pyrazol-5-yl)carbamate (1.2 g, 2.06 mmol) in HCOOH (10 mL) was stirred at 50 °C for 5 hr. Spin the cooled reaction liquid dry. The residue was dissolved in MeOH (5 mL) and H2O (5 mL), LiOH (0.4 g, 10.3 mmol) was added. The following mixture was stirred at room temperature for 1 h. TLC (PE / EA=1: 1) showed starting material was consumed and new spot was observed. The reaction mixture was diluted with water 50 mL, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0 - 50% EtOAc / hexane to afford benzyl (l-(tert-butyl)-3-((ls,3s)-3-hydroxycyclobutyl)-lH-pyrazol-5-yl)carbamate (670 mg, 1.95 mmol, 95%) as a colorless oil. LCMS: 344 [M+H]+.JH NMR (400 MHz, DMSO) 5 9.12 (s, 2H), 7.46 - 7.28 (m, 5H), 5.96 (s, 1H), 5.12 (s, 2H), 5.02 (d, J= 6.8 Hz, 1H), 4.01-3.92 (m, 1H), 3.17 (d, .7= 5.2 Hz, 1H), 2.81 - 2.60 (m, 1H), 2.51-2.42 (m, 1H), 1.95-1.80 (m, 2H), 1.47 (s, 9H).

[0240] Step F: (ls,3s)-3-(5-(((benzyloxy)carbonyl)amino)-l-(tert-butyl)-lH-pyrazol-3- yl)cyclobutyl isopropylcarbamate To a solution of benzyl (l-(tert-butyl)-3-((ls,3s)-3- hydroxycyclobutyl)-lH-pyrazol-5-yl)carbamate (670 mg, 1.95 mmol) in THF (10 mL) was added potassium 2-methylpropan-2-olate (328 mg, 2.92 mmol) and l-oxo-N-(prop-2-yl)methanimine (249 mg, 2.92 mmol) at 0 °C for 30 min. The reaction mixture was stirred at room temperature for 1 h. TLC (PE / EA=1: 1) showed starting material was consumed and new spot was observed. The reactionmixture was diluted with water 50 mL, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (15.0 g column) using 0 - 50% EtOAc / hexane to afford (ls,3s)-3-(5- (((benzyloxy)carbonyl)amino)-l -(tert-butyl)- lH-pyrazol-3-yl)cyclobutyl isopropylcarbamate (530 mg, 1.24 mmol, 63.4%) as a white solid. LCMS: 429 [M+H]+. 'H NMR (400 MHz, DMSO) 8 9.11 (s, 1H), 7.47 - 7.28 (m, 5H), 7.04 (d, J= 7.2 Hz, 1H), 5.99 (s, 1H), 5.13 (s, 2H), 4.81-4.72 (m, 1H), 3.61-3.53 (m, 1H), 2.99-2.91 (m, 1H), 2.67 - 2.53 (m, 2H), 2.13 - 1.93 (m, 2H), 1.49 (d, J= 4.4 Hz, 9H), 1.04 (d, 7 = 6.4 Hz, 6H).

[0241] Step G: (ls,3s)-3-(5-amino-l-(tert-butyl)-lH-pyrazol-3-yl)cydobutyl isopropylcarbamate To a solution of (ls,3s)-3-(5-(((benzyloxy)carbonyl)amino)-l-(tert-butyl)-lH- pyrazol-3-yl)cyclobutyl isopropylcarbamate (530 mg, 1.23 mmol) in THF (2.5 mL) and EA (2.5 mL) was added Pd / C (100 mg, 0.940 mmol) under H2 protect. The mixture was stirred at room temperature for 1 h. TLC (PE / EA=1: 1) showed starting material was consumed and new spot was observed. The reaction mixture was diluted with water 50 mL, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na^SCfi and concentrated to afford (ls,3s)-3-(5- amino-1 -(tert-butyl)- lH-pyrazol-3-yl)cyclobutyl isopropylcarbamate (350 mg, 1.19 mmol, 96%) as a colorless oil. LCMS: 295 [M+H]+. ’H NMR (400 MHz, CDCI3) 6 5.50 (s, 1H), 4.97 - 4.84 (m, 1H), 4.49 (s, 1H), 3.84-3.76 (m, 1H), 3.48 (s, 1H), 3.02 - 2.87 (m, 1H), 2.79 - 2.62 (m, 2H), 2.18-2.03 (m, 2H), 1.61 (s, 9H), 1.15 (d, J = 6.4 Hz, 6H).Example 1: (lR,3S)-3-(3-((l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl)amino)-lH-pyrazol-5- yl)cyclopentyl isopropylcarbamate

[0242] Step A: 6-bromo-2-(4-methoxybenzyl)-l-methyl-l,2-dihydro-3H-indazol-3-one To a solution of 6-bromo-l-methyl-2,3 -dihydro- lH-indazol-3 -one (0.5 g, 2.20 mmol) in DMF (10 rnL) were added NaH (0.26 g, 6.60 mmol, 60% in mineral oil), and the reaction was stirred at room temperature for 30 min. After that l-(chloromethyl)-4-methoxybenzene (0.360 mL, 2.642 mmol) was added. The reaction was stirred at room temperature for extra 2 hours. The reaction was diluted with EA and saturated NH4CI solution. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (1 / 2). The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 6-bromo-2-[(4-methoxyphenyl)methyl]-l-methyl-2,3-dihydro-lH- indazol-3-one (300 mg, 0.864 mmol, 39.2%) as a yellow solid. LCMS: ESI m / z 347, 349 [M + H]+

[0243] Step B: 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyI)-l-methyl-l,2-dihydro-3H-indazol-3-one To a solution of l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (320.85 mg, 0.950 mmol) in dioxane (5 mL) were added 6-bromo-2-[(4-methoxyphenyl)methyl]-l-methyl- 2,3 -dihydro- lH-indazol-3 -one (300 mg, 0.864 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H- xanthen-4-yl]diphenylphosphane (99.99 mg, 0.173 mmol), sodium 2-methylpropan-2-olate (1.72 rnL, 1.72 mmol) and Pd2(dba)s (79.1 mg, 0.086 mmol), and the reaction was stirred at 90 °C under ISbfor 18 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (3 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 6-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-l- methyl-2,3 -dihydro- lH-indazol-3 -one (200 mg, 0.331 mmol, 38.3%) as a yellow oil. LCMS: ESI m / z 604 [M + H]+

[0244] Step C: 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- 2-(4-methoxybenzyl)-l-methyl-l,2-dihydro-3H-indazol-3-one To a flask containing 6-({l-tert- butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl]amino)-2-[(4- methoxyphenyl)methyl]-l-methyl-2,3-dihydro-lH-indazol-3-one (200 mg, 0.331 mmol) was added formic acid (10 mL) The mixture was stirred at rt for 18 hr. The mixture was concentrated in vacuo to give a residue, which was purified by using silica gel column chromatography eluting with (DCM / MeOH=3:l) to afford the title compound 6-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-l-methyl-2,3-dihydro-lH-indazol-3-one (100 mg, 0.204 mmol, 61.7%) as a yellow oil. LC / MS (ESI) (m / z): 490 [M+H]+.

[0245] Step D: (lR,3S)-3-(l-(tert-butyl)-5-((2-(4-methoxybenzyl)-l-methyl-3-oxo-2,3- dihydro-lH-indazol-6-yl)amino)-lH-pyrazoI-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a flask containing 6-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4- methoxyphenyl)methyl]-l-methyl-2,3-dihydro-lH-indazol-3-one (100 mg, 0.204 mmol) was added THF (10 mL) and DCM (10 mL) followed by the addition of 4-nitrophenyl chloroformate (82.33 mg, 0.408 mmol) and Pyridine (0.050 mL, 0.613 mmol). The mixture was stirred at rt for 2 hr. The mixture was concentrated in vacuo to give a residue, which was purified using silica gel column chromatography eluting with (PE / EA=1:3) to afford the title compound (lR,3S)-3-[l-tert-butyl-5- ( {2-[(4-methoxyphenyl)methyl] - 1 -methyl -3 -oxo-2, 3 -dihydro- 1 H-indazol-6-yl } amino)- 1 H-pyrazol-3 - yl] cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.153 mmol, 74.8%) as ayellow oil. LCMS: ESI m / z 655 [M + H]+

[0246] Step E: (lR,3S)-3-(5-((l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a flask containing (lR,3S)-3-[l-tert-butyl- 5-({2-[(4-methoxyphenyl)methyl]-l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl}amino)-lH-pyrazol- 3 -yl] cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.153 mmol) was added formic acid (5 mL). The mixture was stirred at 80 °C for 18 hr. After completion the solvent was removed on vacuum to give (lR,3S)-3-{5-[(l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4- nitrophenyl carbonate (70 mg, 0.146 mmol, 96%) as a yellow oil, which was used into next step without further purification. LCMS: ESI m / z 479 [M + H]+

[0247] Step F: (lR,3S)-3-(3-((l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate To a solution of (lR,3S)-3-{5-[(l-methyl-3-oxo- 2,3-dihydro-lH-indazol-6-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.146 mmol) in propan-2-amine (5 mL), the reaction mixture was stirred at rt for 2 hours. The solvent was removed on vacuun to give a residue, which was purified by prep-HPLC (Cl 8, FA condition, 56% ACN) to afford (lR,3S)-3-{5-[(l-methyl-3-oxo-2,3-dihydro-lH-indazol-6-yl)amino]- 1 H-pyrazol-3 -yl} cyclopentyl N-(propan-2-yl)carbamate (3.7 mg) a white solid. LCMS: ESI m / z 399 [M + H]+. 'H NMR (400 MHz, DMSO-c / 6) 6 8.59 (s, 1H), 7.48 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.95 (d, J= 7.6 Hz, 1H), 6.73 (d, J= 8.4 Hz, 1H), 5.66 (s, 1H), 4.99 (s, 1H), 3.62-3.50 (m, 1H), 3.47 (s, 3H), 3.13 - 2.99 (m, 1H), 2.55-2.42 (m, 1H), 2.10 - 1.83 (m, 2H), 1.79 - 1.52 (m, 3H), 1.03 (d, J = 6.4 Hz, 6H).Example 2: (lR,3S)-3-(3-((l,l-dioxido-3,4-dihydro-2H-benzo[e] [l,2]thiazin-6-yl)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0248] Step A. methyl 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetate A mixture of methyl 2- (3-bromophenyl)acetate (3 g, 13.1 mmol) in HSO3CI (1.31 g, 13.1 mmol) was stirred at rt overnight. The mixture was poured into ice-water (50 ml) slowly and extracted with EtOAc (20 mL*3). The combined organic phase was washed with brine, dried over Na2SC>4, fdtered and concentrated to give crude methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (1.8 g, 5.52 mmol, 42.2%) as a yellow oil. LCMS: m / z 327 [M+H]+.

[0249] Step B. methyl 2-(5-bromo-2-(N-(4-methoxybenzyl)sulfamoyl)phenyl)acetate To a stirred mixture of methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (1.8 g, 5.49 mmol) in DCM (15 mL) was added (4-methoxyphenyl)methanamine (0.75 g, 5.49 mmol) and TEA (1.11 g, 10.9 mmol) slowly at 0 °C. After stirred at rt for 2h, the mixture was poured into water (30 mL) and extracted with DCM (20 mL*2). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-35%, EtOAc in PE) to give methyl 2-(5-bromo-2-{[(4- methoxyphenyl)methyl]sulfamoyl}phenyl)acetate (800 mg, 1.86 mmol, 33.9%) as a brown solid. LCMS: m / z 429 [M+H]+.

[0250] Step C. 4-bromo-2-(2-hydroxyethyl)-N-(4-methoxybenzyl)benzenesulfonamide To a stirred mixture of methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl]phenyl)acetate (800 mg, 1.86 mmol) in THF (10 mL) / MeOH (2 mL) was added NaBEf (189 mg, 5.60 mmol) slowly at 0 °C. After stirred at rt for Ih, the mixture was poured into ice-water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with bnne, dried with Na2SO4, filtered and concentrated to give crude 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene- 1-sulfonamide (700 mg, 1.74 mmol, 93.6%) as ayellow solid. LCMS: m / z 401 [M+H]+.

[0251] Step D. 6-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][ 1,2] thiazine 1,1- dioxide To a stirred mixture of 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-1-sulfonamide (700 mg, 1.74 mmol) in THF (20 mL) was added DIAD (0.693 mL, 3.49 mmol) and PPh? (917 mg, 3.49 mmol) at rt. After stirred at rt overnight, the mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-50%, EtOAc in PE) to give 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H- lλΛ6,2-benzothiazine-l,l-dione (400 mg, 1.04 mmol, 59.8%) as ayellow solid. LCMS: m / z 383 [M+H]+.

[0252] Step E. 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e] [l,2]thiazine 1,1-dioxide To a stirred mixture of 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H- 1 / / 6,2-benzothiazine- 1, 1-dione (400 mg, 1.04 mmol) in dioxane (15 mL) was added l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (353 mg, 1.04 mmol), RuPhos Pd G2 (81.2 mg, 0.105 mmol), RuPhos (97.6 mg, 0.209 mmol) and CS2CO3 (852. mg, 2.61 mmol) at rt. After stirred at 100 °C overnight, the mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60%, EtOAc in PE) to give 6-({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5- yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-17,A6,2-benzothiazine-l,l-dione (400 mg, 0.626 mmol, 60%) as a brown solid. LCMS: m / z 640 [M+H]+.

[0253] Step F. 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e][l,2]thiazine 1,1-dioxide A mixture of 6-({l-tert- butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine- 1,1 -dione (400 mg, 0.626 mmol) in HCOOH (10 mL) was stirred at RT for 1 h, then concentrated under reduced pressure. The residue was treated with a mixture of LiOH (0.174 mL, 6.26 mmol) in EtOH (5 mLyFEO (5 mL). The resulting mixture was stirred at rt for 2 h, the mixture was concentrated under reduced pressure. The mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-8%, MeOH in DCM) to give 6-({l-tert-butyl-3- [(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lA6,2-benzothiazine-l, 1-dione (300 mg, 0.572 mmol, 91.3%) as a white solid. LCMS: m / z 526 [M+H]+.

[0254] Step G. (lR,3S)-3-(l-(tert-butyl)-5-((2-(4-methoxybenzyl)-l,l-dioxido-3,4-dihydro- 2H-benzo[e] [l,2]thiazin-6-yl)ainino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonateTo a stirred solution of 6-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)- 2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine-l, 1-dione (180 mg, 0.343 mmol) in DCM (5 mL) / THF (5 mL) was added 4-nitrophenyl chloroformate (138 mg, 0.686 mmol), Pyridine (0.083 mL, 1.02 mmol) and DMAP (12.5 mg, 0.103 mmol) at rt. After stirred at rt for 3h, the mixture was poured into water (30 ml) and extracted with EtOAc (20 ml*3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give (1R,3 S)-3 -[ 1 - tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-3,4-dihydro-2H-lλΛ6,2-benzothi azin-6- yl}amino)-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.145 mmol, 42.2%) as a yellow solid. LCMS: m / z 691 [M+H]+.

[0255] Step H. (lR,3S)-3-(5-((l,l-dioxido-3,4-dihydro-2H-benzo[e][l,2]thiazin-6-yl)amino)- lH-pyrazol-3-yl)cyclopentyI (4-nitrophenyl) carbonate A mixture of (lR,3S)-3-[l-tert-butyl-5- ( {2-[(4-methoxypheny l)methy 1] - 1 , 1 -dioxo-3 ,4-dihy dro-2H- 1 λΛ6,2-benzothiazin-6-yl } amino)- 1 H- pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.145 mmol) in HCOOH (5 mL) was stirred at 100 °C overnight, then concentrated under reduced pressure to give crude (lR,3S)-3-{5- [(1,1 -dioxo-3, 4-dihydro-2H-lA.A6,2-benzothiazin-6-yl)amino]-lH-pyrazol-3-yl] cyclopentyl 4- nitrophenyl carbonate (70 mg, 0.136 mmol, 94.0%) as a brown oil. LCMS: m / z 515 [M+H]+.

[0256] Step I. (lR,3S)-3-(3-((l,l-dioxido-3,4-dihydro-2H-benzo[e][l,2]thiazin-6-yl)amino)- lH-pyrazol-5-yl)cyclopentyI isopropylcarbamate To a stirred solution of (lR,3S)-3-{5-[(l,l- dioxo-3,4-dihydro-2H-lλΛ6,2-benzothiazin-6-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (70 mg, 0.136 mmol) in THF (5 mL) was added DIPEA (35.1 mg, 0.272 mmol) and propan-2-amine (0.058 mL, 0.680 mmol) slowly, the reaction mixture was stirred at room temperature for 2h. The reaction was concentrated. The residue was purified by prep-HPLC (Cl 8, 40 ~ 90 % MeCN in H2O with 0.1 % HCOOH) to give (lR,3S)-3-{3-[(l,l-dioxo-3,4-dihydro-2H- lλΛ6,2-benzothiazin-6-yl)amino]-lH-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate (22.8 mg, 0.053 mmol, 38.9%) as a white solid. LCMS: m / z 434 [M+H]+. 'HNMR (400 MHz, DMSO) 5 8.82 (s, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.26-7.14 (m, 2H), 7.15 (brs, 1H), 6.95 (d, J= 7.2 Hz, 1H), 5.69 (s, 1H), 4.99 (brs, 1H), 3.65-3.50 (m, 1H), 3.50 (d, J = 4.8 Hz, 2H), 3.11 - 2.99 (m, 1H), 2.81 (t, 7= 6.0Hz, 2H), 2.49-2.33 (m, 1H), 2.12-1.98 (m, 1H), 1.94 - 1.85 (m, 1H), 1.83-1.67 (m, 2H), 1.65-1.54 (m, 1H), 1.03 (d, J= 6.4 Hz, 6H).Example 3: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yI)amino)-lH-pyrazol-5-yI)cyclopentyl isopropylcarbamate

[0257] Step A: 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide To a solution of 4- bromo-2-methylbenzene-l -sulfonyl chloride (5 g, 18.5 mmol) in DCM (20 mL) were added triethylamine (7.73 mL, 55.6 mmol), 2-methylpropan-2-amine (3.93 mL, 37.1 mmol) and the reaction was stirred at room temperature for overnight. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with [gradient: 0-50%] to afford the title compound 4-bromo-N-tert-butyl-2-methylbenzene-l -sulfonamide (5 g, 16.3 mmol, 88.0%) as a white solid. LCMS: ESI m / z 306 [M + H]+. ' H NMR (400 MHz, DMSO) 5 7.75 (d, J = 8.4 Hz, 1H), 7.65 - 7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0258] Step B: 4-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide To a solution of 4-bromo-N-tert-butyl-2-methylbenzene-l -sulfonamide (5 g, 16.3 mmol) in CHCh (10 mL) were added AIBN (268 mg, 1.63 mmol), DIEA (0.448 mL, 2.71 mmol), and NBS (2.91 g, 16.3 mmol), and the reaction was stirred at 60 °C overnight. The reaction was concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-30%] to afford the title compound 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-l -sulfonamide (1.9 g, 4.9 mmol, 30.2%) as a white solid. LCMS: ESI m / z 384 [M + H]+. 'H NMR (400 MHz, DMSO) 8 7.91 - 7.86 (m, 2H), 7.82 (d, J= 8.4 Hz, 1H), 7.74 - 7.68 (m, 1H), 5.03 (s, 2H), 1.13 (s, 9H).

[0259] Step C: 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-l -sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and H2O (5 mL) was added NaOH (0.44 g, 10.9 mmol) and the reaction was stirred at room temperature for 3 hr. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-80%] to afford the title compound 5-bromo-2-tert-butyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (900 mg, 2.95 mmol, 81.4%) as a white solid. LCMS: ESI m / z 304 [M + H]+. 'H NMR (400 MHz, DMSO) 5 7.83 (d, J= 0.8 Hz, 1H), 7.77 (dt, J= 14.4, 4.8 Hz, 2H), 4.55 (s, 2H), 1.46 (s, 9H).

[0260] Step D: 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 5- bromo-2-tert-butyl-2,3-dihydro-llA6,2-benzothiazole-l, 1-dione (900 mg, 2.95 mmol) in HCOOH (10 mL) and the reaction was stirred at room temperature for 1 hr. The reaction was concentrated and were added MeOH (10 mL), and Li OH (496 mg, 11.8 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-100%] to afford the title compound 5-bromo-2,3-dihydro- lλΛ6,2-benzothiazole-l,l-dione (600 mg, 2.41 mmol, 81.7%) as a white solid. LCMS: ESI m / z 248 [M + H]+. 'H NMR (400 MHz, DMSO) 57.92 (s, 1H), 7.85 - 7.73 (m, 3H), 4.40 (s, 2H).

[0261] Step E: 5-bromo-2-(4-methoxybenzyI)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxideTo a solution of 5-bromo-2,3-dihydro-lλΛ6,2-benzothiazole-l,l-dione (500 mg, 2.01 mmol) in DMF (10 mL) were added l-(chloromethyl)-4-methoxybenzene (0.412 mL, 3.023 mmol), and CS2CO3 (1 .97 g, 6.04 mmol), and the reaction was stirred at room temperature for overnight. The reaction was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by Na2SC>4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-30%] to afford the title compound 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lA.A6,2-benzothiazole-l,l- dione (350 mg, 0.950 mmol, 47.1%) as a white solid. LCMS: ESI m / z 368 [M + H]+.1H NMR (400 MHz, DMSO) 8 7.90 - 7.82 (m, 2H), 7.80 (dd, J= 8.4, 1.6 Hz, 1H), 7.42-7.32 (m, 2H), 6.99 - 6.91 (m, 2H), 4.33 (s, 2H), 4.27 (s, 2H), 3.76 (s, 3H).

[0262] Step F: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (350mg, 0.950 mmol) in dioxane (10 mL) were added l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (353 mg, 1.04 mmol), Pd2(dba)s (87.1 mg, 95.1 pmol), Xantphos (110 mg, 0.190 mmol) and CS2CO3 (619 mg, 1.90 mmol). The reaction was stirred at 100 °C for 6 h. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The residue was purified using silica gel column chromatography elutied with ethyl acetate in petroleum ether (gradient: 0- 50%) to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3- dihydro-lλΛ6,2-benzothiazole-l,l-dione (500 mg, 0.800 mmol, 84.2%) as a white solid. LCMS: ESI m / z 625 [M + H]+

[0263] Step G: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- 2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazoIe 1,1-dioxide A solution of 5-({l-tert-butyl-3- [(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro- l / / 6,2-benzothiazole-l , 1-dione (500 mg, 0.800 mmol) in HCOOH (10 mL) was stirred at rt for Ih. LCMS showed the reaction had been completed. The solvent was removed under vacuum. The residue was purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give 5-({l-tert-butyl-3-[(lS,3R)-3- hydroxy cyclopentyl]- lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2, 3-dihydro- 1 / / 6, 2- benzothiazole- 1,1 -dione (400 mg, 0.697 mmol, 87.1%) as a yellow solid. LCMS: ESI m / z 511 [M + H]+

[0264] Step H: (lR,3S)-3-(l-(tert-butyl)-5-((2-(4-methoxybenzyl)-l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro- l / .' 6,2-benzothiazole-l , 1-dione (400 mg, 0.783 mmol) in THF / DCM(1:1) (12 mL) was added Pyridine (0.190 mL, 2.35 mmol), DMAP (9.57 mg, 78.1 pmmol) and 4-nitrophenyl chloroformate (316 mg, 1.57 mmol). The mixture was stirred at room temperature for 4h. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (5 mL*3), washed with sat. aq. NaCl, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give(lR,3S)-3-[l- tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-2,3-dihydro-lZA6,2-benzothiazol-5- yl} amino)- lH-pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate (300 mg, 0.444 mmol, 56.7%) as a yellow solid. LCMS: ESI m / z 676 [M + H]+

[0265] Step I: (lR,3S)-3-(5-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-[l-tert-butyl-5-({2- [(4-methoxyphenyl)methyl]-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl}amino)-lH-pyrazol-3- yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 0.444 mmol) in HCOOH (8 mL) was stirred at 90 °C overnight. The reaction was complete detected by LCMS. The residue was concentrated to afford (lR,3S)-3-{5-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3- yl} cyclopentyl 4-nitrophenyl carbonate (150 mg, 0.300 mmol, 67.6%) as ayellow oil. LCMS: ESI m / z 500 [M + H]+

[0266] Step J: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate A solution of of (lR,3S)-3-{5-[(l,l-dioxo-2,3- dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (150 mg, 0.300 mmol) in propan-2-amine (10 mL, 117 mmol) was stirred at rt for 3h. The mixture was concentrated under vacuum. The residue was purified by prep-HPLC to give(lR,3S)-3-{3-[(l,l- dioxo-2,3-dihydro-lz / 6,2-benzothiazol-5-yl)amino]-l H-pyrazol-5-yl ; cyclopentyl N-(propan-2- yl)carbamate (30 mg, 72.2 pmmol, 23.8%) as a yellow solid. LCMS: ESI m / z 420 [M + H]+.XH NMR (400 MHz, DMSO) § 9.02 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.45 (s, 1H), 7.30 (dd, J= 8.6, 1.8 Hz, 1H), 6.95 (d, J= 7.6 Hz, 1H), 5.72 (s, 1H), 4.99 (brs, 1H), 4.29 (s, 1H), 3.62-3.48 (m, 1H), 3.15 - 2.96 (m, 1H), 2.48 - 2.40 (m, 1H), 2.08-1.94 (m, 1H), 1.93-1.81 (m, 1H), 1.78-1.66 (m, 2H), 1.65- 1.52 (m, 1H), 1.03 (d, J= 6.4 Hz, 6H).Example 4: (lR,3S)-3-(3-((l,3-dioxoisoindolin-5-yl)amino)-lH-pyrazol-5-yl)cyclopentylI l l

[0267] Step A: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yI)amino)isoindoline-l, 3-dione To a solution of l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (300 mg, 0.889 mmol) in dioxane (2 mL) were added 5-bromo-2,3-dihydro-lH-isoindole-l, 3-dione (200 mg, 0.889 mmol), Xant-PHOS (102 mg, 0.178 mmol), sodium 2-methylpropan-2-olate (1.77 mL, 1.778 mmol) and Pd2(dba)s (81.4 mg, 0.089 mmol). The reaction was stirred at 100 °C under N2 using M.W for Ihr. The cooled reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-100%]. The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lH-isoindole-l, 3-dione (240 mg, 0.497 mmol, 55.9%) as a white solid. LCMS: ESI m / z 483 [M + H]+

[0268] Step B: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)amino)isoindoline-l, 3-dione A solution of 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lH-isoindole- 1,3-dione (240 mg, 0.497 mmol) in HCOOH (3 mL) was stirred at room temperature for 1 hr. The reaction was concentrated and were added MeOH (3 mL), and LiOH (41.7 mg, 0.994 mmol). The following reaction mixture was stirred at room temperature for 30 min. The reaction was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by ISfeSCL, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-100%] to afford the title compound 5-({ l-tert-butyl-3-[(lS,3R)-3-hydroxy cyclopentyl]- lH-pyrazol-5-yl}amino)-2,3-dihydro- IH-isoindole- 1,3 -dione (50 mg, 0.136 mmol, 27.2%) as a white solid. LCMS: ESI m / z 387 [M + H]+

[0269] Step C: (lR,3S)-3-(l-(tert-butyI)-5-((l,3-dioxoisoindolin-5-yI)amino)-lH-pyrazol-3- yl)cyclopentyl (4-nitrophenyI) carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3- hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lH-isoindole- 1,3-dione (50 mg, 0.136 mmol) in DCM (2 mL) were added 4-nitrophenyl chloroformate (41. mg, 0.204 mmol), DMAP (1.66 mg, 0.014 mmol), pyridine (0.022 mL, 0.271 mmol). The reaction was stirred at 40 °C for 3 hr. The reaction was and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA inPE [Gradient: 0-100%] to afford the title compound (lR,3S)-3- {l-tert-butyl-5-[(l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4- nitrophenyl carbonate (27 mg, 0.051 mmol, 37.2%) as a white solid. LCMS: ESI m / z 534 [M + H]+

[0270] Step D: (lR,3S)-3-(5-((l,3-dioxoisoindolin-5-yI)amino)-lH-pyrazol-3-yI)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-{l-tert-butyl-5-[(l,3-dioxo-2,3-dihydro-lH- isoindol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (27 mg, 0.051 mmol) in HCOOH (3 mL) was stirred at 100 °C overnight. The cooled reaction mixture was concentrated in vacuo to afford the title compound (lR,3S)-3-{5-[(l,3-dioxo-2,3-dihydro-lH- isoindol-5-yl)amino]-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (20 mg, 0.042 mmol, 82.8%) as a white solid. LCMS: ESI m / z 478 [M + H]+

[0271] Step E: (lR,3S)-3-(3-((l,3-dioxoisoindolin-5-yI)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate A solution of (lR,3S)-3-{5-[(l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl)amino]- lH-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (20 mg, 0.042 mmol) in propan-2-amine(2 mL) was stirred at RT for 2 hr. The reaction concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound 5-({3-[(lS,3R)-3-{[(propan-2-yl)amino]oxy]cyclopentyl]- lH-pyrazol-5-yl}amino)-2,3-dihydro-lH-isoindole-l, 3-dione (3.2 mg, 0.009 mmol, 20.7%) as a yellow solid. LCMS: ESI m / z 398 [M + H]+. 'H NMR (400 MHz, DMSO) 8 12.01 (s, 1H), 10.86 (s, 1H), 9.34 (s, 1H), 7.87 (s, 1H), 7.56 (dd, J= 29.2, 8.4 Hz, 2H), 6.95 (d, J= 7.2 Hz, 1H), 5.72 (s, 1H), 5.01 (s, 1H), 3.75-3.53 (m, 1H), 3.12 - 3.04 (m, 1H), 2.09 - 2.00 (m, 1H), 1.96 - 1.86 (m, 1H), 1.82- 1.64 (m, 2H), 1.64-1.53 (m, 1H), 1.24 (s, 1H), 1.04 (d, J= 6.4 Hz, 6H).Example 5: (lR,3S)-3-(5-((l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH- pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0272] Step A: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)benzo[d]isothiazol-3(2H)-one 1,1-dioxide To a solution of 1 -tert-butyl -3- [(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (500 mg, 1.48 mmol) indioxane (2 mL) were added 5-bromo-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1,3-trione (582 mg, 2.22 mmol), Xant-PHOS (171 mg, 0.296 mmol), CS2CO3 (482 mg, 1.481 mmol) and Pd2(dba)s (135 mg, 0.148 mmol). The reaction mixture was stirred at 100 °C under N2 for 16 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with further brine, dried over Na2SO4 and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (3 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5-( {l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl] - 1 H-pyrazol-5-yl } amino)-2, 3 -dihydro- 1λΛ6, 2-benzothiazole- 1,1, 3-trione (500 mg, 0.964 mmol, 65.0%) as a yellow solid. LCMS: ESI 519 [M+H]+

[0273] Step B: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)amino)benzo[d]isothiazol-3(2H)-one 1,1-dioxide A solution of 5-({ l-tert-butyl-3-[(lS,3R)-3- [(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lλΛ6,2- benzothiazole-1, 1,3-trione (500 mg, 0.964 mmol) in HCOOH (5 mL) was stirred at room temperature for 1 hr. The reaction was concentrated and were added MeOH (50 mL), and LiOH (161 mg, 3.85 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was diluted with H2O. The aqueous layer was extracted with EA. Combined the EA layer and washed with brine. The EA layer was dried by anhydrous Na2SCU, fdtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-100%] to afford the title compound 5- ({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl]amino)-2,3-dihydro-lλΛ6,2- benzothiazole- 1, 1,3-trione (300 mg, 0.742 mmol, 76.9%) as a white solid. LCMS: ESI m / z 405 [M + H]+

[0274] Step C: (lR,3S)-3-(l-(tert-butyl)-5-((l,l-dioxido-3-oxo-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyI (4-nitrophenyl) carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2,3- dihydro- l / / 6,2-benzothiazole- 1,1, 3 -trione (300 mg) in THF (10 mL) and DCM (10 mL) was added 4-nitrophenyl chloroformate (568 mg, 2.82 mmol) and pyridine (0.456 mL, 5.64 mmol). The reaction was stirred at 50 °C for 30 min. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 80-100%] to afford the title compound (lR,3S)-3-{l-tert-butyl-5-[(l,L3-trioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5- yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (200 mg, 0.351 mmol, 18.7%) as a white solid. LCMS: ESI m / z 570 [M + H]

[0275] Step D: (lR,3S)-3-(5-((l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)- lH-pyrazol-3-yl)cyclopentyl (4-nitro phenyl) carbonate A solution of (lR,3S)-3-{l-tert-butyl-5- [(l,l,3-trioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4- nitrophenyl carbonate (200 mg) in HCOOH (5 mL) was stirred at 80 °C overnight. The reaction was concentrated in vacuo to afford the title compound 4-nitrophenyl (lR,3S)-3-(5-((l,l-dioxido-3-oxo- 2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg) as a white solid, which was used into next step without further purification. LCMS: ESI m / z 514 [M + H]+

[0276] Step E: (lR,3S)-3-(5-((l,l-dioxido-3-oxo-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)- lH-pyrazol-3-yl)cyclopentyl isopropylcarbamate To a solution of 4-nitrophenyl (lR,3S)-3-{5- [(1,1, 3-trioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl} cyclopentyl carbonate (100 mg, 0.195 mmol) in THF (2 mL) was added propan-2-amine (0.167 mL, 1.95 mmol) and the reaction was stirred at 50 °C for 2 hr. The reaction concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA) to afford the title compound (lR,3S)-3-{5-[(l,l,3-trioxo-2,3-dihydro- lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (10.4 mg) as a white solid. LCMS: ESI m / z 434 [M + H]+. 'H NMR (400 MHz, DMSO-<76) 5 12.05 (s, 1H), 9.46 (s, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.65 (dd, J= 8.8, 2.0 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 5.00 (s, 1H), 3.11 - 3.04 (m, 1H), 2.13 - 1.55 (m, 6H), 1.03 (d, J = 8.0 Hz, 6H).Example 6: (lR,3S)-3-(3-((l,l-dioxido-3,4-dihydro-2H-benzo[b] [l,4,5]oxathiazepin-7- yl)amino)- lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0277] Step A: 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide To a solution of 2-aminoethan- 1 -ol (2.2 mL, 36.6 mmol), K2CO3 (5.05 g, 36.5 mmol) in THF (200 mL) and H2O (50 mL) was added 4-bromo-2-fluorobenzene-l -sulfonyl chloride (10 g, 36.6 mmol) in portion. Themixture was stirred at rt for 2h, then diluted with EA and aq.NaCl. The organic layer was separated, washed with further brine, and concentrated in vacuo to afford the title compound S-(4-bromo-2- fluorophenyl)-2-hy droxy ethane- 1-sulfonami do (10 g, 33.5 mmol, 91.7%) as a white solid.

[0278] Step B: 7-bromo-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1,1-dioxide To a solution of S-(4-bromo-2-fluorophenyl)-2-hy droxy ethane- 1 -sulfonamide (5 g, 16.8 mmol) in DMF (50 mL) was added NaH (1.48 g, 0.370 mmol, 60% in mineral oil) at 0 °C. The reaction was stirred at RT overnight. The reaction was diluted with EA and H2O, adjusted pH=6 with IM HC1. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-50%] to afford the title compound 7-bromo-3,4-dihydro-2H-5,llA6,2-benzoxathiazepine-l, 1-dione (1.3 g, 4.67 mmol, 27.9%) as a colorless oil. LCMS: ESI m / z 280 [M +2+ H]+

[0279] Step C: 7-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1,1-dioxide To a solution of 7-bromo-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepine-l, 1-dione (690 mg, 2.48 mmol) and CS2CO3 (1.62 g, 4.96 mmol) in DMF (10 mL) was added 1 -(chloromethyl)-4- methoxybenzene (0.5 mL, 3.72 mmol) at 0 °C. The reaction was stirred at 80 °C for 3 h. The reaction was diluted with EA and H2O. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-50%] to afford the title compound 7-bromo-2-[(4-methoxyphenyl)methyl]- 3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepine-l,l-dione (900 mg, 2.26 mmol, 91.1%) as a colorless oil.

[0280] Step D: 7-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo [ b] [1,4,5] oxathiazepine 1,1- dioxide To a solution of 7-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,lλΛ6,2- benzoxathiazepine- 1,1 -dione (650 mg, 1.63 mmol) in dioxane (15 mL) were added l-tert-butyl-3- [(3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (551 mg, 1.63 mmol), Pd2(dba)s (149 mg, 0.163 mmol), Xantphos (189 mg, 0.326 mmol) and CS2CO3 (1.60 g, 4.90 mmol). The reaction was stirred at 100 °C under N2 overnight. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [Gradient: 0-50%] to afford the compound 7-({l-tert-butyl-3-[(3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4- dihydro-2H-5, IXA6,2-benzoxathiazepine-l,l -dione (900 mg, 1.37 mmol, 84.2%) as a brown solid. LCMS: ESI m / z 655 [M + H]+

[0281] Step E: 7-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4-methoxybenzyI)-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepine 1,1-dioxide A solution of 7- [( 1 -tert-butyl-3 - { 3 - [(tert-butyldimethy lsilyl)oxy ] cyclopentyl } - 1 H-py razol-5 -yl)amino]-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepine-l, 1-dione (900 mg, 1.37 mmol) in HCOOH (6 mL) was stirred at rt for Ih. The reaction was concentrated and added MeOH (10 mL) and LiOH (2 mL, 4.12 mmol), and the reaction was stirred at rt for 30 min. The reaction was diluted with H2O, the aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by ISfeSCL, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-100%] to afford the title compound 7-{[l-tert-butyl-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl]amino}-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepine-l, 1-dione (700 mg, 1.30 mmol, 94.2%) as a white solid.

[0282] Step F: (lR,3S)-3-(l-(tert-butyl)-5-((2-(4-methoxybenzyl)-l,l-dioxido-3,4-dihydro- 2H-benzo[b][l,4,5]oxathiazepin-7-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of 7-{[l-tert-butyl-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl]amino}-2- [(4-methoxyphenyl)methyl]-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepine-l, 1-dione (400 mg, 0.740 mmol) in THF (5 mL) and DCM (5 mL) were added Py (117 mg, 1.48 mmol), DMAP (0.900 mg, 7 pmol) and 4-mtrophenyl chloroformate (194 mg, 0.962 mmol). The reaction was stirred at rt for 3h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-100%] to afford the title compound 3-[l-tert- butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepin-7- yl} amino)- lH-pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate (450 mg, 0.638 mmol, 86.2%) as a white solid. LCMS: ESI m / z 706 [M + H]~

[0283] Step G: (lR,3S)-3-(5-((l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-7- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of 7-{[l-tert-butyl-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl]amino}-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H- 5, l / / 6,2-benzoxathiazepinc-l , 1-dione (400 mg, 0.740 mmol) in HCOOH (10 mL) was stirred at100 °C overnight. The cooled reaction mixture was concentrated in vacuo to afford the title compound 3-{5-[(l,l-dioxo-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepin-7-yl)amino]-lH-pyrazol-3- yl] cyclopentyl 4-nitrophenyl carbonate (250 mg, 0.472 mmol, 83.3%) as a brown solid.

[0284] Step H: (lR,3S)-3-(3-((l,l-dioxido-3,4-dihydro-2H-benzo[b][l,4,5]oxathiazepin-7- yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate A solution of 3-{5-[(l,l-dioxo-3,4-dihydro-2H-5,lλΛ6,2-benzoxathiazepin-7-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (250 mg, 0.472 mmol) in isopropylamine (5 mL) was stirred at 50 °C for 2h. The reaction concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound 3-{5- [(1,1 -di oxo-3 ,4-dihy dro-2H-5 , 1 / / 6,2-benzoxathiazepin-7-y l)amino] - 1 H-pyrazol-3 -yl } cyclopentyl N- (propan-2-yl)carbamate (100 mg, 0.222 mmol, 47.1%) as a white solid. LCMS: ESI m / z 450 [M + H]+

[0285] XH NMR (400 MHz, DMSO) 8 11.89 (s, 1H), 8.94 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.02 (d, J= 8.8 Hz, 1H), 6.95 (s, 1H), 5.67 (s, 1H), 5.00 (s, 1H), 4.04 (s, 2H), 3.57 (s, 1H), 3.37 (s, 2H), 3.05 (s, 1H), 2.48 - 2.37 (m, 1H), 2.25-1.80 (m, 2H), 1.71 (s, 2H), 1.60 (s, 1H), 1.03 (d, .7= 4.8 Hz, 6H).Example 7: (ls,4s)-4-{3-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-5-

[0286] Step A: 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide To a solution of 4- bromo-2-methylbenzene-l -sulfonyl chloride (5 g, 18.5 mmol) in DCM (20 mL) were added triethylamine (7.73 mL, 55.6 mmol), 2-methylpropan-2-amine (3.93 mL, 37.1 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with [gradient: 0-50%] to afford the title compound 4-bromo-N-tert-butyl-2-methylbenzene-l -sulfonamide (5 g, 16.3 mmol, 88.0%) as a white solid. LCMS: ESI m / z 306 [M + H]+. ’H NMR (400 MHz, DMSO) 87.75 (d, J = 8.4 Hz, 1H), 7.65 - 7.49 (m, 3H), 2.54 (s, 3H), 1.06 (s, 9H).

[0287] Step B: 4-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide To a solution of 4-bromo-N-tert-butyl-2-methylbenzene-l -sulfonamide (5 g, 16.3 mmol) in CHCh (10 mL) were added AIBN (268 mg, 1.63 mmol), DIEA (0.448 mL, 2.71 mmol), and NBS (2.91 g, 16.3 mmol). The reaction was stirred at 60 °C overnight. The reaction was concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-30%] to afford the title compound 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-l -sulfonamide (1.9 g, 4.9 mmol, 30.2%) as a white solid. LCMS: ESI m / z 384 [M + H]+.

[0288] Step C: 5-bromo-2-(tert-butyI)-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzene-l -sulfonamide (1.4 g, 3.63 mmol) in MeOH (20 mL) and H2O (5 mL) was added NaOH (0.44 g, 10.9 mmol) and the reaction was stirred at room temperature for 3 hr. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-80%] to afford the title compound 5-bromo-2-tert-butyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (900 mg, 2.95 mmol, 81.4%) as a white solid. LCMS: ESI m / z 304 [M + H]+. 'H NMR (400 MHz, DMSO) 8 7.83 (d, J= 0.8 Hz, 1H), 7.85-7.63 (m, 2H), 4.55 (s, 2H), 1.46 (s, 9H).

[0289] Step D: 5-bromo-2,3-dihydro -lλΛ6,2-benzothiazole-l, 1-dione A solution of 5-bromo- 2-tert-butyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (3 g, 9.86 mmol) in TFA (50 mL) was stirred at 60 °C 3 hr. The reaction mixture was concentrated. The residue was adjusted to pH value 7- 8 with aq.l N NaOH solution (3 mL). The following mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient:0-50%) to afford the title compound 5-bromo-2,3-dihydro-lA.A6,2-benzothiazole-l,l- dione (2.1 g, 8.46 mmol, 85.8%) as a white solid. LCMS: ESI m / z 248.10 [M + H]+

[0290] Step E: 5-bromo-2-[(4-methoxyphenyl)methyI]-2,3-dihydro-lλΛ6,2-benzothiazole- 1, 1-dione To a solution of 5-bromo-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (2.1 g, 8.46 mmol) in DMF (20 mL) were added 4-Methoxybenzylchloride (1.99 g, 12.7 mmol) and CS2CO (5.52 g, 16.9 mmol). The reaction was stirred at 35 °C overnight. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (gradient: 0-20%) to afford the title compound 5-bromo-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (2.45 g, 6.65 mmol, 78.6%) as a white solid. LCMS: ESI m / z 368.25 [M + H]+

[0291] Step F: 5-({l-tert-butyl-3-[(ls,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-lH- pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lX.A6,2-benzothiazole-l, 1-dione To a solution of 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (500 mg, 1.36 mmol) in dioxane (10 mb) were added l-tert-butyl-3-[(ls,4s)-4-[(tert- butyldiphenylsilyl)oxy]cyclohexyl]-lH-pyrazol-5-amine (775 mg, 1.63 mmol), CS2CO3 (1.32g, 4.07 mmol), Pd2(dba)s (124 mg, 0.136 mmol) and Xant-PHOS (157 mg, 0.272 mmol). The reaction was stirred at 100 °C under N2 for 6 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over Na2SC>4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-50%) to afford the title compound 5-({l-tert-butyl-3-[(ls,4s)-4-[(tert- butyldiphenylsilyl)oxy]cyclohexyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3- dihydro- l / / 6,2-benzothiazole-l , 1-dione (700 mg, 0.917 mmol, 67.6%) as a white solid. LCMS: ESI m / z 763.09 [M + H]+

[0292] Step G: 5-({l-tert-butyl-3-[(ls,4s)-4-hydroxycyclohexyl]-lH-pyrazol-5-yl}amino)-2- [(4-methoxyphenyl)methyl]-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione To a solution of 5-({l- tert-butyl-3 - [( 1 s,4s)-4- [(tert-butyldiphenylsily l)oxy ] cyclohexyl] - 1 H-pyrazol-5 -yl } amino)-2- [(4- methoxyphenyl)methyl]-2,3-dihydro- l / .' 6,2-benzothiazole-l , 1-dione (700 mg, 0.917 mmol) in TBAF (20 mL, IM in THF) and the reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the title compound 5 -( { 1 -tert-butyl-3 - [( 1 s,4s)-4-hy droxy cyclohexyl] - 1 H-pyrazol-5 -yl } amino)-2- [(4- methoxyphenyl)methyl]-2,3-dihydro-lZA6,2-benzothiazole-l, 1-dione (400 mg, 0.762 mmol, 83.1%) as a white solid. LCMS: ESI m / z 524.69 [M + H]+

[0293] Step H: 4-nitrophenyl (ls,4s)-4-[l-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l- dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl}amino)-lH-pyrazol-3-yl]cyclohexyl carbonate To a solution of 5 -({1 -tert-butyl-3 -[(ls,4s)-4-hy droxy cy clohexyl]-lH-pyrazol-5-yl] amino)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro- l / .' 6,2-benzothiazole-l , 1-dione (400 mg, 0.762 mmol) in THF (5 mL) and DCM (5 mL) were added 4-mtrophenyl chloroformate (230 mg, 1.14 mmol), DMAP (9.31 mg, 0.076 mmol) and Py (0.123 mL, 1.53 mmol). The reaction was stirred at room temperature under N2 for 3 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, dried over ISfeSCL and concentrated in vacuo. The residue was purified usingsilica gel column chromatography elutied with ethyl acetate in petroleum ether (gradient:0-50%) to afford the title compound 4-nitrophenyl (ls,4s)-4-[l-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]- l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl}amino)-lH-pyrazol-3-yl]cyclohexyl carbonate (250 mg, 0.362 mmol, 47.5%) as a white solid. LCMS: ESI m / z 689.79 [M + H]+

[0294] Step I: 4-nitrophenyl (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5- yl)amino]-lH-pyrazol-3-yl]cyclohexyl carbonate A solution of 4-nitrophenyl (ls,4s)-4-[l-tert- butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl} amino)- lH-pyrazol-3-yl] cyclohexyl carbonate (70 mg, 0.101 mmol) in formic acid (5 rnL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound 4-nitrophenyl (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-llA6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl} cyclohexyl carbonate (50 mg, 0.097 mmol, 96.0%) as a brown solid. LCMS: ESI m / z 513.53 [M + H]+

[0295] Step J: (ls,4s)-4-{3-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazoI-5-yl)amino]-lH- pyrazol-5-yl] cyclohexyl N-(propan-2-yl)carbamate To a solution of 4-nitrophenyl (ls,4s)-4-{5- [(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl} cyclohexyl carbonate (50 mg, 0.097 mmol) in isopropylamine (3 rnL). The reaction was stirred at room temperature for 1 hr. The reaction was purified by prep-HPLC (Cl 8, 0~50 % acetonitrile in H2O) to afford the title compound (ls,4s)-4-{3-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-5- yl}cyclohexyl N-(propan-2-yl)carbamate (14.5 mg, 0.033 mmol, 34.4%) as a white solid. LCMS: ESI m / z 433.5311.89 (s, 1H), 9.01 (s, 1H), 7.57 - 7.26 (m, 4H), 6.88 (s, 1H), 5.68 (s, 1H), 4.75 (s, 1H), 4.29 (s, 2H), 3.60 (s, 1H), 2.68 (s, 1H), 1.85-1.59 (m, 8H), 1.05 (d, J = 5.2 Hz, 6H).Example 8: (lR,3S)-3-(3-((l-oxoisoindolin-5-yl)amino)-lH-pyrazol-5-yI)cyclopentyl isopropylcarbamate

[0296] Step A: 5-bromo-2-(4-methoxybenzyI)isoindolin-l-one To a solution of methyl 4- bromo-2-(bromomethyl)benzoate (4.50 g, 14.6 mmol) in tetrahydrofuran (100 mL) was added (4- methoxyphenyl)methanamine (2.20 g, 16.0 mmol). The mixture was stirred at 80 °C for 2 h. The cooled mixture was concentrated under vacuum. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford 5-bromo-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (2 g, 6.02 mmol, 41.2%) as a white solid. LCMS: ESI 332.4, 334.4 [M+H]+. 'H NMR (400 MHz, methyl sulfoxide-d6) 8 7.81 (s, 1H), 7.72 - 7.61 (m, 2H), 7.25 - 7.17 (m, 2H), 6.95 - 6.86 (m, 2H), 4.64 (s, 2H), 4.32 (s, 2H), 3.73 (s, 3H).

[0297] Step B: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyl)isoindolin-l-one To a solution of l-tert-butyl-3- [(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (500 mg, 1.48 mmol) in dioxane (5 mL) were added 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (737 mg, 2.22 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (171 mg, 0.296 mmol), sodium 2-methylpropan-2-olate (2.96 mL, 2.96 mmol) and Pd2(dba)s (135 mg, 0.148 mmol), the reaction was stirred at 90 °C under N2 for 18 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (3 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol- 5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (500 mg, 57% yield) as a yellow solid. LCMS: ESI m / z 589 [M + H]+

[0298] Step C: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- 2-(4-methoxybenzyl)isoindolin-l-one To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3- dihydro-lH-isoindol-l-one (500 mg, 0.85 mmol) in HCOOH (5 mL) and the reaction was stirred at room temperature for 1 hr. The reaction was concentrated and were added MeOH (5 mL), and LiOH (142 mg, 3.39 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was diluted with water The aqueous layer was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 0-100%] to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (300 mg, 74% yield) as a yellow oil. LCMS: ESI m / z 475 [M + H]+

[0299] Step D: (3S,5S)-l-acetyl-5-(l-(tert-butyl)-5-(3-(methoxymethyl)-l-methyl-lH- pyrazole-5-carboxamido)-lH-pyrazol-3-yl)pyrrolidin-3-yl (4-nitrophenyl) carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl]amino)-2-[(4- methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (300 mg, 0.632 mmol) in THF (10 mL) and DCM (10 mL) were added 4-nitrophenyl chloroformate (191 mg, 0.948 mmol), pyridine (0.153 mL, 1.896 mmol). The reaction was stirred at 30 °C for 30 min. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0- 100%] to afford the title compound (lR,3S)-3-[l-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]-l-oxo- 2,3-dihydro-lH-isoindol-5-yl}amino)-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 75% yield) as a white solid. LCMS: ESI m / z 640 [M + H]+

[0300] Step E: 4-nitrophenyl ((lR,3S)-3-(3-((l-oxoisoindolin-5-yl)amino)-lH-pyrazol-5- yl)cyclopentyl) carbonate A solution of (lR,3S)-3-[l-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]- 1 -oxo-2, 3-dihydro-lH-isoindol-5-yl]amino)-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (300 mg, 0.469 mmol) in HCOOH (5 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound 4-nitrophenyl (lR,3S)-3-{5-[(l-oxo-2,3-dihydro- lH-isoindol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl carbonate (300 mg, crude) as a white solid, which was used into next step without further purification. LCMS: ESI m / z 464 [M + H]+

[0301] Step F: (lR,3S)-3-(3-((l-oxoisoindolin-5-yI)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate To a solution of 4-nitrophenyl (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-isoindol- 5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl carbonate (300 mg, 0.647 mmol) in THF (2 mL) was added propan-2-amine (0.555 mL, 6.47 mmol). The reaction was stirred at 50 °C for 2 hr. The reaction concentrated in vacuo. The residue was purified by prep-HPLC (0.1% TFA) to afford the title compound (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-lH-pyrazol-3- yl} cyclopentyl N-(propan-2-yl)carbamate (4.8 mg, 1.9% yield) as a white solid. LCMS: ESI m / z 384 [M + H]+. 'H NMR (400 MHz, DMSO-cL) 5 8.78 (brs, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.43 (d, 7 =8.4 Hz, 1H), 7.24 (d, 7= 8.4 Hz, 1H), 6.94 (d, 7= 7.6 Hz, 1H), 5.70 (s, 1H), 5.00 (s, 1H), 4.26 (s, 2H), 3.11-3.03 (m, 1H), 2.11 - 1.52 (m, 6H), 1.03 (d, 7 = 6.4 Hz, 6H).Example 9: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5- yl)cyclopentyl isopropylcarbamate

[0302] Step A: 5-bromo-llA6-benzothiophene-l, 1-dione To a solution of 5-bromo-l- benzothiophene (1 g, 4.69 mmol) in DCM (8 mL) was added H2O2 (2 mL, 19.6 mmol, 30% in H2O) and TFA (2 mL, 26.92 mmol). The mixture was stirred at 20 °C for 5 hours. The reaction mixture was diluted with water, extracted with DCM (30 mL x 3). The organic phase was washed with aqueous Na2S20s, dried over ISfeSCL and concentrated. The residue was purified by silica gel chromatography (10 g column) using 0 - 30% EtOAc / hexane to afford 5 -bromo- 1 / / 6- benzothiophene- 1,1 -dione (700 mg, 2.85 mmol, 60.8%) as a brown oil.

[0303] Step B: 5-bromo-2,3-dihydro-lλΛ6-benzothiophene-l, 1-dione To a solution of 5- bromo-lλΛ6-benzothiophene- 1,1 -dione (700 mg, 2.85 mmol) in MeOH (30 mL) was added NaBHi (221 mg, 5.71 mmol) and the mixture was stirred at 20 °C for 2 hours. H2O (0.5 mL) was added to quench. The following mixture was concentrated and the residue was purified by silica gel chromatography (10 g column) using 0 - 30% EtOAc / hexane to afford 5-bromo-2,3-dihydro- 1 / / 6- benzothiophene- 1,1 -dione (540 mg, 2.18 mmol, 76.5%) as a brown oil. *HNMR (400 MHz, DMSO) 8 7.84 (s, 1H), 7.72 (s, 2H), 3.66-3.54 (m, 2H), 3.42-3.28 (m, 2H).

[0304] Step C: 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH- pyrazol-5-yl]amino)-2,3-dihydro-lλΛ6-benzothiophene-l, 1-dione To a solution of 5-bromo-2,3- dihydro- l / / 6-benzothiophene- 1,1 -dione (100 mg, 0.40 mmol) and l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (150 mg, 0.44 mmol) in dioxane (5 mL) was added CS2CO3 (263 mg, 0.81 mmol), Pd2(dba)? (37.0 mg, 0.04 mmol) and Xant-PHOS (23.4 mg, 0.04 mmol). The reaction mixture was stirred at 100 °C under N2 for 5 hours. The mixture was purified by silica gel chromatography (2 g column) using 0 - 50% EtOAc / hexane. The productcontaining fractions were concentrated to afford 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy] cyclopentyl]- 1 H-pyrazol-5-yl} amino)-2, 3 -dihydro- 1 λΛ6-benzothiophene- 1, 1-dione (160 mg, 0.32 mmol, 78.5%) as a brown solid. LCMS: ESI m / z 504.3 [M + H]+

[0305] Step D: 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yI]amino)- 2, 3-dihydro-llA6-benzothiophene-l, 1-dione A solution of 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl] - lH-pyrazol-5-yl} amino)-2,3 -dihydro- 1 ? / 6-benzothiophene- 1,1- dione (160 mg, 0.32 mmol) in formic acid (4 mL) was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum to remove formic acid to give a crude, which was added MeOH (3 mL) and Li OH (100 mg) was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum and poured into LA (30 mL), extracted with water. The organic layer was concentrated to give 5-({ 1- tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lZA6- benzothiophene- 1,1 -dione (120 mg, 0.31 mmol, 97.0%) as a brown solid. LCMS: ESI m / z 390.1 [M + H]+

[0306] Step E: (lR,3S)-3-{l-tert-butyl-5-[(l,l-dioxo-2,3-dihydro-lλΛ6-benzothiophen-5- yl)amino]-lH-pyrazol-3-yI]cyclopentyl 4-nitrobenzoate To a solution of 5-({l-tert-butyl-3- [(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-2,3-dihydro-lλΛ6-benzothiophene-l,l- dione (120 mg, 0.31 mmol) in DCM (2 mL) and THF (2 mL) was added 4-nitrophenyl chloroformate (93.14 mg, 0.46 mmol), pyridine (0.05 mL, 0.62 mmol) and DMAP (3.76 mg, 0.03 mmol). The mixture was stirred at 20 °C for 1 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (2 g column) using 0 - 50% EtOAc / hexane to afford (lR,3S)-3-{l-tert-butyl-5-[(l,l-dioxo-2,3-dihydro-lλΛ6-benzothiophen-5-yl)amino]-lH- pyrazol-3-yl}cyclopentyl 4-nitrobenzoate (130 mg, 0.24 mmol, 78.3%) as a brown solid. LCMS: ESI m / z 555.2 [M + H]+

[0307] Step F: (lR,3S)-3-{5-[(l,l-dioxo-2,3-dihydro-lλΛ6-benzothiophen-5-yl)amino]-lH- pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate A solution of (lR,3S)-3-{l-tert-butyl-5-[(l,l- dioxo-2, 3-dihydro-l / . 6-benzothiophen-5-yl)amino]-lH-pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate (130 mg, 0.23 mmol) in formic acid (4 mL) was stirred at 100 °C for 12 hours. The cooled mixture was concentrated under vacuum to give ( l R,3S)-3-[5-[(l, l-dioxo-2,3-dihydro-l / .A6- benzothiophen-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (110 mg, 0.2 mmol, 84.7%) as a brown solid. The crude product was used for the next step without purification. LCMS: ESI m / z 499.1 [M + H]+

[0308] Step G: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH- pyrazol-5-yI)cyclopentyl isopropylcarbamate To a solution of (lR,3S)-3-{5-[(l,l-dioxo-2,3- dihydro- 1 / .' 6-benzothiophen-5-yl)amino]- 111-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (110 mg, 0.2 mmol) in THF (5 mL) was added ethyldiisopropylamine (0.11 mL, 0.66mmol). Then propan-2-amine (0.09 mL, 1.10 mmol) was added dropwise. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was concentrated and the residue was purified by prep-TLC (EA) to give (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)amino)-lH-pyrazol-5- yl)cyclopentyl isopropyl carbamate (14.7 mg, 0.035 mmol, 16%) as a white solid. LCMS: ESI m / z 419.1 [M + H]+ XH NMR (400 MHz, DMSO) 5 11.92 (s, 1H), 8.99 (s, 1H), 7.52-7.40 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.71 (s, 1H), 5.00 (brs, 1H), 3.64-3.52 (m, 1H), 3.48 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 3.12 - 3.01 (m, 1H), 2.49 - 2.42 (m, 1H), 2.03 (dd, J = 15.6, 7.6 Hz, 1H), 1.94-1.82 (m, 1H), 1.78-1.64 (m, 2H), 1.63-1.52 (m, 1H), 1.04 (d, J = 6.4 Hz, 6H).Example 10: (lR,3S)-3-(5-((3-methyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)- lH-pyrazol-3-yl)cyclopentyI isopropylcarbamate

[0309] Step A: 5-bromo-3-methylbenzo[d]isothiazole 1,1-dioxide A solution of 5-bromo-2,3- dihydro-lλΛ6,2-benzothiazole- 1,1, 3-trione (500 mg, 1.91 mmol) in THF (0.1 M) was treated with MeMgBr (5.7 mL, 5.72 mmol, IM in THF) at 0 °C. The mixture was stirred at rt overnight, then quenched with water and extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PE / EA=2: 1) to afford pure product 5-bromo-3 -methyl- 1λΛ6, 2- benzothiazole- 1,1 -dione (400 mg, 1.54 mmol, 80.6%) as a white solid. LCMS: ESI 259.9, 261.9 [M+H]+

[0310] Step B: 5-bromo-3-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 5-bromo-3-methyl-lZA6,2-benzothiazole-l, 1-dione (400 mg, 1.54 mmol) in THF (20 mL) was added NaBFL (104 mg, 3.07 mmol), after that the reaction mixture was stirred at 25 °C for 5 h. After completion, the reaction mixture was quenched by NH4CI (aq.) 2 mL. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated invacuo. The residue was purified using silica gel column chromatography eluting with PE / EA=1 : 3. The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5- bromo-3-methyl-2,3-dihydro-lλΛ6,2-benzothiazole-l,l-dione (350 mg, 1.33 mmol, 86.8%) as a colorless oil. LCMS: ESI m / z 261.9, 263.9 [M + H]+

[0311] Step C: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethyIsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yI)amino)-3-methyl-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide To a solution of 1-tert- butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (350 mg, 1.04 mmol) in dioxane (2 mL) were added 5-bromo-3-methyl-2, 3 -dihydro- lA6,2-benzothiazole- 1,1- dione (300 mg, 1.14 mmol), [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4- yl]diphenylphosphane (120 mg, 0.207 mmol), CS2CO3 (675 mg, 2.074 mmol)and Pd2(dba)s (95 mg, 0.104 mmol). The reaction mixture was stirred at 90 °C for 18 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (3 / 1) afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-lλΛ6,2- benzothiazole- 1,1 -dione (200 mg, 0.386 mmol, 37.2%) as a yellow solid. LCMS: ESI m / z 519.2 [M + H]+

[0312] Step D: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- 3-methyl-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide A solution of 5-({l-tert-butyl-3-[(lS,3R)-3- [(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-lλΛ6,2- benzothiazole- 1,1 -dione (200 mg, 0.386 mmol) in HCOOH (50 mL) was stirred at room temperature for 1 hr. The reaction was concentrated and were added MeOH (50 mL), and LiOH (64.7 mg, 1.54 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was diluted with H2O. The following mixture was extracted with EA. Combined the EA layer and washed with saturated NaCl solution. The EA layer was dried by Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with [gradient: 80-100%] to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5- yl}amino)-3-methyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (120 mg, 0.297 mmol, 76.9%) as a white solid. LCMS: ESI m / z 405 [M + H]

[0313] Step E: (lR,3S)-3-(l-(tert-butyI)-5-((3-methyl-l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-3-methyl-2,3-dihydro-lZA6,2-benzothiazole-l, 1-dione (120 mg, 0.297 mmol) in THF (10 mL) and DCM (10 mL) were added 4-nitrophenyl chloroformate (89.7 mg, 0.445 mmol), pyridine (0.072 mL, 0.890 mmol). The reaction was stirred at 50 °C for 30 min. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 70-90%] to afford the title compound (lR,3S)-3-{l-tert-butyl-5-[(3-methyl-l,l-dioxo-2,3- dihydro- 1 / .A6,2-benzothiazol-5-yl)amino]- 1 H-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.176 mmol, 59.2%) as a white solid. LCMS: ESI m / z 570.1 [M + H]1

[0314] Step F: (lR,3S)-3-(5-((3-methyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-{l- tert-butyl-5-[(3-methyl-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3- yl} cyclopentyl 4-nitrophenyl carbonate (100 mg, 0.176 mmol) in HCOOH (5 mL) was stirred at 80 °C overnight. The reaction was concentrated in vacuo to afford the title compound (lR,3S)-3-{5-[(3- methyl-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl] cyclopentyl 4- nitrophenyl carbonate (80 mg, 0.156 mmol, 88.9%) as a white solid, which was used into next step without further purification. LCMS: ESI m / z 514 [M + H]+.

[0315] Step G: (lR,3S)-3-(5-((3-methyI-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-3-yl)cyclopentyl isopropylcarbamate To a solution of (lR,3S)-3-{5-[(3- methyl-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4- nitrophenyl carbonate (80 mg, 0.156 mmol) in THF (2 mL) was added propan-2-amine (0.133 mL, 1.558 mmol) and the reaction was stirred at 50 °C for 2 hr. The reaction concentrated in vacuo. The residue was purified by prep-HPLC (FA condition) to afford the title compound (lR,3S)-3-{5-[(3- methyl- 1 , 1 -dioxo-2,3-dihydro- 1 / / 6,2-benzothiazol-5-yl)amino]- 1 H-pyrazol-3-yl [ cyclopentyl N- (propan-2-yl)carbamate (2.4 mg, 3.55%) as a white solid. LCMS: ESI m / z 434 [M + H]+. 'H NMR (400 MHz, DMSO-t / e) 5 11.92 (s, 1H), 9.01 (s, 1H), 7.57 (d, J= 4.4 Hz, 1H), 7.50 (d, J= 8.8 Hz, 2H), 7.32 (d, J= 8.8 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.69 (s, 1H), 5.06 - 4.94 (m, 1H), 4.67 - 4.54 (m, 1H), 3.65 - 3.53 (m, 1H), 3.13 - 2.98 (m, 1H), 2.48 - 2.40 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95- 1.82 (m, 1H), 1.79 - 1.53 (m, 3H), 1.39 (d, J= 6.4 Hz, 3H), 1.03 (d, J= 8 Hz, 6H).Example 11: (ls,4s)-4-{3-[(l,l-dioxo-3,4-dihydro-2H-lλΛ6,2-benzothiazin-6-yl)amino]-lH- pyrazol-5-yl] cyclohexyl N-(propan-2-yl)carbamate

[0316] Step A. methyl 2-(5-bromo-2-(chlorosulfonyl)phenyl)acetate A reaction mixture of methyl 2-(3-bromophenyl)acetate (10 g, 43.8 mmol) in HSO3CI (5.10 g, 43.8 mmol) was stirred at rt overnight. The reaction mixture was poured into ice-water slowly and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give crude methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (3 g, 9.2 mmol, 21%) as a yellow oil. LCMS: m / z 327 [M+H]+.

[0317] Step B. methyl 2-(5-bromo-2-(N-(4-methoxybenzyl)sulfamoyl)phenyl)acetate To a stirred mixture of methyl 2-[5-bromo-2-(chlorosulfonyl)phenyl]acetate (3 g, 9.2 mmol) in DCM (30 mL) was added (4-methoxyphenyl)methanamine (1.26 g, 9.2 mmol) and TEA (1.86 g, 18.4 mmol) slowly at 0 °C. After stirred at rt overnight, the mixture was poured into water and extracted with DCM. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-35%, EtOAc in PE) to give methyl 2-(5-bromo-2-[[(4-methoxyphenyl)methyl] sulfamoyl }phenyl)acetate (2 g, 4.65 mmol, 33.9%) as a brown solid. LCMS: m / z 429 [M+H]+.

[0318] Step C. 4-bromo-2-(2-hydroxyethyl)-N-(4-methoxybenzyl)benzenesulfonamide To a stirred mixture of methyl 2-(5-bromo-2-{[(4-methoxyphenyl)methyl]sulfamoyl]phenyl)acetate (2.5 g, 5.84 mmol) in THF (30 mL) was added lithium(l+) ion boranuide (5.84 mL, 11.6 mmol) slowly at 0 °C. After stirred at rt overnight, the mixture was poured into ice-water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated in vacuum and the residue was purified by flash chromatography to afford 4-bromo-2- (2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene-l-sulfonamide (1.5 g, 3.75 mmol, 64.2%) as a colorless oil. LCMS: m / z 401 [M+H]+.

[0319] Step D. 6-bromo-2-(4-methoxybenzyl)-3,4-dihydro-2H-benzo[e] [l,2]thiazine 1,1- dioxide To a stirred mixture of 4-bromo-2-(2-hydroxyethyl)-N-[(4-methoxyphenyl)methyl]benzene- 1-sulfonamide (700 mg, 1.749 mmol) in THF (10 mL) was added triphenylphosphane (917 mg, 3.49 mmol) and (E)-N-{[(propan-2-yloxy)carbonyl]imino}(propan-2-yloxy)formamide (0.69 mL, 3.49mmol) at rt. After stirred at rt overnight, the mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 6-bromo-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-l / / 6,2-benzothiazine- l , 1-dione (300 mg, 0.785 mmol, 44.9%) as a white solid. LCMS: m / z 383 [M+H]+.

[0320] Step E. 6-({l-tert-butyl-3-[(ls,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-lH- pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine-l,l- dione To a stirred mixture of 6-bromo-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lZA6,2- benzothiazine- 1,1 -dione (600 mg, 1.570 mmol) in dioxane (10 mL) was added l-tert-butyl-3- [(ls,4s)-4-[(tert-butyldiphenylsilyl)oxy]cyclohexyl]-lH-pyrazol-5-amine (746 mg, 1.570 mmol), CS2CO3 (1.28 g, 3.92 mmol), RuPhos (146 mg, 0.314 mmol) and 2-(2-aminophenyl)benzen- 1 -ide; chloropalladiumylium; {2-[2,6-bis(propan-2-yloxy)phenyl]phenyl}dicyclohexylphosphane (122 mg, 0.157 mmol) at rt. After stirred at 100 °C overnight, the mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 6-({ 1 -tert-butyl -3- [(1 s,4s)-4- [(tert-butyldiphenylsilyl)oxy ] cyclohexyl] - 1 H-pyrazol-5 -yl } amino)-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine-l,l-dione (600 mg, 0.772 mmol, 49.2%) as a colorless oil. LCMS: m / z 777 [M+H]1.

[0321] Step F. 6-({l-tert-butyl-3-[(ls,4s)-4-hydroxycyclohexyl]-lH-pyrazoI-5-yl}amino)-2- [(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine-l, 1-dione A mixture of 6-({l- tert-butyl-3 - [( 1 s,4s)-4- [(tert-butyldiphenylsily l)oxy ] cyclohexyl] - 1 H-pyrazol-5 -yl } amino)-2-[(4- methoxyphenyl)methyl]-3,4-dihydro-2H-1 iA6,2-benzothiazine-l,l-dione (450 mg, 0.579 mmol) in THF (10 mL) was added pyridine hydrofluoride (5 mL). The reaction mixture was stirred at 25 °C overnight. The mixture was adjusted pH to 8 by NaHCOs (aqueous), extracted with. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with ethyl acetate in petroleum ether to afford the title compound 6-({l-tert-butyl-3-[(ls,4s)-4-hydroxycyclohexyl]-lH- pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lλΛ6,2-benzothiazine-l,l-dione (130 mg, 0.241 mmol, 41.6%)as a colorless oil. LCMS: m / z 539 [M+H]1.

[0322] Step G. 4-nitrophenyl (ls,4s)-4-[l-tert-butyl-5-({2-[(4-methoxyphenyI)methyl]-l,l- dioxo-3,4-dihy dro-2H- lλΛ6,2-benzothiazin-6-yl} amino)- lH-pyrazol-3-yl] cyclohexyl carbonate To a stirred solution of 6-({l-tert-butyl-3-[(ls,4s)-4-hydroxycyclohexyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-3,4-dihydro-2H-lZA6,2-benzothiazine-l, 1-dione (130 mg, 0.241 mmol) in DCM (2 mL) / THF (2 mL) was added 4-nitrophenyl chloroformate (145 mg, 0.724 mmol), Py (0.039 mL, 0.483 mmol) and DMAP (2.95 mg, 0.024 mmol) at rt. After stirred at rt for 3h, the mixture was poured into water (30 ml) and extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 4-nitrophenyl (ls,4s)-4-[l-tert-butyl-5-({2-[(4-methoxyphenyl)methyl]- 1 , 1 -di oxo-3, 4-dihydro-2H- lλΛ6,2-benzothiazin-6-yl} amino)- 1H- pyrazol-3-yl]cyclohexyl carbonate (70 mg, 0.099 mmol, 41.2%) as a brown solid. LCMS: m / z 704 [M+H]+.

[0323] Step H. 4-nitrophenyl (ls,4s)-4-{5-[(l,l-dioxo-3,4-dihydro-2H-lλΛ6,2-benzothiazin-6-yl)amino]-lH-pyrazol-3-yl]cyclohexyl carbonate A mixture of 4-nitrophenyl (ls,4s)-4-[l-tert- butyl-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-3,4-dihydro-2H-lZA6,2-benzothi azin-6- yl}amino)-lH-pyrazol-3-yl]cyclohexyl carbonate (70 mg, 0.099 mmol) in formic acid (3 mL) was stirred at 100 °C overnight, then concentrated under reduced pressure to give crude 4-nitrophenyl (1 s,4s)-4-{5-[(l,l-dioxo-3,4-dihydro-2H-l λΛ6,2-benzothiazin-6-yl)amino]-lH-pyrazol-3- yl}cyclohexyl carbonate (60 mg, 0.097 mmol, 97.2%) as a brown oil. LCMS: m / z 528 [M+H]+.

[0324] Step I. (ls,4s)-4-{3-[(l,l-dioxo-3,4-dihydro-2H-lλΛ6,2-benzothiazin-6-yl)amino]-lH- pyrazol-5-yl} cyclohexyl N-(propan-2-yl)carbamate To a stirred solution of 4-nitrophenyl (ls,4s)- 4- { 5 - [( 1 , 1 -dioxo-3 ,4-dihy dro-2H- 1 / / 6,2-benzothi azin -6-yl )amino]- 1 H-pyrazol-3 -yl } cyclohexyl carbonate (60 mg, 0.114 mmol) in THF (3 mL) was added propan-2-amine (0.019 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for 2h. The reaction was concentrated. The residue was purified by prep-HPLC to give (ls,4s)-4-{3-[(l,l-dioxo-3,4-dihydro-2H-lλΛ6,2- benzothiazin-6-yl)amino]-lH-pyrazol-5-yl}cyclohexyl N-(propan-2-yl)carbamate (46.4 mg, 0.104 mmol, 91.1%) as a brown solid. LCMS: m / z 448 [M+H]+. 'H NMR (400 MHz, DMSO) 5 11.86 (s, 1H), 8.80 (s, 1H), 7.47 (d, J= 8.8 Hz, 1H), 7.34 - 7.19 (m, 2H), 7.14 (s, 1H), 6.88 (d, J = 7.2 Hz, 1H), 5.64 (s, 1H), 4.75 (s, 1H), 3.65 - 3.55 (m, 1H), 3.50 (dd, J = 12.8, 6.4 Hz, 2H), 2.83-2.77 (m, 2H), 2.73-2.65 (m, 1H), 1.82-1.75 (m, 4H), 1.75-1.62 (m, 4H), 1.05 (d, J= 6.4 Hz, 6H).Example 12: (lR,3S)-3-{3-[(4-methyl-l,l-dioxo-3,4-dihydro-2H-lλΛ6,2,4-benzothiadiazin-6- yl)amino]-lH-pyrazol-5-yl]cyclopentyl N-(propan-2-yl)carbamate

[0325] Step A: 4-bromo-2-nitrobenzene-l-sulfonic acid To a solution of 4-bromo-l-fluoro-2- mtrobenzene (2.80 mL, 22.7 mmol) in EtOH (60 mL) was added a suspension of Na2SOs (2.72 mL, 56.8 mmol) in EtOH (100 mL) and H2O (125 mL) dropwise. The reaction was stirred at70 °C overnight. The cooled reaction mixture was acidified with HC1 (2N) to PH 2. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution, and concentrated in vacuo to afford the title compound 4-bromo-2-nitrobenzene-l -sulfonic acid (12.4 g, 44.0 mmol, 100%) as a white solid. LCMS: ESI m / z 282.07 [M + H]+.

[0326] Step B: 4-bromo-2-nitrobenzene-l-sulfonamide To a solution of 4-bromo-2- nitrobenzene- 1 -sulfonic acid (10 g, 35.5 mmol) in SOCI2 (20 mL) was added DMF (0.5 mL). The reaction was stirred at 90 °C for 2 hr. The cooled reaction mixture was concentrated in vacuo. The residue was azeotroped with chloroform. The residue is dissolved in tetrahydrofuran. The following solution was added dropwise into NH4OH (40 mL) at 0 °C. The reaction mixture was stirred at rt for Ih and then was acidified with HC1 (2N) to PH 7. The following mixture was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo to afford the title compound 4-bromo-2-nitrobenzene- 1 -sulfonamide (4.57 g, 16.3 mmol, 45.9%) as a white solid. LCMS: ESI m / z 281.09 [M + H]+

[0327] Step C: 2-amino-4-bromobenzene-l-sulfonamide To a solution of 4-bromo-2- nitrobenzene-1 -sulfonamide (4.57 g, 16.3 mmol) in EtOH (10 mL) and H2O (10 mL) were added NH4CI (4.35 g, 81.3 mmol) and Fe (4.54 g, 81.3 mmol). The reaction was stirred at 70 °C for 2 h. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified using silica gel column chromatography eluted with methanol in dichloroform (gradient: 0-10%) toafford the title compound 2-amino-4-bromobenzene-l -sulfonamide (3.02 g, 12.0 mmol, 74.0%) as a white solid. LCMS: ESI m / z 251.0 [M + H]

[0328] Step D: 6-bromo-4H-lλΛ6, 2, 4-benzothiadiazine-l , 1-dione A reaction mixture of 2- amino-4-bromobenzene-l -sulfonamide (400 mg, 1.593 mmol) in (diethoxymethoxy)ethane (10 mL) was stirred at 70 °C for 1 hr. The reaction mixture was cooled to rt and then filtered. The filter cake was washed with MTBE and dried in vacuo to afford the title compound 6-bromo-4H- 1 Z / 6,2,4- benzothiadiazine-l,l-dione (350 mg, 1.34 mmol, 84.2%) as a white solid. LCMS: ESI m / z 261.10 [M + H]+

[0329] Step E: 6-bromo-4-methyl-4H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione To a solution of 6-bromo-4H-l / ,A6, 2, 4-benzothiadiazine-l,! -dione (1.2 g, 4.60 mmol) in DMF (5 mL) were added CH3I (0.98 g, 6.89 mmol) and CS2CO3 (2.99 g, 9.19 mmol). The reaction was stirred at 80 °C overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-80%) to afford the title compound 6-bromo-4-methyl-4H-lλΛ6, 2, 4-benzothiadiazine-l,! -dione (370 mg, 1.35 mmol, 29.3%) as a white solid. LCMS: ESI m / z 275.13 [M + H]+

[0330] Step F: 6-bromo-4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione To a solution of 6-bromo-4-methyl-4H-lλΛ6, 2, 4-benzothiadiazine-l,! -dione (370 mg, 1.35 mmol) in isopropyl alcohol (20 mL) was added NaBEL (182 mg, 5.38 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-50%) to afford the title compound 6-bromo-4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione (340 mg, 1.27mmol, 91.2%) as a white solid. LCMS: ESI m / z 277.14 [M + H]+

[0331] Step G: 6-({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH- pyrazol-5-yI]amino)-4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione To a solution of 6-bromo-4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione (340 mg, 1.23 mmol) in dioxane (10 mL) were added l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (414 mg, 1.23 mmol), CS2CO3 (1.20 g, 3.68 mmol), Pd2(dba)s (112 mg, 0.123 mmol) and Xant-PHOS (142 mg, 0.245 mmol). The reaction was stirred at 100 °C under N2 for 3 h. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography eluted with methanol in DCM (gradient: 0-10%) to afford the title compound 6-({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH- pyrazol-5-yl}amino)-4-methyl-3, 4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine-l, 1-dione (320 mg, 0.599 mmol, 48.9%) as a yellow oil. LCMS: ESI m / z 533.82 [M + H]+

[0332] Step H: 6-({l-tert-butyI-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)- 4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzo thiadiazine- 1, 1-dione A solution of 6-({l-tert-butyl-3- [(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-4-methyl-3,4- dihydro-2H- 1 / / 6, 2, 4-benzothiadiazine-l, 1-dione (320 mg, 0.599 mmol) in formic acid (5 mL) was stirred at room temperature for 1 hr. Then concentrated in vacuo. The residue was dissolved with methanol and adjusted to pH value 12-13 with LiOH (2M in H2O). The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with methanol in dichloroform (gradient:0-10%) to afford the title compound 6-({l-tert-butyl-3-[(lS,3R)-3- hydroxy cyclopentyl]- lH-pyrazol-5-yl}amino)-4-methyl-3,4-dihydro-2H-lλΛ6, 2, 4-benzothiadiazine- 1,1 -dione (90 mg, 0.215 mmol, 35.8%) as a yellow oil. LCMS: ESI m / z 419.55 [M + H]+

[0333] Step I: (lR,3S)-3-{l-tert-butyl-5-[(4-methyl-l,l-dioxo-3,4-dihydro-2H-lλΛ6,2,4- benzothiadiazin-6-yl)amino]-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate To a solution of 6-({ l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-4-methyl- 3,4-dihydro-2H-lZA6,2,4-benzothiadiazine-l,l-dione (90 mg, 0.215 mmol) in THF (5 mL) and DCM (5 mL) were added 4-mtrophenyl chloroformate (64.7 mg, 0.322 mmol), DMAP (2.62 mg, 0.021 mmol) and Py (33.9 mg, 0.429 mmol). The reaction was stirred at room temperature for 3 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient:0-50%) to afford the title compound ( 1R,3 S)-3 - { 1 -tert-butyl-5-[(4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-2H- 1λΛ6,2,4- benzothiadiazin-6-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.068 mmol, 31.9%) as a brown solid. LCMS: ESI m / z 584.65 [M + H]+

[0334] Step J: (lR,3S)-3-{5-[(4-methyl-l,l-dioxo-3,4-dihydro-2H-lλΛ6,2,4-benzothiadiazin- 6-yl)amino]-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate To a solution of (lR,3S)-3-{ l- tert-butyl-5-[(4-methyl-l, 1 -dioxo-3, 4-dihy dro-2H-lA6, 2, 4-benzothi adiazin-6-yl)amino]- 1H- pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.068 mmol) in formic acid (5 mL). The reaction was stirred at 100 °C for overnight. The reaction was concentrated in vacuo to afford the titlecompound (lR,3S)-3-{ 5 -[(4-methyl- 1 , 1 -dioxo-3 ,4-dihydro-2H- 1 λΛ6,2,4-benzothiadiazin-6- yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (30 mg, 0.057 mmol, 82.9%) as a brown solid. LCMS: ESI m / z 528.55 [M + H]+

[0335] Step K: (lR,3S)-3-{5-[(4-methyl-l,l-dioxo-4H-llA6,2,4-benzothiadiazin-6- yl)amino]-lH-pyrazol-3-yl]cyclopentyI N-(propan-2-yl)carbamate To a solution of (lR,3S)-3- {5-[(4-methyl-l,l-dioxo-4H-lλΛ6,2,4-benzothiadiazin-6-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4- mtrophenyl carbonate (40 mg, 0.076 mmol) in propan-2-amine (5 mL, 58.4 mmol). The reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to afford the title compound (lR,3S)-3-{5-[(4-methyl-l,l-dioxo-4H-lλΛ6,2,4-benzothiadiazin-6-yl)amino]-lH- pyrazol-3-yl}cyclopentyl N-(propan-2-yl)carbamate (30 mg, 0.067 mmol, 88.4%) as a yellow oil. LCMS: ESI m / z 446.53 [M + H]+

[0336] Step L: (lR,3S)-3-{3-[(4-methyl-l,l-dioxo-3,4-dihydro-2H-llA6,2,4-benzothiadiazin- 6-yl)amino]-lH-pyrazol-5-yl]cyclopentyl N-(propan-2-yl)carbamate To a solution of (lR,3S)-3- { 5-[(4-methyl- 1 , 1 -dioxo-4H- 1 / / 6,2,4-benzothi adiazin-6-yl )amino]- lH-pyrazol-3 -yl } cyclopentyl N- (propan-2-yl)carbamate (20 mg, 0.045 mmol) in Isopropyl alcohol (5 mL) was added NaBIL(6.06 mg, 0.179 mmol). The reaction was stirred at room temperature for 1 hr. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC (Cl 8, 0~50 % acetonitrile in H2O) to afford the title compound (lR,3S)-3-{3-[(4-methyl-l,l-dioxo-3,4-dihydro-2H-lλΛ6,2,4- benzothiadiazin-6-yl)amino]-lH-pyrazol-5-yl}cyclopentyl N-(propan-2-yl)carbamate (2.8 mg, 0.006 mmol, 14.0%) as a white solid. LCMS: ESI m / z 448.55 [M + H]+.NMR (400 MHz, DMSO) 5 11.88 (s, 1H), 8.69 (s, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.95 (s, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.66 (s, 1H), 5.00 (s, 1H), 4.60 (d, J = 8.0 Hz, 2H), 3.63-3.53 (m, 1H), 3.11-3.01(m, 1H), 2.88 (s, 3H), 2.08-1.88 (m, 2H), 1.85-1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 1.04 (d, J = 6.4 Hz, 6H).Example 13: (lR,3S)-3-(3-((3,3-dimethyI-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0337] Step A: l-(benzylsulfanyl)-4-bromo-2-(propan-2-yI)benzene To a solution of 4- bromo-l-iodo-2-(propan-2-yl)benzene (4 g, 12.3 mmol) in toluene (100 mL) was added Xant-PHOS (0.71 g, 1.23 mmol), DIEA EthyldiisopropylaMine (4.06 mL, 24.6 mmol), Pd2(dbaf (1.13 g, 1.23 mmol) and phenylmethanethiol (1.53 g, 1.44 mL, 12.3 mmol). The mixture was stirred at 100 °C under N2 for 12 hours. The cooled reaction mixture was concentrated and the residue was purified by silica gel chromatography (20 g column) using 0 - 5% EtOAc / hexane to afford l-(benzylsulfanyl)-4- bromo-2-(propan-2-yl)benzene (2.66 g, 8.27 mmol, 67.3%) as a brown oil.

[0338] Step B: 4-bromo-2-(propan-2-yl)benzene-l-sulfonyl chloride To a solution of 1- (benzylsulfanyl)-4-bromo-2-(propan-2-yl)benzene (2.67 g, 8.31 mmol) in HO Ac (15 mL) and water (7.5 mL) was added NCS (3.33 g, 24.9 mmol). The mixture was stirred at 20 °C for 30 mm. The reaction mixture was diluted with water 50 mL, extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (15 g column) using 0 - 5% EtOAc / hexane to afford 4-bromo-2-(propan-2- yl)benzene- 1 -sulfonyl chloride (2.4 g, 8.06 mmol, 97.0%) as a white solid. 'H NMR (400 MHz, DMSO) 5 7.90 (d, J = 12.0 Hz, 1H), 7.71 (s, 1H), 7.52 (t, J = 4.0 Hz, 1H), 4.05-3.98 (m, 1H), 1.35 (d, J = 8.0 Hz, 6H).

[0339] Step C: 4-bromo-2-(propan-2-yl)benzenesulfonamido acetate To a solution of 4- bromo-2-(propan-2-yl)benzene-l -sulfonyl chloride (2.4 g, 8.06 mmol) in DCM (30 mL) was added pyridine (1.95 mL, 24.1 mmol) and amino acetate (0.61 g, 8.06 mmol). The reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was diluted with water, extracted with DCM (50 mL x 3). The organic phase was washed with brine, dned over Na2SO4 and concentrated. The residuewas purified by silica gel chromatography (10 g column) using 0 - 30% EtOAc / hexane to afford 4- bromo-2-(propan-2-yl)benzenesulfonamido acetate (900 mg, 2.67 mmol, 33.2%) as a brown oil. LCMS: ESI m / z 338.0 [M + H]+.

[0340] Step D: 5-bromo-3,3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione A solution of 4-bromo-2-(propan-2-yl)benzenesulfonamido acetate (500 mg, 1.48 mmol) in DMSO (5 mL) was stirred at 130 °C under N2 for 3 hours. The cooled reaction mixture was diluted with water (50 mL), extracted with EA (50 mL x 3). The organic phase was washed with brine, dried over Na2SC>4 and concentrated. The residue was purified by silica gel chromatography (5 g column) using 0 - 50% EtOAc / hexane to afford 5-bromo-3,3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (270 mg, 0.978 mmol, 65.7%) as a clear oil. LCMS: ESI m / z 277.9 [M + H]+.

[0341] Step E: ({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH- pyrazol-5-yl]amino)-3,3-dimethyI-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (270 mg, 0.978 mmol) and 1- tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (330 mg, 0.978 mmol) in dioxane (5 mL) was added CS2CO3 (637 mg, 1.95 mmol), Xant-PHOS (56.5 mg, 0.098 mmol) and Pd2(dba)3 (89.5 mg, 0.098 mmol). The reaction mixture was stirred at 100 °C under N2 for 5 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography (5 g column) using 0 - 50% EtOAc / hexane to afford 5-({l-tert-butyl-3-[(lS,3R)-3- [(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro- lλΛ6,2-benzothiazole-l,l-dione (500 mg, 0.938 mmol, 95.9%) as a brown oil. LCMS: ESI m / z 533.4 [M + H]+.

[0342] Step F: 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)- 3, 3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazoIe-l, 1-dione A solution of 5-({l-tert-butyl-3- [(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-3,3-dimethyl-2,3- dihydro- l / / 6,2-benzothiazole-l , 1-dione (500 mg, 0.938 mmol) in formic acid (7 mL) was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum to give 5-({l-tert-butyl-3-[(lS,3R)-3- hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazole-l,l- dione (370 mg, 0.884 mmol, 94.2%) as a brown oil, which was used for next step without purification. LCMS: ESI m / z 419.2 [M + H]+.

[0343] Step G: (lR,3S)-3-{l-tert-butyl-5-[(3,3-dimethyl-l,l-dioxo-2,3-dihydro-lλΛ6,2- benzothiazol-5-yl)amino]-lH-pyrazol-3-yl} cyclopentyl 4-nitrophenyl carbonate To a solution of 5-({l-tert-butyl-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5-yl}amino)-3,3-dimethyl-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (370 mg, 0.884 mmol) and 4-nitrophenyl chloroformate (267 mg, 1.32 mmol) in THF (5 mL) and DCM (5 mL) was added pyridine (0.143 mL, 1.76 mmol) and DMAP (21.6 mg, 0.177 mmol). The reaction mixture was stirred at rt for 1 hour. The mixture was concentrated and the residue was purified by silica gel chromatography (2 g column) using 0 - 50% EtOAc / hexane to afford (lR,3S)-3-{l-tert-butyl-5-[(3,3-dimethyl-l,l-dioxo-2,3-dihydro- lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3-yl}cyclopentyl 4-nitrophenyl carbonate (380 mg, 0.651 mmol, 73.6%) as a brown solid. LCMS: ESI m / z 584.2 [M + H]1.

[0344] Step H: (lR,3S)-3-{5-[(3,3-dimethyl-l,l-dioxo-2,3-dihydro-llA6,2-benzothiazol-5- yl)amino]-lH-pyrazol-3-yl]cyclopentyI 4-nitrophenyl carbonate A solution of (lR,3S)-3-{l-tert- butyl-5-[(3,3-dimethyl-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-lH-pyrazol-3- yl} cyclopentyl 4-nitrophenyl carbonate (380 mg, 0.651 mmol) in formic acid (10 mL) was stirred at 100 °C for 10 hours. The cooled mixture was concentrated under vacuum to give (lR,3S)-3-{5-[(3,3- dimethyl-l , I -dioxo-2,3-dihydro-l / / 6,2-benzothiazol-5-yl)amino]-l H-pyrazol-3-yl] cyclopentyl 4- nitrophenyl carbonate (340 mg, 0.644 mmol, 98.9%) as a brown solid, which was used for next step without purification. LCMS: ESI m / z 528.2 [M + H]+.

[0345] Step I: (lR,3S)-3-(3-((3,3-dimethyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate To a solution of (lR,3S)-3-{5-[(3,3- dimethyl- 1 , 1 -dioxo-2,3-dihydro- 1 Z / 6,2-benzothiazol-5-yl )aminoj- lH-pyrazol-3-yl}cyclopentyl 4- nitrophenyl carbonate (150 mg, 0.284 mmol) in THF (10 mL) was added DIEA (0.141 mL, 0.853 mmol) and propan-2-amine (25.2 mg, 0.037 mL, 0.426 mmol). The mixture was stirred at 20 °C for 30 min and then concentrated. The residue was purified by prep-TLC (EA) to give (lR,3S)-3-(3- ((3,3-dimethyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate (46.1 mg, 0.103 mmol, 36.2%) as a white solid. LCMS: ESI m / z 448.2 [M + H]+.1HNMR (400 MHz, DMSO) 6 11.98 (s, 1H), 9.03 (s, 1H), 7.53 (d, J = 1.6 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.8, 1.6 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.69 (s, 1H), 5.00 (s, 1H), 3.58 (dd, J = 13.2, 6.4 Hz, 1H), 3.13 - 2.99 (m, 1H), 2.49-2.44 (m, 1H), 2.02 (dd, 1 = 15.6, 7.6 Hz, 1H), 1.96 - 1.83 (m, 1H), 1.78-1.70 (m, 2H), 1.68-1.59 (m, 1H), 1.47 (s, 6H), 1.03 (d, J = 6.4 Hz, 6H).

[0346] Step J: amino acetate To a solution of [(tert-butoxy)carbonyl] amino acetate (1.1 g, 6.27 mmol) in DCM (4 mL) was added trifluoromethanesulfonic acid (0.558 mL, 6.28 mmol) and the reaction mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under vacuum to give amino acetate (500 mg, 5.99 mmol, 95.4%) as a brown solid, which was used for the next step without purification.Example 14. (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4-fluoro-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0347] Step A: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yI)amino)-2-(4-methoxybenzyI)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-amine (300 mg, 0.889 mmol) in dioxane (2 m ) were added 5-bromo-2-[(4-methoxyphenyl)methyl]-2,3- dihydro-lλΛ6,2-benzothiazole- 1,1 -dione (392 mg, 1.06 mmol), [5-(diphenylphosphanyl)-9,9- dimethyl-9H-xanthen-4-yl]diphenylphosphane (103 mg, 0.178 mmol), CS2CO3 (290 mg, 0.889 mmol)and Pd2(dba)s (81.3 mg, 0.089 mmol), and the reaction was stirred at 90 °C under N2 for 18 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (3 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5-({l-tert-butyl-3-[(lS,3R)-3-[(tert- butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3- dihydro-lλΛ6,2-benzothiazole-l,l-dione (500 mg, 0.8 mmol, 90%) as a yellow oil. LC-MS (ESI): m / z 625.3 [M+H]+.

[0348] Step B: 5-((l-(tert-butyl)-4-fluoro-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 5- ({l-tert-butyl-3-[(lS,3R)-3-[(tert-butyldimethylsilyl)oxy]cyclopentyl]-lH-pyrazol-5-yl]amino)-2- [(4-methoxyphenyl)methyl]-2,3-dihydro- l / / 6,2-benzothiazole- 1 , 1-dione (300 mg, 0.48 mmol) in acetonitrile (10 mL) was added selectfluor (170 mg, 0.48 mmol). The reaction mixture was stirred at 60 °C for 1 hour. After completion, the solvent was removed on vacuum to give a residue, which was purified by flash column (PE / EA=5: 1) to afford title 5-({l-tert-butyl-4-fluoro-3-[(lS,3R)-3-hydroxy cyclopentyl]- 1 H-pyrazol-5-yl]amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro- 1 / / 6,2- benzothiazole- 1,1 -dione (40 mg, 0.076 mmol, 15.8%) as a yellow solid. LC-MS (ESI): m / z 529.2 [M+H]+.

[0349] Step C: (lR,3S)-3-(l-(tert-butyl)-4-fluoro-5-((2-(4-methoxybenzyl)-l,l-dioxido-2,3- dihydrobenzo[d]isothiazoI-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of 5-({l-tert-butyl-4-fluoro-3-[(lS,3R)-3-hydroxycyclopentyl]-lH-pyrazol-5- yl}amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lλΛ6,2-benzothiazole-l, 1-dione (40 mg, 0.076 mmol) in pyridine (5 rnL) were added 4-nitrophenyl chloroformate (23 mg, 0.113 mmol), the reaction was stirred at 50 °C for 3 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-100%] to afford the title compound (lR,3S)-3-[l-tert-butyl-4-fluoro-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-2,3- dihydro-lλΛ6,2-benzothiazol-5-yl]amino)-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.06 mmol, 80.0%) as a white solid. LC-MS (ESI): m / z 694.2 [M+H]+.

[0350] Step D: (lR,3S)-3-(5-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4- fluoro-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-[l-tert- butyl-4-fluoro-5-({2-[(4-methoxyphenyl)methyl]-l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5- yl}amino)-lH-pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (40 mg, 0.06 mmol) in HCOOH (10 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound (lR,3S)-3-{5-[(l,l-dioxo-2,3-dihydro-lλΛ6,2-benzothiazol-5-yl)amino]-4-fluoro-lH- pyrazol-3-yl] cyclopentyl 4-nitrophenyl carbonate (30 mg, 0.06 mmol, crude) as a white solid. LC- MS (ESI): m / z 518 [M+H]+.

[0351] Step E: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)amino)-4- fluoro-lH-pyrazol-5-yI)cyclopentyl isopropylcarbamate To a solution of (lR,3S)-3-{5-[(l,l- dioxo-2,3-dihydro-l / / 6,2-benzothiazol-5-yl)amino]-4-fluoro- 1 H-pyrazol-3-yl } cyclopentyl 4- nitrophenyl carbonate (30 mg, 0.06 mmol) in THF (2 mL) was added propan-2-amine (300 mg, 5.08 mmol) and the reaction was stirred at 25 °C for 2 hr. The reaction concentrated in vacuo. The residue was purified by prep-HPLC (FA condition) to afford the title compound (lR,3S)-3-{5-[(l,l-dioxo- 2, 3-dihydro- l / / 6,2-benzothiazol-5-yl)amino]-4-fluoro-l H-pyrazol-3-yl] cyclopentyl N-(propan-2- yl)carbamate (1.2 mg, 4.0%) as a white solid. LC-MS (ESI): m / z 438.2 [M+H]+.XH NMR (400 MHz, Methanol-rA) 5 7.51 (d, .7= 8.4 Hz, 1H), 7.17 (s, 2H), 5.10 (s, 1H), 4.34 (s, 2H), 3.79 - 3.62 (m, 1H), 3.25-3.15 (m, 1H), 2.61-2.52 (m, 1H), 2.23 - 1.80 (m, 5H), 1.31 (d, J= 6.4 Hz, 1H), 1.11 (d, J= 6A Hz, 6H).Example 15: (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-l)j6-benzothiophen-5-yI)ainino]-2H-pyrazol-3-yl] cyclopentyl (prop-2-ylamino)methanoate

[0352] Step A: 5-bromo-lX6-benzothiophene-l, 1-dione To a stirred solution of 5- bromobenzothiophene (2 g, 9.39 mmol) in DCM (16 mL) was added H2O2(4 mL, 39.2 mmol, 30% in H2O) and TFA (4 mL, 53.8 mmol) at rt. After stirred at rt for 5h, the mixture was poured into aqueous Na2S2O? and extracted with DCM (30 mL X 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40%, EA in PE) to give 5-bromo-lA,6-benzothiophene-l, 1-dione (1.7 g, 6.94 mmol, 73.9%) as a white solid.

[0353] Step B: 5-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-116-benzothiophene-l, 1-dione To a solution of 5-[(lS,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2- yl)pyrazol-3 -amine (300 mg, 0.889 mmol) was added 5-bromo-l / ,6-benzothiophene-l, 1-dione (191 mg, 0.779 mmol), Pd2(dba)3 (59.4 mg, 0.065 mmol), Xantphos (75.1 mg, 0.130 mmol) and CS2CO3 (529 mg, 1.62 mmol). The reaction was purged with N2 and stirred at 100 °C under N2 for 1.5 h. The reaction was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (2 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 5-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy } cy clopentyl]py razol-3 -yl] ammo } - 1 X6-benzothiophene- 1 , 1 -dione (350 mg, 0.559 mmol, 86.2%) as a yellow oil. LCMS: ESI m / z 626 [M +H]+.

[0354] Step C: 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yI)pyrazol-3- yl]amino)-3-methoxy-2,3-dihydro-1λ6-benzothiophene-l, 1-dione A mixture of 5-{[2-(2- methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3- yl]amino}-17,6-benzothiophene- 1, 1-dione (350 mg, 0.559 mmol) in HCOOH (4 mL) was stirred at RT overnight and then concentrated under reduced pressure. The residue was treated with a mixture of L1OH-H2O (0.062 mL, 2.24 mmol) in MeOH (2 mL) / H20 (2 mL). The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The following mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with ISfeSCL, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-80%, EA in PE) to give 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)- 3-methoxy-2,3-dihydro-l / / '-benzothiophene- 1, 1-dione (220 mg, 0.524 mmol, 93.8%) as a white solid. LCMS: m / z 420 [M+ H]+. 'H NMR (400MHz, DMSO) 5 8.24 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 6.80 (dd, J = 8.8, 2.0 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.99 (s, 1H), 5.07 (dd, J = 6.8, 3.6 Hz,lH), 4.56 (d, J = 4.4 Hz, 1H), 4.19-4.13 (m, 1H), 3.87 (dd, J = 13.6, 6.8 Hz, 1H), 3.47 (dd, J = 13.6, 3.6 Hz, 1H), 3.35 (s, 3H), 2.99 - 2.89 (m, 1H), 2.25-2.18 (m, 1H), 1.90 - 1.83 (m, 1H), 1.77 - 1.68 (m, 2H), 1.65 - 1.50 (m, 1H), 1.50 (s, 9H),.

[0355] Step D: (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5- yl)amino]-l-(2-methylprop-2-yl)pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate To a solution of 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3- methoxy-2,3-dihydro-1λ6-benzothiophene-l,l-dione (220 mg, 0.524 mmol) in THF (3 mL) and DCM (3 mL) were added 4-nitrophenyl chloromethanoate (317 mg, 1.58 mmol), DMAP (6.41 mg, 0.052 mmol) and Py (0.127 mL,1.57 mmol), the reaction was stirred at rt for 2h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-50%]. to afford the title compound (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3- dihydro-lA,6-benzothiophen-5-yl)amino]-l-(2-methylprop-2-yl)pyrazol-3-yl}cyclopentyl [(4- nitrophenyl)oxy]methanoate (210 mg, 0.359 mmol, 68.5%) as a white solid. LCMS: ESI 585 [M + H]+

[0356] Step E: (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5- yl)amino]-lH-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]methanoate A solution of(lR,3S)-3- { 5- [(3 -methoxy- 1 , 1 -dioxo-2,3 -dihydro- 1 Z6-benzothiophen-5 -yl)amino] - 1 -(2-methylprop-2- yl)pyrazol-3-yl} cyclopentyl [(4-nitrophenyl)oxy]methanoate (100 mg, 0.171 mmol) in HCOOH (2 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the titlecompound (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-lH- pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]methanoate (88 mg, 0.166 mmol, 97.4 %) as ayellow oil, which was used into next step without further purification. LCMS: ESI m / z 529 [M + H]+Step F: (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5-yl)amino]-2H- pyrazol-3-yl] cyclopentyl (prop-2-ylamino)methanoate

[0357] To a solution of (lR,3S)-3-{5-[(3-methoxy-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5- yl)amino]-lH-pyrazol-3-yl} cyclopentyl [(4-nitrophenyl)oxy]methanoate (88 mg, 0.166 mmol) in THF (2 mL) was added isopropylamine (0.043 mL, 0.499 mmol) and DIPEA (64.6 mg, 0.499 mmol) at rt. After stirred at rt for 30 min, the mixture was concentrated. The residue was purified by prep-HPLC (C18, 20 ~ 95 % MeCN in H2O with 0.1 % HCOOH) to (lR,3S)-3-{5- [(3 -methoxy- 1,1 -di oxo-2, 3-dihydro-l A.6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl] cyclopentyl (prop-2 -ylamino)methanoate (37.6 mg, 0.084 mmol, 50.4 %) as a white solid. LCMS: ESI m / z 449.2 [M+H]+. 1H NMR (4OO MHz, DMSO) 6 11.96 (s, 1H), 9.10 (s, 1H), 7.70 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.68 (s, 1H), 5.10 (dd, J = 6.8, 3.6 Hz, 1H), 5.00 (s, 1H), 3.88 (dd, J = 13.6, 6.8 Hz, 1H), 3.63-3.55 (m, 1H), 3.48 (dd, J = 13.6, 3.6 Hz, 1H), 3.39 (s, 3H), 3.10 - 3.00 (m, 1H), 2.48 - 2.42 (m, 1H), 2.02 (dd, J = 15.2, 7.6 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.76-1.53 (m, 3H), 1.03 (d, J = 6.4 Hz, 6H).Example 16: (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lX6-benzothiophen-5-yl)amino]-2H-pyrazol-3- yl] cyclohexyl (prop-2-ylamino)methanoate

[0358] Step A: 5-bromo-2,3-dihydro-lA6-benzothiophene-l, 1-dione To a solution of 5- bromo-l 6-benzothiophene-l, 1-dione (1.1 g, 4.49 mmol) in MeOH (50 mL) was added NaBFL (0.30g, 8.98 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the title compound 5-bromo-2,3-dihydro-l 6- benzothiophene- 1,1 -dione (1.1 g, 4.45 mmol, 99.2%) as a white solid. LCMS: m / z 247.11 [M+H]+.

[0359] Step B: 5-({5-[(ls,4s)-4-{[(2-methylprop-2-yI)diphenyIsilyl]oxy]cyclohexyI]-2-(2- inethylprop-2-yl)pyrazol-3-yl]amino)-2,3-dihydro-1 6-benzothiophene-l, 1-dione To a solution of 5-bromo-2,3-dihydro-lX6-benzothiophene-l, 1-dione (200 mg, 0.809 mmol) in dioxane (10 mL) were added 5-[(ls,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy]cyclohexyl]-2-(2-methylprop- 2-yl)pyrazol-3 -amine (385 mg, 0.809 mmol), CS2CO3 (791 mg, 2.43 mmol), Pd2(dba)s (74.1 mg, 0.081 mmol) and Xant-PHOS (93.7 mg, 0.162 mmol). The reaction was stirred at 100 °C under N2 for 3 hr. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the title compound 5-({5-[(ls,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2- yl)pyrazol-3-yl}amino)-2,3-dihydro-116-benzothiophene-l, 1-dione (240 mg, 0.374 mmol, 46.2%) as a yellow solid. LCMS: m / z 641.95 [M+H]+.

[0360] Step C: 5-({5-[(ls,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3- yl]amino)-2,3-dihydro-116-benzothiophene-l, 1-dione A solution of 5-({5-[(ls,4s)-4-{[(2- methylprop-2-yl)diphenylsilyl]oxy}cyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl]amino)-2,3- dihydro-lX6-benzothiophene-l,l-dione (240 mg, 0.374 mmol) in TBAF (5 mL, IM in THF) was stirred 70 °C overnight. The cooled reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with methanol in di chloroform (gradient: 0-10%) to afford the title compound 5-({5-[(ls,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl]amino)-2,3- dihydro-l 6-benzothiophene-l,l-dione (150 mg, 0.372 mmol, 99.4%) as ayellow oil. LCMS: m / z 403.0 [M+H]+.

[0361] Step D: (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lX6-benzothiophen-5-yI)amino]-l-(2- methylprop-2-yl)pyrazol-3-yl]cyclohexyl [(4-nitrophenyl)oxy]methanoate To a solution of 5- ({5-[(ls,4s)-4-hydroxycyclohexyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lA.6- benzothiophene- 1,1 -dione (180 mg, 0.446 mmol) in THF (5 mL) and DCM (5 mL) were added 4- nitrophenyl chloromethanoate (135 mg, 0.669 mmol), DMAP (5.45 mg, 0.045 mmol) and Py (70.6mg, 0.892 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaCl solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the title compound (ls,4s)-4-{5- [(l,l-dioxo-2,3-dihydro-lX6-benzothiophen-5-yl)amino]-l-(2-methylprop-2-yl)pyrazol-3- yl}cyclohexyl [(4-nitrophenyl)oxy]methanoate (120 mg, 0.211 mmol, 47.3%) as a yellow solid. LCMS: m / z 568.64 [M+H]1.

[0362] Step E: (lR,3S)-3-{5-[(4-methyI-l,l-dioxo-4H-116-benzo[2,l-e][l,2,4]thiadiazin-6- yl)amino]-2H-pyrazol-3-yl]cyclopentyI (prop-2-y!amino)methanoate A solution of (ls,4s)-4-{5- [(1,1 -dioxo-2,3 -dihydro- 1 / .6-benzothiophen-5-yl )amino]- 1 -(2-methylprop-2-yl)pyrazol-3 - yl} cyclohexyl [(4-nitrophenyl)oxy]methanoate (60 mg, 0.106 mmol) in formic acid (5 mL) was stirred at 100 °C overnight. The reaction was concentrated in vacuo to afford the title compound (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lX6-benzothiophen-5-yl)amino]-2H-pyrazol-3- yl}cyclohexyl [(4-nitrophenyl)oxy]methanoate (50 mg, 0.098 mmol, 92.5%) as a yellow oil. LCMS: m / z 512.54 [M+H]+.

[0363] Step F: (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lkt>-benzothiophen-5-yI)amino]-2H- pyrazol-3-yl] cyclohexyl (prop-2-ylamino)methanoate A solution of (ls,4s)-4-{5-[(l,l-dioxo-2,3- dihydro- l / .6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl [ cyclohexyl [(4- nitrophenyl)oxy]methanoate (50 mg, 0.098 mmol) in propan-2-amine (3 mL, 35.0 mmol) was stirred at room temperature for 1 hr. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC (C18, 0~70 % acetonitrile in H2O) to afford the title compound (ls,4s)-4-{5-[(l,l-dioxo- 2,3-dihydro-lA,6-benzothiophen-5-yl)amino]-2H-pyrazol-3-yl} cyclohexyl (prop-2- ylamino)methanoate (20.9 mg, 0.048 mmol, 49.5%) as a white solid. LCMS: m / z 432.54 [M+H]+. 'H NMR (400 MHz, DMSO) § 11.90 (s, 1H), 9.00 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 9.2 Hz, 1H), 6.88 (s, 1H), 5.67 (s, 1H), 4.75 (s, 1H), 3.63-3.50 (m, 1H), 3.47 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 2.68 (s, 1H), 1.83-1.75 (m, 4H), 1.75-1.58 (m, 4H), 1.05 (d, J = 6.4 Hz, 6H).Example 17: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol- 5-yl)cydopentyl isopropylcarbamate

[0364] Step A: 5-bromo-2-methylbenzenesulfonamide To a solution of 5-bromo-2- methylbenzenesulfonyl chloride (3.70 g, 13.7 mmol) in THF (50 mL) was added NH? MeOH (2 mol / L, 108 mL, 216 mmol) and the mixture was stirred at room temperature for 1 hr. The reaction was complete detected by LCMS. The reaction mixture was concentrated to afford 5-bromo-2- methylbenzenesulfonamide (3.30 g, 13.2 mmol, 96.0 %) as a white solid. LCMS: ESI m / z 251.12 [M+H]+.

[0365] Step B: 5-bromo-2-(bromomethyl)benzenesulfonamide To a solution of 5-bromo-2- methylbenzenesulfonamide (3.30 g, 13.2 mmol) in CCI4 (40 mL) was added NBS (3.52 g, 19.7 mmol) and BPO (1.60 g, 6.60 mmol) and the mixture was stirred at 80 °C for 2 hrs. The reaction was complete detected by TLC. The reaction mixture was dissolved in EA (50 mL), washed with H2O (20 mL) and brine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-30% EA in PE) to afford 5-bromo-2- (bromomethyl)benzenesulfonamide (2.90 g, 8.81 mmol, 67.6%) as a white solid.

[0366] Step C: 6-bromo-2,3-dihydrobenzo[d]isothiazoIe 1,1-dioxide To a solution of 5- bromo-2-(bromomethyl)benzenesulfonamide (2.90 g, 8.81 mmol) in MeOH (45 mL) and H2O (11.3 mL) was added NaOH (0.710 g, 17.6 mmol) and the mixture was stirred at room temperature for 3 hrs. The reaction was complete detected by LCMS. The reaction mixture was concentrated in vacuoand purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford 6-bromo-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (880 mg, 3.55 mmol, 40.2%) as a white solid. LCMS: ESI m / z 248.10 [M + H]+.

[0367] Step D: 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (450 mg, 1.81 mmol) in DMF (10 mL) was added PMBC1 (426 mg, 2.72 mmol) and CS2CO3 (1.18 mg, 3.63 mmol) and the mixture was stirred at room temperature for 3 hrs. The reaction was complete detected by LCMS. The reaction mixture was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% EA in PE) to afford 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.679 mmol, 37.4%) as a faint yellow solid. LCMS: ESI m / z 368.25 [M + H]+.

[0368] Step E: 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide To a solution of 6-bromo-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (250 mg, 0.679 mmol) in dioxane (8 mL) was added l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-amine (150 mg, 0.325 mmol), CS2CO3 (317 mg, 0.975 mmol), Pd2(dba)s (29.8 mg, 0.0320 mmol) and Xantphos (37.6 mg, 0.065 mmol). The reaction mixture was stirred at 100 °C under N2 atmosphere for 1 hr. The reaction was complete detected by LCMS. The cooled reaction mixture was dissolved in EA (50 mL), washed with H2O (20 mL) and brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% EA in PE) to afford 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (150 mg, 0.200 mmol, 61.6%) as a white solid. LCMS: ESI m / z 749.06 [M + H]+.

[0369] Step F: 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide A solution of 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4- methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (150 mg, 0.200 mmol) in formic acid (2 mL) was stirred at 50 °C for 5 hrs. The reaction was complete detected by TLC. The solvents were removed under vacuum. Then add EtOH (2 mL), H2O (2 mL) and Lithium Hydroxide Monohydrate (25.2 mg, 0.601 mmol) to alkaline pH. The reaction mixture was stirred at room temperature for 1 hr. LCMS showed the reaction was completed. The reaction mixture was dissolved in EA (50 mL),washed with H2O (10 mL) and shrine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA in PE) to afford 6-((l-(tert- butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4-methoxybenzyl)-2,3- dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.196 mmol, 97.8%) as a faint yellow oil. LCMS: ESI m / z 511.65 [M + H]+.

[0370] Step G: (lR,3S)-3-(l-(tert-butyl)-5-((2-(4-methoxybenzyl)-l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonateA suspension of 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-2-(4- methoxybenzyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (100 mg, 0.196 mmol), DMAP (2.39 mg, 0.0200 mmol), Py (0.0480 mL, 0.588 mmol) and 4-nitrophenyl chloromethanoate (198 mg, 0.980 mmol) in DCM (2 mL) and THF (2 mL) was stirred at room temperature for 3 hrs. The solvents were removed under vacuum. The residue was dissolved in EA (50 mL), washed with H2O (5 mL) andbrine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-80% EA in PE) to afford (lR,3S)-3-(l-(tert-butyl)-5-((2-(4- methoxybenzyl )-l,l -dioxi do-2, 3-dihydrobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol-3- yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg, 0.148 mmol, 75.6%) as a faint yellow oil. LCMS: ESI m / z 676.76 [M+H]+.

[0371] Step H: (lR,3S)-3-(5-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-6-yl)amino)-lH- pyrazol-3-yI)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-(l-(tert-butyl)-5-((2- (4-methoxybenzyl)-l, 1 -dioxi do-2, 3-dihy drobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol-3- yl)cyclopentyl (4-nitrophenyl) carbonate (100 mg, 0.148 mmol) was dissolved in formic acid (2 mL) and stirred at 100 °C overnight. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated to give (lR,3S)-3-(5-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-6- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate(70.0 mg, 0.140 mmol, 94.7%) as a yellow oil. LCMS: ESI m / z 500.50 [M+H]+.

[0372] Step I: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[d]isothiazoI-6-yl)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate To a suspension of (lR,3S)-3-(5-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate(70.0 mg, 0.140 mmol) in THE (2 mL) was added propan-2-amine (0.0360 mL, 0.420 mmol) and DIEA (0.0690 mL, 0.420 mmol). The reaction mixture was stirred at room temperature for 2 hrs. LCMS showed the reaction had been completed. The reaction mixture was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated. The residue waspurified by silica gel chromatography (eluting with 12% MeOH in DCM) and pre-HPLC (Cl 8, 15 - 95 % MeCN in H2O with 0.1 % FA) to afford (lR,3S)-3-(3-((l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-6-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate (2.00 mg, 0.00500 mmol, 3.40%) as a white solid. LCMS: ESI m / z 420.50 [M+H]+. 'H NMR (400 MHz, DMSO) 5 8.90 (s, 1H), 7.97 (s, 1H), 7.62 (br s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 6.8 Hz, 1H), 5.65 (s, 1H), 5.00 (s, 1H), 4.27 (s, 2H), 3.11 - 3.05 (m, 1H), 2.48 - 2.40 (m, 1H), 2.04 - 1.89 (m, 2H), 1.77 - 1.53 (m, 3H), 1.04 (d, J = 6.0 Hz, 6H).Example 18: (lR,3S)-3-(3-((4-methyl-l,l-dioxido-3-oxo-3,4-dihydro-2H- benzo[e][l,2,4]thiadiazin-6-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0373] Step A: 4-bromo-2-(methylamino)benzene-l-sulfonamide To a solution of 4-bromo- 2-fluorobenzene-l -sulfonamide (300 mg, 1.2 mmol) in 1,4-dioxane (4 mL) were added CH3NH2 (3 mL, 2M in THF). The reaction was stirred at 100 °C in a sealed tube for 18 h. TLC and LCMS indicated the reaction was over. The cooled reaction mixture was concentrated and the residue was purified by a silica gel column chromatography eluted with ethyl acetate in petroleum ether (gadient: 0-30%) to afford the title compound 4-bromo-2-(methylamino)benzene-l -sulfonamide (260 mg, 1.0 mmol, 83.0%) as a yellow solid. LCMS m / z: 266 [M + H]+

[0374] Step B: 4-({5-[(lS,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2- methylprop-2-yl)pyrazol-3-yl}amino)-2-(methylamino)benzene-l-sulfonamide To a solution of 4-bromo-2-(methylamino)benzene- 1 -sulfonamide (210 mg, 0.792 mmol), 5-[(lS,3R)-3- {[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (268 mg, 0.8 mmol), Xantphos (68 mg, 0.12 mmol) and CS2CO3 (774 mg, 2.4 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (72 mg, 0.08 mmol). The reaction was stirred at 100 °C underN2 atmosphere for 5h. TLC and LCMS indicted the reaction was over. The cooled reaction mixture was poured into ice-water, adjust pH to 5-6 with IN HC1, extracted with EA (20 mL*3), the combined organic layer was washed with brine, dried over Na2SC>4, fdtered and concentrated. The residue was purified by a silica column eluted with PE: EA (gradient: 0~ 50%) to give the desire product 4-({5-[(lS,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy]cyclopentyl]-2-(2-methylprop-2- yl)pyrazol-3-yl}amino)-2-(methylamino)benzene-l-sulfonamide (130 mg, 0.25 mmol, 31%) as a yellow solid. LCMS m / z:522 [M + H]1

[0375] Step C: 6-({5-[(lS,3R)-3-{[dimethyI(2-methylprop-2-yl)silyl]oxy]cyclopentyl]-2-(2- methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-lX6-benzo[2,l- e][l,2,4]thiadiazine-l, 1-dione To a solution of 4-({5-[(lS,3R)-3-{[dimethyl(2-methylprop-2- yl)silyl]oxy } cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3 -yl } amino)-2-(methylamino)benzene- 1 - sulfonamide (430 mg, 0.8 mmol) in DMF (10 mL) was added NaH (165 mg, 4.1 mmol, 60% in mineral oil) at 0 °C and the reaction was stirred for 30 min. Triphosgene (244 mg, 0.8 mmol) was added into the reaction and the reaction was stirred at room temperature overnight. The reaction was poured into ice-water and adjust pH to 5-6 with IN HC1, extracted with EA, the organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with methanol in dichloroform (gadient: 0-10%) to afford the title compound 6-({5-[(lS,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2- methylprop-2-yl)pyrazol -3 -yl } amino)-4-methyl -3 -oxo-3 ,4-dihy dro-2H- 1 X6-benzo[2, 1 - e] [1,2, 4]thiadiazine- 1,1 -dione (280 mg, 0.5 mmol, 62%) as a gray solid. LCMS m / z:548 [M + H]+.

[0376] Step D: 6-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3- yl]amino)-4-methyl-3-oxo-3,4-dihydro-2H-1λ6-benzo[2,l-e] [1,2, 4]thiadiazine-l, 1-dione A solution of 4-methyl-6-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy]cyclopentyl]pyrazol-3-yl]amino}-3-oxo-3,4-dihydro-2H-lX6-benzo[2,l- e][l,2,4]thiadiazine-l,l-dione (300 mg, 0.45 mmol) in HCOOH (4 mL) was stirred at room temperature for 18 hr. The reaction was concentrated and the residue was dissolved in 10ml THF and H2O (1 : 1). LiOH was added and stirred for another 30min. The reaction was adjusted pH to 5-6 with IN HC1, extracted with EA. The combined organic layer was separated, washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with methanol in dichloroform (gradient: 0-10%) to afford the title compound 6-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl]amino)-4-methyl-3-oxo-3,4-dihydro-2H-176-benzo[2,l-e][l, 2, 4]thiadiazine-l, 1-dione (180 mg, 0.4 mmol, 93%) as a gray solid. LCMS m / z:434 [M + H]+.

[0377] Step E: (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(4-methyl-l,l,3-trioxo-3,4-dihydro-2H- 176-benzo[2,l-e][l,2,4]thiadiazin-6-yl)amino]pyrazol-3-yl]cyclopentyI [(4- nitrophenyl)oxy]methanoate To a solution of 6-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2- methylprop-2-yl)pyrazol-3-yl}amino)-4-methyl-3-oxo-3,4-dihydro-2H-116-benzo[2,l- e][l,2,4]thiadiazine-l,l-dione (200 mg, 0.46 mmol) and DMAP (6 mg, 0.05 mmol) in pyridine (4 mL) were added 4-Nitrophenyl chloroformate (139 mg, 0.7 mmol), and the reaction was stirred at 60 °C for 18 hr. TLC and LCMS indicated the reaction was over. The cooled reaction mixture was concentrated. The residue was dissolved in EA, washed with brine, dried over Na2SC>4, filtered and concentrated, the residue was purified by silica gel column chromatography eluted with methanol in dichloroform (gradient: 0~ 10%) to afford the title compound (lR,3S)-3-[l-(2- methylprop-2-yl)-5-[(4-methyl-l, l,3-trioxo-3,4-dihydro-2H-lX6-benzo[2,l-e][l, 2, 4]thiadi azin-6- yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate (80 mg, 0.13mmol, 29%) as a gray solid. LCMS m / z: 599 [M + H]+.

[0378] Step F: (lR,3S)-3-{5-[(4-methyI-l,l,3-trioxo-3,4-dihydro-2H-116-benzo[2,l- e] [ 1,2,4] thiadiazin-6-yl)amino] - IH-py razol-3-yl] cyclopentyl [(4-nitrophenyI)oxy ] methanoate A solution of (lR,3S)-3-[l -(2-methylprop-2-yl)-5 -[(4-methyl- 1,1,3 -trioxo-3 ,4-dihy dro-2H- 17.6- benzo[2, 1 -e] [ 1 ,2,4]thiadiazin-6-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate (80 mg, 0.13mmol) in HCOOH (5 mL) was stirred at 100 °C at N2 atmosphere for 16h. LCMS showed ok. The reaction solution was concentrated to give (lR,3S)-3-{5-[(4-methyl-l,l,3-trioxo-3,4- dihydro-2H-17,6-benzo[2, 1 -e][l, 2, 4]thiadiazin-6-yl)amino]-lH-pyrazol-3-yl} cyclopentyl [(4- nitrophenyl)oxy]methanoate (60 mg, 0.11 mmol, 83%) as yellow solid which was used directly for next step without purification. LCMS m / z: 543 [M + H]+.

[0379] Step G: (lR,3S)-3-{5-[(4-methyl-l,l,3-trioxo-3,4-dihydro-2H-lX6-benzo[2,l- e][l,2,4]thiadiazin-6-yl)amino]-lH-pyrazoI-3-yl}cyclopentyl (prop-2-ylamino)methanoate To a solution of (lR,3S)-3-{5-[(4-methyl-l,l,3-trioxo-3,4-dihydro-2H-lX6-benzo[2,l-e][l,2,4]thiadiazin- 6-yl)amino]-lH-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]methanoate (100 mg, 0.18 mmol) in THF (3 mL) was added isopropylamine (3 mL). The reaction was stirred at room temperature for 1 hr. The reaction mixture was concentrated and the residue was purified by prep- HPLC to afford the title compound (lR,3S)-3-{5-[(4-methyl-l,l,3-trioxo-3,4-dihydro-2H-17,6- benzo[2,l-e][l, 2, 4]thiadiazin-6-yl)amino]-lH-pyrazol-3-yl} cyclopentyl (prop-2 -ylamino)methanoate(10.4 mg, 0.02 mmol, 12%) as an off-white solid. LCMS m / z: 463 [M + H]+.JH NMR (400 MHz, DMSO) 8 11.99 (s, 1H), 8.91 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.31 - 6.92 (m, 4H), 5.74 (s, 1H), 5.05 (s, 1H), 3.64 (d, J = 6.4 Hz, 1H), 3.33 (s, 3H), 3.15 - 3.05 (m, 1H), 2.52 - 2.44 (m, 1H), 2.10-2.05(m, 1H), 2.01 - 1.90 (m, 1H), 1.80-1.65 (m, 3H), 1.09 (d, J = 6.4 Hz, 6H).Example 19: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-lH-pyrazol-5-yl)cycIopentyl isopropylcarbamate

[0380] Step A: 6-bromobenzo[b] thiophene 1,1-dioxide To a solution of 6- bromobenzothiophene (2.0 g, 9.39 mmol) in DCM (15 mL) was added H2O2 (4 mL, 39.2 mmol, 30% in H2O) and TFA (4 mL, 53.8 mmol). The mixture was stirred at 20 °C for 5 hours. The mixture was purified by silica gel chromatography (20 g column) using 0 - 30% EtOAc / hexane. The productcontaining fractions were concentrated to afford 6-bromobenzo[b]thiophene 1,1-dioxide (2.1 g, 8.57 mmol, 91%) as a white solid.

[0381] Step B: 6-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide To a solution of 6- bromo-lA6-benzothiophene-1, 1-dione (1.0 g, 4.08 mmol) in MeOH (30 mL) was added NaBJL (300 mg, 8.98 mmol) and the mixture was stirred at 20 °C for 2 hours and then concentrated. The residue was purified by silica gel chromatography (10 g column) using 0 - 40% EtOAc / hexane. The productcontaining fractions were concentrated to afford 6-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (900 mg, 3.64 mmol, 89%) as a white solid.

[0382] Step C: 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yl)amino)-2,3-dihydrobenzo[b] thiophene 1,1-dioxide To a solution of 6-bromo-2,3- dihydro-16-benzo thiophene- 1, 1-dione (300 mg, 1.214 mmol) and 2-(2-methylprop-2-yl)-5- [(lS,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (616 mg, 1.34 mmol) inl,4-dioxane (8 mL) was added CS2CO3 (791 mg, 2.43 mmol). Then Pd2(dba)s (111 mg, 0.121 mmol) and Xantphos (140 mg, 0.24 mmol) was added into the mixture and the mixture wasstirred at 100 °C under N2 for 5 hours. The mixture was purified by silica gel chromatography (2 g column) using 0 - 50% EtOAc / hexane. The product-containing fractions were concentrated to afford 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5- yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (530 mg, 0.84 mmol, 69%) as a brown solid. LCMS: ESI m / z 628.4 [M + H]+

[0383] Step D: 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- 2,3-dihydrobenzo[b]thiophene 1,1-dioxide A solution of 6-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3- {[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ6- benzothiophene- 1,1 -dione (520 mg, 0.83 mmol) in formic acid (4 mL) was stirred at 20 °C for 30 min. The mixture was concentrated under vacuum to remove formic acid to give a crude, which was added MeOH (3 mL) and LiOH (100 mg) was stirred at 20 °C for 30 min. The reaction mixture was concentrated under vacuum and poured into EA (30 mL), extracted with water. The organic layer was concentrated to give 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (270 mg, 0.69 mmol, 84%) as a brown solid. LCMS: ESI m / z 390.2 [M + H]+

[0384] Step E: (lR,3S)-3-(l-(tert-butyl)-5-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a solution of 6-({5- [(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-1λ6- benzothiophene-1, 1-dione (270 mg, 0.69 mmol) in DCM (3 mL) and THF (3 mL) was added 4- nitrophenyl chloromethanoate (210 mg, 1.04 mmol). Then pyridine (0.11 mL, 1.39 mmol) and DMAP (17 mg, 0.14 mmol) was added. The reaction mixture was stirred at 20 °C for 1 hours. The mixture was purified by silica gel chromatography (2 g column) using 0 - 50% EtOAc / hexane. The product-containing fractions were concentrated to afford (lR,3S)-3-(l-(tert- butyl)-5-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4- nitrophenyl) carbonate (160 mg, 0.29 mmol, 42%) as a brown solid. LCMS: ESI m / z 555.2 [M + H]+

[0385] Step F: (lR,3S)-3-(l-(tert-butyl)-3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6- yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate To a solution of (1R,3 S)-3 - { 5-[(l , 1 - dioxo-2, 3-dihy dro- IX6-benzo [b]thiophen-6-yl)amino]-l-(2-methylprop-2-yl)pyrazol-3- yl} cyclopentyl [(4-nitrophenyl)oxy]methanoate (100 mg, 0.18 mmol) in THF (5 mL) was added DIEA (0.045 mL, 0.27 mmol). Then propan-2-amine (0.09 mL, 1.10 mmol) was added into the mixture dropwise and the mixture was stirred at 20 °C for 2 hours and then concentrated. The residue was purified by silica gel chromatography to give (lR,3S)-3-(l-(tert-butyl)-3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate (70 mg, 0.15 mmol, 82%) as a yellow oil. LCMS: ESI m / z 475.2 [M + H]+

[0386] Step G: (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate A slution of (lR,3S)-3-{5-[(l,l-dioxo-2,3-dihydro- IX6-benzo[b]thiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl] cyclopentyl (prop-2- ylamino)methanoate (70 mg, 0.15 mmol) in formic acid (4 mL) was stirred at 100 °C for 12 hours. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give (lR,3S)-3-(3-((l,l-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate (16.3 mg, 0.04 mmol, 26%) as a white solid. LCMS: ESI m / z 419.2 [M + H]+.1HNMR (400 MHz, DMSO) 5 11.81 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.38 (d, J= 8.4 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 6.95 (d, J= 9.6 Hz, 1H), 5.61 (s, 1H), 5.07 - 4.93 (m, 1H), 3.64 - 3.55 (m, 1H), 3.52 (t, J= 6.8 Hz, 2H), 3.20 (t, J= 6.8 Hz, 2H), 3.12 - 2.99 (m, 1H), 2.48 - 2.40 (m, 1H), 2.07 - 1.97 (m, 1H), 1.97 - 1.84 (m, 1H), 1.80 - 1.66 (m, 2H), 1.66 - 1.53 (m, 1H), 1.03 (d, J= 6.4 Hz, 6H).Example 20: (lR,3S)-3-{5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-2H-pyrazol-3- yl] cyclopentyl (prop-2-ylamino)methanoate

[0387] Step A: 5-bromo-2-(bromomethyl)benzoate To a solution of methyl 5-bromo-2- methylbenzoate (3 g, 13.1 mmol) in CCI4 (30 mL) was added NBS (3.50 g, 19.6 mmol) and BPO (1.59 g, 6.55 mmol). The reaction mixture was stirred at 80 °C for 6 h. The cooled reaction mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash columnchromatography with 0-10% ethyl acetate in petroleum ether to afford crude methyl 5-bromo-2- (bromomethyl)benzoate (3 g, 9.74 mmol, 74.4%) as a white solid.Step B: 6-bromo-2- [(4-methoxy henyl)methyl] -2,3-dihy dro- IH-isoindol- 1-one

[0388] To a solution of methyl 5-bromo-2-(bromomethyl)benzoate (3 g, 9.74 mmol) in THF (30 mL) was added (4-methoxyphenyl)methanamine (1.40 mL, 10.7 mmol). The reaction mixture was stirred at 80 °C for 2 h. The cooled reaction mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography with 0-50% ethyl acetate in petroleum ether to afford 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (2 g, 6.02 mmol, 61.8%) as a white solid. LCMS: ESI m / z 332 [M + H]+

[0389] Step C: 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2- methylprop-2-yl)diphenylsi!yI] oxy} cyclopentyl] pyrazoI-3-yl] amino}-2,3-dihydro- IH-isoindol- 1- one To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (258 mg, 0.779 mmol) in dioxane (10 mL) was added 2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2- methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-amine (300 mg, 0.650 mmol), CS2CO3 (529 mg, 1.62 mmol), xantphos (75.2 mg, 0.130 mmol) and XantPhos Pd G4 (62.6 mg, 0.065 mmol), and the reaction was purged with N2 and stirred at 100 °C under N2 overnight. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (2 / 1) The organic layer was collected, concentrated in vacuo, and dried to afford the title compound 2-[(4-methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5- [(lS,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino} -2,3-dihy dro- IH-isoindol-l-one (420 mg, 0.589 mmol, 90.7%) as a yellow oil. LCMS: ESI m / z 713 [M + H]+.

[0390] Step D: 6-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3- yl]amino)-2-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one A mixture of 2-[(4- methoxyphenyl)methyl]-6-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-lH-isoindol-l-one (420 mg, 0.589 mmol) in HCOOH (6 mL) was stirred at RT overnight and then concentrated under reduced pressure. The residue was treated with a mixture of L1OH-H2O (0.065 mL, 2.36 mmol) in MeOH (3 mLyiLO (3 mL). The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The following mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue waspurified by chromatography (silica gel, 0-70%, EA in PE) to give 6-({5-[(lS,3R)-3- hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl]amino)-2-[(4-methoxyphenyl)methyl]-2,3- dihydro-lH-isoindol-l-one (210 mg, 0.442 mmol, 75.1%) as a white solid. LCMS: ESI m / z 475 [M+ H]+.

[0391] Step E: (lR,3S)-3-[5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-isoindol- 5-yl] amino)- l-(2-methylprop-2-yl)pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate To a solution of 6-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2- [(4-methoxyphenyl)methyl]-2,3-dihydro-lH-isoindol-l-one (210 mg, 0.442 mmol) in THF (2.5 mL) and DCM (2.5 mL) were added 4-nitrophenyl chloromethanoate (267 mg, 1.33 mmol), DMAP (5.40 mg, 0.044 mmol) and Py (0.107 mL, 1.326 mmol), the reaction was stirred at rt for 2h. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-50%]. to afford the title compound (lR,3S)-3- [5-({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-isoindol-5-yl]amino)-l-(2-methylprop-2- yl)pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate (160 mg, 0.250 mmol, 56.5%) as a white solid. LCMS: ESI 640[M + H]+

[0392] Step F: (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-lH-isoindol-5- yl)amino] pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate A solution of (lR,3S)-3-[5- ({2-[(4-methoxyphenyl)methyl]-3-oxo-2,3-dihydro-lH-isoindol-5-yl}amino)-l-(2-methylprop-2- yl)pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate (60 mg, 0.09mmol) in HCOOH (4 mL) and TfOH (0.4 mL) was stirred at 80 °C at N2 atmosphere for 2 hours. LCMS showed 50% desire product was found. The reaction was concentrated to give a crude desire product (lR,3S)-3-[l- (2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4- nitrophenyl)oxy]methanoate (60 mg, 0.08 mmol, -50% purity, yield 61%) as a gray solid which was used directly for next step without purification. LCMS: ESI 520 [M + H]+

[0393] Step G: (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-lH-isoindol-5- yl)amino]pyrazol-3-yl] cyclopentyl (prop-2-ylamino)methanoate To a solution of ((lR,3S)-3-[l- (2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4- nitrophenyl)oxy]methanoate (80 mg, 0.125 mmol) in THF (3 mL) was added isopropylamine (3 mL). The reaction solution was stirred at room temperature for Ih. LCMS showed the reaction was over. The reaction mixture was concentrated and purified by silica gel column chromatography eluted with EA in PE [gradient: 0-100%] to give (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl (prop-2-ylamino)methanoate (40 mg, 0.09 mmol, 72.8%) as a yellow solid. LCMS: ESI 440 [M + H]+

[0394] Step H: (lR,3S)-3-{5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-2H-pyrazol-3- yl] cyclopentyl (prop-2-ylamino)methanoate A solution of (lR,3S)-3-[l-(2-methylprop-2-yl)-5- [(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]pyrazol-3-yl]cyclopentyl (prop-2-ylamino)methanoate (40 mg, 0.09 mmol) in HCOOH (4 mL) was stirred at 100 °C for 16 h. The cooled reaction mixture was concentrated. The residue was purified by prep-HPLC to afford the title compound (lR,3S)-3- {5-[(3-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-2H-pyrazol-3-yl} cyclopentyl (prop-2- ylamino)methanoate (1.3 mg, 0.003 mmol, 3.7%) as a white solid. LCMS: ESI 384[M + H]+.1HNMR (400 MHz, DMSO) 8 11.73 (s, 1H), 8.50 (s, 1H), 8.36 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.94 (s, 1H), 5.63 (s, 1H), 5.01 (s, 1H), 4.24 (s, 2H), 3.63-3.55 (m, 1H), 3.11-3.03 (m, 1H), 2.51-2.43 (m, 1H), 2.08-1.97 (m, 1H), 1.97-1.84 (m, 1H), 1.84-1.61 (m, 3H), 1.04 (d, J = 6.4 Hz, 6H).Example 21 : (lR,3S)-3- {5- [(3,3-dimethyl- l,l-dioxo-2,3-dihydro- 1λ6-benzothiophen-5- yl)amino]-2H-pyrazol-3-yl}cyclopentyl (prop-2-ylamino)methanoate

[0395] Step A: l-[(4-bromophenyl)sulfanyl]-2-methylpropan-2-ol To a solution of compound 4-bromobenzene-l -thiol (10 g, 52.9 mmol) in DMF (100 mL) was added 2,2- dimethyloxirane (5.19 mL, 58.2 mmol) and K2CO3 (10.9 g, 79.3 mmol). The resulting reaction solution was stirred at 20 °C for 0.5 hours. The reaction was quenched by the addition of saturated sodium chloride solution (500 mL) and then extracted with ethyl acetate (300 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (100 mL x 3), dried overanhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100-0%) to give compound l-[(4-bromophenyl)sulfanyl]-2-methylpropan-2-ol (10 g, 38.288 mmol, 72.39%) as a colorless oil. 'H NMR (400 MHz, DMSO) 5 7.46 (d, J= 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.68 (s, 1H), 3.04 (s, 2H), 1.19 (s, 6H).

[0396] Step B: 5-bromo-3,3-dimethyI-2,3-dihydrobenzothiophene To a suspension of aluminum chloride (7.66 g, 57.432 mmol) in carbon disulfide (100 mL) was added a solution of 1- [(4-bromophenyl)sulfanyl]-2-methylpropan-2-ol (5 g, 19.144 mmol) in 100 mL of a carbon disulfide solution at -10°C. The resulting reaction solution was stirred at 50 °C for 0.5 hours and then cooled to 0 °C. IN Dilute hydrochloric acid was added to the reaction system, followed by extraction with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was separated and purified by column chromatography (petroleum ether / ethyl acetate= 100-0%) to give compound 5-bromo-3,3-dimethyl-2,3-dihydrobenzothiophene (1 .2 g, 4.935 mmol, 25.78%) as a yellow oil. 'H NMR (400 MHz, CDCh) 8 7.24 (dd, .7= 8.0, 2.0 Hz, 1H), 7.16 (d, J= 2.0 Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 3.20 (s, 2H), 1.39 (d, J= 4.4 Hz, 6H).

[0397] Step C: 5-bromo-3,3-dimethyI-2,3-dihydro-lk4-benzothiophen-l-one To a solution of 5-bromo-3,3-dimethyl-2,3-dihydrobenzothiophene (1 g, 4.1 mmol) in 1 ,2-di chloroethane (10 mL) was added slowly acetic acid (0.825 mL, 14.4 mmol) and H2O2 (1 mL, 30 wt % in H2O, 9.8 mmol). The reaction mixture was stirred at 40 °C for 3.5 hours. Ice water was added to the reaction mixture, and then Na2S20s (aqueous) was added. The following mixture was extracted with ethyl acetate, washed with a sodium carbonate aqueous solution twice, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography to 5-bromo-3,3-dimethyl-2,3-dihydro-lX4-benzothiophen-l-one (500 mg, 1.929 mmol, 46.91%) as a white solid. LCMS: ESI m / z 259 [M + H]+.

[0398] Step D: 5-bromo-3,3-dimethyl-2,3-dihydro-1λ6-benzothiophene-l, 1-dione To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-lX4-benzothiophen-l-one (500 mg, 1.929 mmol) in DCM (10 mL) was added 85% 3 -chlorobenzene- 1 -carboperoxoic acid (832 mg, 4.82 mmol) at 0 °C. The reaction mixture was stirred at 5-15 °C for 3 hr. The reaction mixture purified by silica gel column chromatograph to afford the title compound 5-bromo-3,3-dimethyl-2,3-dihydro- I6-benzothiophene- 1,1 -dione (300 mg, 1.09 mmol, 56.5%) as a white solid. LCMS: ESI m / z 275 [M + H]+.

[0399] Step E: 3,3-dimethyI-5-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yI]amino}-2,3-dihydro-1λ6-benzothiophene-l,l- dione To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-lA6-benzothiophene-l, 1-dione (300 mg, 1.090 mmol) in dioxane (10 mL) were added 2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2- yl)diphenylsilyl]oxy]cyclopentyl]pyrazol-3-amine (503 mg, 1.09 mmol), CS2CO3 (710.47 mg, 2.18 mmol), Xant-PHOS (126 mg, 0.218 mmol) and Pd2(dba)s (99.8 mg, 0.109 mmol). The reaction mixture was stirred at 100 °C under N2 overnight. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford the title compound 3,3-dimethyl-5-{[2-(2-methylprop-2-yl)-5-[(lS,3R)-3- {[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol-3-yl]amino}-2,3-dihydro-1λ6- benzothiophene- 1,1 -dione (500 mg, 0.762 mmol, 69.9%) as a yellow oil. LCMS: ESI m / z 656 [M + H]+.

[0400] Step F: 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3- yl]amino)-3,3-dimethyl-2,3-dihydro-1λ6-benzothiophene-l, 1-dione A mixture of 3,3-dimethyl-5- {[2-(2-methylprop-2-yl)-5-[(lS,3R)-3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl]pyrazol- 3-yl]ammo}-2,3-dihydro- l / .6-benzothiophene- 1 , 1-dione (500 mg, 0.762 mmol) in formic acid (3 mL) was stirred at RT for 1 h and then concentrated under reduced pressure. The residue was treated with a mixture of lithium hydroxide hydrate (31.98 mg, 0.762 mmol) in MeOH (3.00 mLyEEO (0.30 mL). The resulting mixture was stirred at rt for 2 h, the mixture was concentrated under reduced pressure. The mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2- methylprop-2-yl)pyrazol-3-yl]amino)-3,3-dimethyl-2,3-dihydro-1λ6-benzothiophene-l,l -dione (280 mg, 0.671 mmol, 87.97%) as a colorless oil. LCMS: ESI m / z 418 [M + H]+.

[0401] Step G: (lR,3S)-3-{5-[(3,3-dimethyl-l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-5- yl)amino]-l-(2-methylprop-2-yl)pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate To a solution of 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-3,3- dimethyl-2, 3 -dihydro- 1 / .fi-benzothiophene- 1,1 -dione (300 mg, 0.718 mmol) in DCM (5 mL) and THF (5 mL) were added 4-nitrophenyl chloromethanoate (289 mg, 1.44 mmol), Py (0.174 mL, 2.15 mmol) and DMAP (8.78 mg, 0.072 mmol). The reaction mixture was stirred under at 25 °C for 2 hr. The reaction solution was diluted with EA, washed with water and brine, dried over1λ6

[0404] Step A: 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH- pyrazol-5-yI)amino)-l,3-dihydrobenzo[c]thiophene 2,2-dioxide To a solution of 5-bromo-l,3- dihydrobenzo[c]thiophene 2,2-dioxide (460 mg, 1.86 mmol) in dioxane (15 mL) was added l-(tert- butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-amine (250 mg, 0.541 mmol), CS2CO3 (529 mg, 1.62 mmol), Pd2(dba)? (49.6 mg, 0.0540 mmol) and Xantphos (62.7 mg, 0.108 mmol). The reaction mixture was stirred at 100 °C for 2 hrs under N2 atmosphere. The reaction was complete detected by LCMS. The cooled reaction mixture was dissolved in EA (10 mL*3), washed with H2O (20 mL) and brine, dried over sodium sulfate, fdtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford 5-((l-(tert- butyl)-3-((lS,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)-l,3- dihydrobenzo[c]thiophene 2,2-dioxide (300 mg, 0.478 mmol, 88.2%) as a white solid. LCMS: ESI m / z 628.92 [M + H]+.

[0405] Step B: 5-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)- l,3-dihydrobenzo[c]thiophene 2,2-dioxide A solution of 5-((l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldiphenylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)-l,3-dihydrobenzo[c]thiophene 2,2- dioxide (300 mg, 0.478 mmol) in formic acid (5 mL) was stirred at room temperature for 5 hrs. The reaction was complete detected by LCMS. The solvents were removed under vacuum. Then add EtOH (3 mL), H2O (3 mL) and Lithium Hydroxide Monohydrate (120 mg, 2.87 mmol) to alkaline pH. The mixture was stirred at room temperature for 1 hr. LCMS showed the reaction was completed. The reaction mixture was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford 5-((l-(tert-butyl)-3-((lS,3R)-3- hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-l,3-dihydrobenzo[c]thiophene 2,2-dioxide (260 mg, 0.668 mmol, 69.9%) as a yellow solid. LCMS: ESI m / z 390.51 [M + H]+.

[0406] Step C: (lR,3S)-3-(l-(tert-butyl)-5-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A suspension of 5-((l-(tert- butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)-l,3-dihydrobenzo[c]thiophene 2,2-dioxide (120 mg, 0.308 mmol), DMAP (3.76 mg, 0.0310 mmol), Py (0.0750 mL, 0.924 mmol) and 4-nitrophenyl chloromethanoate (310 mg, 1.54 mmol) in DCM (3 mL) and THF (3 mL) was stirred at room temperature for 3 hrs. The solvents were removed under vacuum. The residue was dissolved in LA (50 mLO), washed with H2O (50 mL) and brine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford (lR,3S)-3-(l-(tert-butyl)-5-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (120 mg, 0.216 mmol, 70.2%) as a yellow solid. LCMS: ESI m / z 555.62 [M+H]+.

[0407] Step D: (lR,3S)-3-(5-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yI)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-(l-(tert-butyl)-5- ((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (120 mg, 0.216 mmol) in formic acid (2 mL) was stirred at 100 °C overnight. LCMS showed the reaction was completed. The cooled reaction mixture was concentrated to give crude (lR,3S)-3-(5-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (105 mg, 0.211 mmol, 97.4%) as ayellow oil. LCMS: ESI m / z 499.51 [M+H]+.

[0408] Step E: (lR,3S)-3-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yI)amino)-lH- pyrazol-5-yl)cyclopentyl isopropylcarbamate A suspension of (lR,3S)-3-(5-((2,2-dioxido-l,3- dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (105 mg, 0.211 mmol) in THF (2 mL) and propan-2-amine (0.0540 mL, 0.632 mmol) and DIEA (0.104 mL, 0.632 mmol) was stirred at room temperature for 3 hrs. LCMS showed the reaction had been completed. The reaction was dissolved in EA (50 mL), washed with H2O (10 mL) and brine, dried over sodium sulfate, filtered, concentrated. The residue was purified by silica gel chromatography (eluting with 0-12% MeOH in DCM) and prep-HPLC (Cl 8, 15 - 95 % MeCN in H2O with 0.1 % NH4OH) to afford (lR,3S)-3-(3-((2,2-dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)amino)-lH-pyrazol- 5-yl)cyclopentyl isopropylcarbamate (21.8 mg, 0.0520 mmol, 24.7%) as a white solid. LCMS: 419.51 [M+H]+. 'H NMR (400 MHz, DMSO) 5 11.74 (s, 1H), 8.48 (s, 1H), 7.42 (s, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.95 (s, 1H), 5.64 (s, 1H), 5.00 (s, 1H), 4.42 (s, 2H), 4.33 (s,2H), 3.58 (s, 1H), 3.05 (s, 1H), 2.50-2.42 (m, 1H), 2.06-1.88 (m, 2H), 1.79-1.56(m, 3H), 1.04 (d, J = 6.0 Hz, 6H).Example 23: racemic cis 3-(5-((2-methyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-3-yl)cyclopentyl isopropylcarbamate

[0409] Step A: 4-bromo-2,N-dimethylbenzenesulfonamide To a solution of 4-bromo-2- methylbenzenesulfonyl chloride (5 g, 18.6 mmol) in DCM (20 mL) was added methanamine-THF (5mL, 10 mmol, 2M in THF) and Et?N (7.74 mL, 55.6 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dissolved in EA (50 mL), washed with I LO (20 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% EA in PE) to afford 4-bromo- 2,N-dimethylbenzenesulfonamide (2.3 g, 8.71 mmol, 46.9%) as a white solid. LCMS: ESI m / z 266 [M+H]+

[0410] Step B: 4-bromo-2-(bromomethyI)-N-methyIbenzenesulfonamide To a solution of 4- bromo-2,N-dimethylbenzenesulfonamide (1.8 g, 6.82 mmol) in tetrachloromethane (15 mL) was added BPO (0.33 g, 1.36 mmol) and NBS (1.33 g, 7.50 mmol) at rt. The reaction mixture was stirred at 80 °C overnight. The cooled reaction mixture was concentrated. The following mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with NajSCL. filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-30%]. to afford the title compound 4-bromo-2-(bromomethyl)-N- methylbenzenesulfonamide (970 mg, 2.83 mmol, 41.5%) as a white solid. LCMS: ESI 343 [M + H]+.

[0411] Step C: 5-bromo-2-methyl-2,3-dihydro-lX6-benzo[2,l-d][l,2]thiazole-l, 1-dione To a solution of 4-bromo-2-(bromomethyl)-N-methylbenzenesulfonamide (970 mg, 2.83 mmol) in H2O (2 mL) and MeOH (8 mL) was added NaOH (226 mg, 5.66 mmol). The reaction mixture was stirred at rt for 3h. The reaction mixture was concentrated in vacuo. The following mixture was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with EA in PE [gradient: 0-30%] to afford the title compound 5-bromo-2-methyl-2,3-dihydro-lX6-benzo[2,l-d][l,2]thiazole-l, 1-dione (390 mg, 1.49 mmol, 52.6%) as a white solid. LCMS: ESI 262 [M + H]+.

[0412] Step D: Racemic cis 3-(5-((2-methyl-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5- yl)amino)-lH-pyrazol-3-yl)cyclopentyl isopropylcarbamate To a solution of 5-bromo-2-methyl- 2, 3-dihydro-lZ6-benzo[2,l-d][l,2]thiazole-l, 1-dione (16.2 mg, 0.062 mmol) in dioxane (6 mL) was added racemic cis ethyl 5-amino-3-(3-((isopropylcarbamoyl)oxy)cyclopentyl)-lH-pyrazole-l- carboxylate (10 mg, 0.031 mmol), xantphos (3.59 mg, 0.006 mmol), Pd2(dba)s (2.84 mg, 0.003 mmol) and CS2CO3 (25.2 mg, 0.077 mmol). The reaction mixture was stirred at 100 °C underN2 atmosphere for 1.5 h. The reaction was complete detected by LCMS. The cooled reaction mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (Cl 8, 10 ~ 95% MeCN in H2O with 0.1 % HCOOH) to give racemic cis 3-(5-((2-methyl-l,l-dioxido-2,3- dihydrobenzo[d]isothiazol-5-yl)amino)-lH-pyrazol-3-yl)cyclopentyl isopropylcarbamate (2 mg, 0.005 mmol, 14.8%) as a white solid. LCMS: ESI m / z 434.2 [M+H]+. ’H NMR (400 MHz, DMSO) 6 11.93 (s, 1H), 9.06 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.71 (s, 1H), 5.00 (s, 1H), 4.29 (s, 2H), 3.64-3.55 (m, 1H), 3.10 - 3.02 (m, IH), 2.74 (s, 3H), 2.50-2.43 (m, IH), 2.06-1.97 (m, IH), 1.96 - 1.86 (m, IH), 1.79-1.69 (m, 2H), 1.68-1.58 (m, IH), 1.03 (d, J = 6.4 Hz, 6H).Example 24: racemic cis 3-{5-[(l,l-dioxo-2,3-dihydro-l 6-benzothiophen-5-yl)amino]-4- methyl-lH-pyrazol-3-yl}cyclopentyl(prop-2-ylamino)methanoate

[0413] Step A: Racemic cis benzyl {[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2- yl)pyrazol-3-yl] amino} me thanoate To a solution of racemic cis benzyl (l-(tert-butyl)-3-(3-hydroxycyclopentyl)-lH-pyrazol-5-yl)carbamate (4 g, 11.2 mmol) in acetonitrile (50 mL) was added 1 -iodotetrahydropyrrole-2, 5-dione (2.52 g, 11.2 mmol), and the reaction was stirred at room temperature for 1 hr. The reaction was diluted with DCM (100 mL) and water (200 mL). The organic layer was separated, washed with brine, dry over NaiSCL and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether (l%~20%) to afford the title compound cis benzyl {[5-(3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2- yl)pyrazol-3-yl] amino }methanoate (5.2 g, 10.7 mmol, 96.1%) as a yellow solid. LCMS:484.1 [M+H]+.

[0414] Step B: Racemic cis benzyl {[4-iodo-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2- yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-yl]amino]methanoate To a solution of cis benzyl {[5- (3-hydroxycyclopentyl)-4-iodo-2-(2-methylprop-2-yl)pyrazol-3-yl]amino}methanoate (5.2 g, 10.7 mmol) in DCM (60 mL) were added DMAP (1.31 g, 10.7 mmol), IH-imidazole (2.20 g, 32.2 mmol), and TBDPS chloride (3.34 g, 12.9 mmol) at 0 °C. The reaction was stirred at room temperature for 18 hr. The reaction solution was dissolved in EtOAc (100 mL), washed with H2O (200 mL) and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 60% ethyl acetate in petroleum ether) to afford benzyl {[4-iodo-2-(2- methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3- yl] amino }methanoate (5.0 g, 6.93 mmol, 64.4%) as a white oil. LCMS: ESI m / z 720.0 [M-H]'.

[0415] Step C: Racemic cis 4-methyl-2-(2-methylprop-2-yI)-5-(3-{[(2-methylprop-2- yl)diphenylsilyl] oxy] cyclopen tyl)pyrazol-3-amine To a mixture of cis benzyl {[4-iodo-2-(2- methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3- yl]amino}methanoate (800 mg, 1.11 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.53 mL, 8.86 mmol) in DMF (10 mL) were added K2CO3 (459 mg, 3.33 mmol) and Pd(dppf)C12 (81.1 mg, 0.111 mmol). The reaction was stirred at 110 °C for 3 hr. The cooled reaction mixture was diluted with water and extracted with EA (50 mL*3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The residue was purified using silica gel column chromatography eluting with PE / EA (100 / 1 ~ 12 / 1) to afford the title compound cis 4-methyl-2-(2- methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy}cyclopentyl)pyrazol-3-amine (140 mg, 0.294 mmol, 26.5%) as a pink oil. LCMS:476.3 [M+H]

[0416] Step D: Racemic cis 5-((l-(tert-butyl)-3-(3-((tert- butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-lH-pyrazol-5-yl)amino)-2,3- dihydrobenzo[b]thiophene 1,1-dioxide To a stirred mixture of cis 4-methyl-2-(2-methylprop-2-yl)-5-(3-{[(2-methylprop-2-yl)diphenylsilyl]oxy]cyclopentyl)pyrazol-3-amine (140 mg, 0.294 mmol) in dioxane (10 mL) was added 5-bromo-2,3-dihydro- 176-benzothiophene- 1, 1-dione (109.08 mg, 0.441 mmol), xant-PHOS (34.05 mg, 0.059 mmol), CS2CO3 (191 mg, 0.589 mmol) and Pd2(dba)s (26.9 mg, 0.029 mmol). The reaction mixture was stirred at 120 °C under N2 for 3hr. The cooled reaction mixture was diluted with water and extracted with EA (20 mL*3). The combined organic layers were washed white brine and dried over Na2SC>4, filtered, concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with PE / EA (100 / 1 ~ 3 / 1) to afford the title compound racemic cis 5-((l-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl- lH-pyrazol-5-yl)amino)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide (110 mg, 0.171 mmol, 58.2%) as a yellowish green oil. LCMS: 642.5 [M+H]+

[0417] Step E: Racemic cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2- yl)pyrazol-3-yl]amino}-2,3-dihydro-116-benzothiophene-l, 1-dione A solution of cis 5-((l-(tert- butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-4-methyl-lH-pyrazol-5-yl)amino)-2,3- dihydrobenzo[b]thiophene 1,1-dioxide (150 mg, 0.234 mmol) in HCOOH (5 mL) was stirred at 40 °C for 18 hr. The reaction mixture was concentrated. The residue was dissolved with methanol and adjusted to pH value 12-13 with aqueous 2 N lithium hydroxide aqueous solution. The reaction mixture was stirred at rt for 30 min and then diluted with EA and water. The organic layer was separated, washed with brine and concentrated. The residue was purified using silica gel column chromatography eluting with PE / EA (100 / 1 ~ 1 / 100) to afford the title compound cis 5- { [5-(3- hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2-yl)pyrazol-3-yl]amino]-2,3-dihydro-lX6- benzothiophene- 1,1 -dione (90 mg, 0.223 mmol, 95.4%) as ayellow oil. LCMS: 404.3 [M+H]+

[0418] Step F: Racemic cis 3-{5-[(l,l-dioxo-2,3-dihydro-116-benzothiophen-5-yl)amino]-4- methyl-l-(2-methyIprop-2-yl)pyrazoI-3-yl}cyclopentyl [(4-nitrophenyI)oxy]methanoate A suspension of cis 5-{[5-(3-hydroxycyclopentyl)-4-methyl-2-(2-methylprop-2-yl)pyrazol-3- yl]amino}-2,3-dihydro-lX6-benzothiophene-l, 1-dione (90 mg, 0.223 mmol), pyridine (0.054 mL, 0.669 mmol), DMAP (2.72 mg, 0.022 mmol) and 4-nitrophenyl chloromethanoate (89.9 mg, 0.446 mmol) in THF (5 mL) and DCM (5 mL) was stirred at 50 °C overnight. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (50 mL), washed with brine (100 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting with 100% ethyl acetate in petroleum ether) to afford cis 3-{5-[(l,l-dioxo-2,3-dihydro-lX6- benzothiophen-5-yl)amino]-4-methyl-l-(2-methylprop-2-yl)pyrazol-3-yl} cyclopentyl [(4- nitrophenyl)oxy]methanoate (50 mg, 0.088 mmol, 39.4%) as a white solid. LCMS: 569.3 [M+H]+.

[0419] Step G: Racemic cis 3-{5-[(l,l-dioxo-2,3-dihydro-l 6-benzothiophen-5-yl)amino]-4- methyl-lH-pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]methanoate A solution of cis 3-{5- [(1,1 -dioxo-2, 3 -dihydro- 1 / .6-benzothiophen-5-yl )amino]-4-methyl - 1 -(2-methylprop-2-yl)pyrazol-3 - yl} cyclopentyl [(4-nitrophenyl)oxy]methanoate (50 mg, 0.088 mmol) in HCOOH (5 mL) was stirred at 100 °C for 18 hr. The cooled reaction mixture was concentrated in vacuo to afford the title compound cis 3- { 5-[(l ,1 -dioxo-2, 3-dihy dro-1 6-benzothiophen-5-yl)ammo]-4-methyl- lH-pyrazol-3- yl} cyclopentyl [(4-nitrophenyl)oxy]methanoate (50 mg, 0.073 mmol, 83.2%) as a yellow oil. LCMS: 513.2 [M+H]’

[0420] Step H: Racemic cis 3-{5-[(l,l-dioxo-2,3-dihydro-lX6-benzothiophen-5-yl)amino]-4- methyl-lH-pyrazol-3-yl]cyclopentyl (prop-2-ylamino)methanoate A solution of cis 3-{5-[(l,l- di oxo-2, 3 -dihydro- 1 X6-benzothiophen-5-y l)amino] -4-methyl- 1 H-pyrazol-3 -yl } cyclopentyl [(4- nitrophenyl)oxy]methanoate (50 mg, 0.073 mmol) in propan-2-amine (5 mL, 58.366 mmol) was stirred at room temperature for 2 hr. The reaction mixture was concentrated. The residue was purified by prep-HPLC (C18, 5%-95% MeCN in H2O with 0.1 % HCOOH) to give cis 3-{5-[(l,l-dioxo-2,3- dihydro-lX6-benzothiophen-5-yl)amino]-4-methyl-lH-pyrazol-3-yl} cyclopentyl (prop-2- ylamino)methanoate (18.9 mg, 0.044 mmol, 59.7%) as a white solid. LCMS: 433 [M+H]+. 'H NMR (400 MHz, DMSO) 8 11.82 (s, 1H), 8.34 (s, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.29-7.19 (m, 2H), 6.97 (d, 7 = 8.4 Hz, 1H), 4.99 (s, 1H), 3.65-3.55 (m, 1H), 3.46 (t, J = 6.8 Hz, 2H), 3.21 (t, J = 6.8 Hz, 2H), 3.15 - 3.02 (m, 1H), 2.44 - 2.35 (m, 1H), 2.03 - 1.91 (m, 2H), 1.88 (s, 3H), 1.83-1.63 (m, 3H), 1.04 (d, J = 6.4 Hz, 6H).Example 25: (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]-2H-pyrazol-3- yl] cyclo pentyl (prop-2-ylamino)methanoate

[0421] Step A: 5-({5-[(lS,3R)-3-{[dimethyl(2-methylprop-2-yl)silyl]oxy]cyclopentyl]-2-(2- methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lH-inden-l-one To a solution of 5-bromo-2,3- dihydro-lH-inden-l-one (0.169 mL, 0.948 mmol) in dioxane (10 mL) were added 5-[(lS,3R)-3- {[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (319 mg, 0.948 mmol), CS2CO3 (617 mg, 1.89 mmol), Xant-PHOS (109 mg, 0.190 mmol) and Pd2(dba)s (86.7 mg, 0.095 mmol). The reaction mixture was stirred at 120 °C under N2 for 3 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with further brine, and concentrated. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to afford the title compound 5-({5-[(lS,3R)-3- {[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl] amino)- 2,3 -dihydro- IH-inden-l -one (200 mg, 0.428 mmol, 45.1%) as a yellow oil. LCMS: ESI m / z 468 [M + H]+.

[0422] Step B: 5-({5-[(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3- yl]amino)-2,3-dihydro-lH-inden-l-one A mixture of 5-({5-[(lS,3R)-3-{[dimethyl(2-methylprop- 2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lH-inden-l-one (150 mg, 0.321 mmol) in formic acid (6 mL) was stirred at RT for 1 h, then concentrated under reduced pressure. The residue was treated with a mixture of lithium hydroxide hydrate (26.9 mg, 0.642 mmol) in MeOH (9 mL) / H20 (3 mL). The resulting mixture was stirred at rt for 2 h, the mixture was concentrated under reduced pressure. The residue was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried with I feSCb, filtered and concentrated. The residue was purified by chromatography to give 5-({5-[(lS,3R)-3- hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lH-inden-l-one (80 mg, 0.226 mmol, 70.5%) as a colorless oil. LCMS: ESI m / z 354 [M + H]+.

[0423] Step C: (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(l-oxo-2,3-dihydro-lH-inden-5- yl)amino]pyrazol-3-yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate To a solution of 5-({5- [(lS,3R)-3-hydroxycyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lH-inden- l-one (100 mg, 0.283 mmol) in DCM (3 mL) and THF (3 mL) were added 4-nitrophenyl chloromethanoate (114 mg, 0.566 mmol), Py (0.046 mL, 0.566 mmol) and DMAP (3.46 mg, 0.028 mmol). The reaction mixture was stirred under at 25 °C for 2 hr. The reaction solution was diluted with EA, washed with water and brine, dried over anhydrous ISfeSCL and concentrated. The residue was purified by flash chromatography to afford (lR,3S)-3-[l-(2-methylprop-2-yl)-5-[(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate (100 mg, 0.193 mmol, 68.1%) as a yellow solid. LCMS: ESI m / z 519 [M + H]+.

[0424] Step D: (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]-lH-pyrazol-3- yl] cyclopentyl [(4-nitrophenyl)oxy]methanoate A solution of (lR,3S)-3-[l-(2-methylprop-2-yl)-5- [(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate (100 mg, 0.193 mmol) in formic acid (5 mL) was stirred at 100 °C overnight. The cooled reaction mixture was concentrated to afford (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]-lH- pyrazol-3-yl}cyclopentyl [(4-nitrophenyl)oxy]methanoate (70 mg, 0.151 mmol, 78.5%) as ayellow oil. LCMS: ESI m / z 463 [M + H]+.

[0425] Step E : ( lR,3S)-3- {5- |(l-oxo-2,3-dihydro- lH-inden-5-yl)amino] -2H-pyrazol-3- yl] cyclopentyl (prop-2-ylamino)methanoate To a solution of (lR,3S)-3-{5-[(l-oxo-2,3-dihydro- lH-inden-5-yl)amino]-lH-pyrazol-3-yl]cyclopentyl [(4-nitrophenyl)oxy]methanoate (70 mg, 0.151 mmol) in THF (5 mL) was added propan-2-amine (0.026 mL, 0.303 mmol). The reaction mixture was stirred at rt for 1 h. The reaction concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (lR,3S)-3-{5-[(l-oxo-2,3-dihydro-lH-inden-5-yl)amino]-2H-pyrazol-3- yl} cyclopentyl (prop-2-ylammo)methanoate (53 mg, 0.139 mmol, 91.5%) as a white solid. LCMS: ESI m / z 383 [M + H]+. 'H NMR (400 MHz, DMSO) 5 11.94 (s, 1H), 9.07 (s, 1H), 7.53 (s, 1H), 7.43 (d, 7 = 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 5.73 (d, 7 = 1.6 Hz, 1H), 5.00 (s, 1H), 3.63-3.53 (m, 1H), 3.13 - 3.01 (m, 1H), 3.00 - 2.93 (m, 2H), 2.48 - 2.42 (m, 1H), 2.008-1.97 (m, 1H), 1.96-1.86 (m, 1H), 1.81-1.68 (m, 2H), 1.68-1.58 (m, 1H), 1.03 (d, 7= 6.4 Hz, 6H).Example 26: (lR,3S)-3-(3-((l,l-dioxidothiochroman-6-yl)amino)-lH-pyrazol-5-yl)cyclopentyl isopropylcarbamate

[0426] Step A: 6-bromo-3,4-dihydro-2H-l-benzothiin-4-ol To a solution of 6-bromo-3,4- dihydro-2H-l-benzothiin-4-one (1 g, 4.11 mmol) in MeOH (5 mL) was added NaBHj (0.28 g, 8.23 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction was diluted with EA and water. The organic layer was separated, washed with brine and concentrated in vacuo to afford the title compound 6-bromo-3,4-dihydro-2H-l-benzothiin-4-ol (900 mg, 3.67 mmol, 89.3%) as a brown oiLLCMS: m / z 245.13 [M+H]+.

[0427] Step B: 6-bromo-3,4-dihydro-2H-l-benzothiine To a solution of 6-bromo-3,4-dihydro- 2H-l-benzothiin-4-ol (900 mg, 3.67 mmol) in TFA (10 mL) was added EtsSiH (2.97 mL, 18.4 mmol). The reaction mixture was stirred at 60 °C overnight. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-1%) to afford the title compound 6-bromo-3,4-dihydro-2H-l-benzothiine (840 mg, 3.67 mmol, 99.9%) as a colorless oil. LCMS: m / z 229.13 [M+H]+.

[0428] Step C: 6-bromothiochromane 1,1-dioxide To a solution of 6-bromo-3,4-dihydro-2H- 1 -benzothiine (900 mg, 3.93 mmol) in 1 ,2-di chloroethane (10 mL) was added 3- Chloroperoxybenzoic acid (2.39 g, 11.8 mmol). The reaction was stirred at 60 °C overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with saturated NaHCCE solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the titlecompound 6-bromothiochromane 1,1-dioxide (780 mg, 2.99 mmol, 76.1%) as a pink solid. LCMS: m / z 261.13 [M+H]+.

[0429] Step D: 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)- lH-pyrazol-5-yl)amino)thiochromane 1,1-dioxide To a stirred solution of 6-bromothiochromane 1,1-dioxide (300 mg, 1.15 mmol) in dioxane (10 mL) were added 5-[(lS,3R)-3-{[dimethyl(2- methylprop-2-yl)silyl]oxy}cyclopentyl]-2-(2-methylprop-2-yl)pyrazol-3-amine (388 mg, 1.15 mmol), Pd2(dba)? (105 mg, 0.115 mmol), Xant-PHOS (133 mg, 0.230 mmol) and CS2CO3 (1.12 g, 3.48 mmol). The reaction was stirred at 100 °C under N2 for 4 hr. The cooled reaction mixture was diluted with EA and water. The organic layer was separated, washed with saturated brine and concentrated in vacuo. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) to afford the title compound 6-((l-(tert- butyl)-3-((lS,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)thiochromane 1,1-dioxide (400 mg, 0.772 mmol, 67.2%) as ayellow solid. LCMS: m / z 517.80 [M+H]+.

[0430] Step E: 6-((l-(tert-butyl)-3-((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5- yl)amino)thiochromane 1,1-dioxide A solution of 6-((l-(tert-butyl)-3-((lS,3R)-3-((tert- butyldimethylsilyl)oxy)cyclopentyl)-lH-pyrazol-5-yl)amino)thiochromane 1,1-dioxide (150 mg, 0.240 mmol) in formic acid (5 mL) was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolve with methanol and adjusted to pH value 12-13 with aq. 2 N lithium hydroxide aqueous solution. The reaction was stirred at rt for 30 min and then diluted with EA and water. The organic layer was separated, washed with brine and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-50%) to afford the title compound 6-((l-(tert-butyl)-3-((lS,3R)-3- hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)thiochromane 1,1-dioxide (90 mg, 0.176 mmol, 73.4%) as a yellow solid. LCMS: m / z 510.65 [M+H]+.

[0431] Step F: (lR,3S)-3-(l-(tert-butyl)-5-((l,l-dioxidothiochroman-6-yl)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate To a stirred solution of 6-((l-(tert-butyl)-3- ((lS,3R)-3-hydroxycyclopentyl)-lH-pyrazol-5-yl)amino)thiochromane 1,1-dioxide (300 mg, 0.743 mmol) in THF (5 mL) and DCM (5 mL) were added 4-nitrophenyl chloromethanoate (225 mg, 1.12 mmol), DMAP (9.08 mg, 0.074 mmol) and Py (118 mg, 1.49 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and water. The organic layer was separated, washed with brine and concentrated. The residue was purified using silica gel column chromatography eluted with ethyl acetate in petroleum ether (gradient: 0-30%) toafford the title compound (lR,3S)-3-(l-(tert-butyl)-5-((l,l-dioxidothiochroman-6-yl)amino)-lH- pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (330 mg, 0.580 mmol, 78.1%) as a yellow solid. LCMS: m / z 568.64 [M+H]+.

[0432] Step G: (lR,3S)-3-(5-((l,l-dioxidothiochroman-6-yl)amino)-lH-pyrazol-3- yl)cyclopentyl (4-nitrophenyl) carbonate A solution of (lR,3S)-3-(l-(tert-butyl)-5-((l,l- dioxidothiochroman-6-yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (150 mg, 0.264 mmol) in formic acid (5 mL) was stirred at 100 °C overnight. The reaction mixture was concentrated to afford the title compound (lR,3S)-3-(5-((l,l-dioxidothiochroman-6-yl)amino)- lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (130 mg, 0.254 mmol, 96.2%) as a brown oil. LCMS: m / z 512.54 [M+H]+.

[0433] Step H: (lR,3S)-3-(3-((l,l-dioxidothiochroman-6-yl)amino)-lH-pyrazol-5- yl)cyclopentyl isopropylcarbamate A solution of (lR,3S)-3-(5-((l,l-dioxidothiochroman-6- yl)amino)-lH-pyrazol-3-yl)cyclopentyl (4-nitrophenyl) carbonate (150 mg, 0.293 mmol) in propan- 2-amine (17.3 mg, 0.293 mmol) was stirred at room temperature for 1 h. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC (Cl 8, 0~70 % acetonitrile in H2O) to afford the title compound (lR,3S)-3-(3-((l,l-dioxidothiochroman-6-yl)amino)-lH-pyrazol- 5-yl)cyclopentyl isopropylcarbamate (31.1 mg, 0.072 mmol, 24.5%) as a white solid. LCMS: m / z 432.54 [M+H]+. 'H NMR (400 MHz, DMSO) 6 11.88 (s, 1H), 8.85 (s, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.91 (dd, J = 26.8, 8.0 Hz, 1H), 5.67 (s, 1H), 4.99 (s, 1H), 3.62-3.52 (m, 1H), 3.42 - 3.34 (m, 2H), 3.12 - 2.98 (m, 1H), 2.89 (t, J = 6.4 Hz, 2H), 2.48 - 2.40 (m, 1H), 2.27 (dt, J = 12.0, 5.6 Hz, 2H), 2.02-1.82 (m, 2H), 1.75-1.54 (m, 3H), 1.03 (d, J = 6.4 Hz, 6H).Example 27: (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-1λ6-benzo[b]thiophen-6- y 1 )amino | -2H-pyrazol-3-yl}cyclohexyl (prop-2-ylamino)methanoate

[0434] Step A. 6-({5-[(ls,4s)-4-{[(2-methylprop-2-yl)diphenylsilyl]oxy]cyclohexyl]-l-(2- methylprop-2-yl)py razol-3-yl] amino)-2,3-dihydro-1λ6-benzo [b] thiophene- 1,1- dione. To a stirred solution of 6-bromo-2,3-dihydro-lA6-benzo[2,l-b]thiophene-l, 1-dione (104 mg, 0.42 mmol) in dioxane (2 mL) was added 5-[(ls,4s)-4-{[(2-methylprop-2- yl)diphenylsilyl]oxy]cyclohexyl]-l-(2-methylprop-2-yl)pyrazol-3-amine (200 mg, 0.42 mmol), Pd2(dba)s (38 mg, 0.04 mmol), Xant-PHOS (49 mg, 0.08 mmol) and CS2CO3 (342 mg, 1.1 mmol) at rt. The reaction mixture was stirred at 100 °C under N2 for 2h. The cooled reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-60%, EtOAc in PE) to give 6-({5-[(ls,4s)-4-{[(2-methylprop-2- yl)diphenylsilyl]oxy } cyclohexyl] - 1 -(2-methylprop-2-yl)pyrazol-3 -yl } amino)-2, 3 -dihydro- 1 A,6- benzothiophene- 1,1 -dione (250 mg, 0.39 mmol, 92 %) as a yellow solid. LCMS: m / z 642 [M+H]+.

[0435] Step B. 6-({5-[(ls,4s)-4-hydroxycyclohexyl]-l-(2-methylprop-2-yl)pyrazol-3- yl]amino)-2,3-dihydro-1λ6-benzo[b]thiophene-l, 1-dione. A mixture of 6-({5- [(1 s,4s)-4- { [(2-methylprop-2-yl)diphenylsilyl]oxy } cyclohexyl]- 1 -(2-methylprop-2-yl)pyrazol-3 - yl}amino)-2,3-dihydro-lA6-benzothiophene-1, 1-dione (260 mg, 0.41 mmol) in HCOOH (5 mL) was stirred at rt overnight. The reaction mixture was concentrated. Then EtOH (1 mL) / H2O (3 mL) and LiOH (15 mg, 3.2 mmol) was added. The following mixture was stirred at rt for 2h and then diluted with water (15 mL), extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give 6-({5-[(ls,4s)-4-hydroxycyclohexyl]-l- (2-methylprop-2-yl)pyrazol-3-yl}amino)-2,3-dihydro-lA6-benzothiophene-1, 1-dione (130 mg, 0.32 mmol, 79 %) as a yellow solid. LCMS: m / z 404 [M+H]+.

[0436] Step C. (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-1λ6-benzo[b]thiophen-6- yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl}cyclohexyl [(4-nitrophenyl)oxy]methanoate. To a stirred solution of 6-({5-[(ls,4s)-4-hydroxycyclohexyl]-l-(2-methylprop-2-yl)pyrazol-3-yl]amino)- 2, 3 -dihydro- 1 A,6-benzothiophene-1, 1-dione (130 mg, 0.32 mmol) in DCM (3 mL) / THF (3 mL) was added 4-nitrophenyl chloromethanoate (324 mg, 1.6 mmol), DMAP (13 mg, 0.11 mmol) and pyridine (2 mL, 24 mmol) slowly at rt. After stirred at rt overnight, the cooled mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*2). The combined organic phase was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10%, MeOH in DCM) to give (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-1λ6-benzothiophen-6-yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yl} cyclohexyl [(4- nitrophenyl)oxy]methanoate (170 mg, 0.3 mmol, 92 %) as a yellow solid. LCMS: m / z 569 [M+H]+.

[0437] Step D. (ls,4s)-4-{5-[(l,l-dioxo-2,3-dihydro-lX.6-benzo[b]thiophen-6- yl)amino]-2-(2-methylprop-2-yl)pyrazol-3-yI] cyclohexyl (prop-2-ylamino)methanoate. To a stirred solution of (ls,4s)-4-{5-[(l,l-dioxo-2,3-di...

Claims

What is claimed is:CLAIMS1. A compound havior a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and Cs-Ce 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 R’ is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-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’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y3is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N; each of X1, X2and X3is selected from CHR7, O and NR, and X2additionally may be absent in which case X1and X3are joined by a single bond; provided that when X1is O or NR, X2is CHR7or if X2is absent X3is CHR7;each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted C1-C6 alkyl or C3-C6 cycloalkyl, unsubstituted or substituted C1-4 alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’ ; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted C 1-4 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;7 is 0, 1, 2, 3, 4 or 5; j is 0, 1, 2 or 3; and k; is 0, 1, 2 or 3.

2. The compound of claim 1, wherein Ring A has the below specified stereochemistry:

3. The compound of claim 1 or 2, wherein Ring A is a substituted or unsubstituted cyclopentyl bivalent radical, having the structural formula:

4. The compound of claim 3, wherein X2is present.

5. The compound of claim 3, wherein X2is absent, having the structural formula:

6. The compound of any one of claims 1-5, wherein X1is NR.

7. The compound of any one of claims 1-5, wherein X1is CHR7, wherein R7is H or substituted or unsubstituted C1-C3 alkyl.

8. The compound of any one of claims 1-7, wherein X3is CHR7, wherein R7is H or substituted or unsubstituted C1-C3 alkyl.

9. The compound of any one of claims 1-8, wherein each of Y1, Y2and Y3is independently CR6.10 The compound of claim 9, wherein each of Y1, Y2and Y3is CH.11 The compound of claim 9, wherein two of Y1, Y2and Y3is CH and the third is CR6, wherein R6is selected from halogen, unsubstituted or substituted C1-C6 alkyl or Cs-Ce cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’.12 The compound of claim 11, wherein each of Y1and Y2is CH, and Y3is CR6.13 The compound of claim 11 , wherein each of Y1and Y3is CH, and Y2is CR6.

14. The compound of claim 11, wherein each of Y2and Y3is CH, and Y1is CR6.

15. The compound of any one of claims 11-14, wherein R6is F, Cl or C1-C3 alkyl.

16. The compound of any one of claims 1-8, wherein one of Y1, Y2and Y’ is N and each of the other two is CH.

17. The compound of claim 16, wherein Y1is N, and each of Y2and Y3is CH.

18. The compound of claim 16, wherein Y2is N, and each of Y1and Y3is CH.

19. The compound of claim 16, wherein Y3is N, and each of Y1and Y2is CH.

20. A compound having the structural Formula (III):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 R ’ is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-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, CM alkyl, CN, NRR’, or C(O)NRR’;Ring B is a 5- or 6-membered carbocyclic or heterocyclic ring comprising a -S(O)2-; each of Y1, Y2and Y3is selected from CR6and N; provided that not more than one of Y1, Y2and Y3is N;each of X4and X5is independently CHR7, and X4additionally may be absent in which case X5and S(O)2 are joined by a single bond; each R6is independently selected from H, halogen, OH, CN, unsubstituted or substituted C1-C6 alkyl or Cs-Ce cycloalkyl, unsubstituted or substituted C1-4 alkoxy, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-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 C1-6 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, 4 or 5; j is 0, 1, 2 or 3; andA: is 0, 1, 2 or 3.

21. The compound of claim 20, wherein Ring A has the below specified stereochemistry:

22. The compound of claim 20 or 21, wherein Ring A is a substituted or unsubstituted cyclopentyl bivalent radical, having the structural formula:

23. The compound of claim 22, wherein X4is present.

24. The compound of claim 22, wherein X4is absent, having the structural formula:(HI )25. The compound of any one of claims 20-24, wherein each of Y1, Y2and Y3is independently CR6.

26. The compound of claim 25, wherein each of Y1, Y2and Y3is CH.

27. The compound of claim 25, wherein two of Y1, Y2and Y3is CH and the third is CR6, wherein R6is selected from halogen, unsubstituted or substituted Ci-Cg alkyl or Cs-Cg cycloalkyl, NRR’, NRC(O)R’, C(O)NRR’, NRC(O)NRR’ and NRC(O)OR’.

28. The compound of claim 27, wherein R6is F, Cl or C1-C3 alkyl.

29. The compound of any one of claims 20-24, wherein one of Y1, Y2and Y3is N and each of the other two is CH.

30. The compound of any one of claims 1-29, having one or more deuterium atoms in place of a hydrogen atom.

31. The compound of claim 30, having one deuterium atom in place of a hydrogen.

32. A pharmaceutical composition comprising a compound according to any one of claims 1-31 and a pharmaceutically acceptable excipient, carrier, or diluent.

33. The pharmaceutical composition of claim 32, being suitable for oral administration.

34. A unit dosage form comprising a pharmaceutical composition according to claim 32 or 33.

35. The unit dosage form of claim 34, being in the form of a tablet or capsule.

36. A method for treating a cannabinoid receptor type 2 (CB2R)-mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-31.

37. The method of claim 36, wherein the CB2R-mediated disease or condition is selected from pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g. trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respirator / distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, nonalcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemiareperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fatty liver (NAFL), atention-deficit hyperactivity disorder (ADHD), anxiety, autistic spectrum disorder,depression, insomnia / sleep disorders, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

38. The method of claim 36, wherein the CB2R-mediated disease or condition is chronic pain.

39. The method of claim 36, wherein the CB2R-mediated disease or condition is osteoarthritis.

40. The method of claim 36, wherein the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

41. The method of claim 36, wherein the CB2R-mediated disease or condition is anxiety and / or depression.

42. The method of claim 36, wherein the CB2R-mediated disease or condition is addiction.

43. A method for modulating the activity of cannabinoid receptor type 2 (CB2R), comprising administer to a subj ect in need thereof a therapeutically effective amount of a compound according to any one of claims 1-31.

44. Use of a compound according to any one of claims 1-31, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a cannabinoid receptor type 2 (CB2R)-mediated disease or condition.

45. Use of a compound according to claim 44, wherein the CB2R-mediated disease or condition is selected from pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g. trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory’ distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenicfibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemia-reperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fatty liver (NAFL), attention-deficit hyperactivity' disorder (ADHD), anxiety, autistic spectrum disorder, depression, insonuua''sleep disorders, obsessive compulsive disorder (OCD), post- traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

46. Use of a compound according to claim 44, wherein the CB2R-mediated disease or condition is chronic pain.

47. Use of a compound according to claim 44, wherein the CB2R-mediated disease or condition is osteoarthritis.

48. Use of a compound according to claim 44, wherein the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

49. Use of a compound according to claim 44, wherein the CB2R-mediated disease or condition is anxiety and / or depression.

50. The compound of any one of claims 1-31, the pharmaceutical composition of claim 32 or 33, the unit dosage form of claim 34 or 35, the method of any one of claims 36-43, or the use of any one of claims 44-49, wherein the compound is characterized by binding affinity to cyclin-dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM.

51. The compound, pharmaceutical composition, unit dosage form, method or use of claim 50, wherein the compound is characterized by binding affinity to CDK2 as measured by IC50 of greater than 200 nM.

52. A method for making a compound of any one claims 1-31.

53. A method for treating a cannabinoid receptor type 2 (CB2R)-mediated disease or condition, comprising administer to a subject in need thereof a therapeutically effective amount of a compound having the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and C3-C.6 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 Ci-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 YJand 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 Ci-6 alkyl, and unsubstituted or substituted C 1-4 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 C1-6 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, 4 or 5; and Afis O, 1, 2, 3, 4 or 5, provided that the compound of formula (I) is characterized by a binding affinity to cyclin- dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM.

54. The method of claim 52, wherein the CB2R-mediated disease or condition is selected from pain, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g. trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SEE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory distress syndrome (ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, liver cirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemiareperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fatty liver (NAFL), attention-deficit hyperactivity disorder (ADHD), anxiety, autistic spectrum disorder, depression, insomnia / sleep disorders, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

55. The method of claim 52, wherein the CB2R-mediated disease or condition is chronic pain.

56. The method of claim 52, wherein the CB2R-mediated disease or condition is osteoarthritis.

57. The method of claim 52, wherein the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition58. The method of claim 52, wherein the CB2R-mediated disease or condition is anxiety and / or depression.

59. The method of claim 52, wherein the CB2R-mediated disease or condition is addiction.

60. A method for modulating the activity of cannabinoid receptor type 2 (CB2R), comprising administer to a subj ect in need thereof a therapeutically effective amount of a compound having the structural Formula (I):R1IR4Qj Yr20R5^N H^A N / NH(I) or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and Cs-Ce 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 R ’ is independently selected from the group consisting of halogen, OH, CN, unsubstituted or substituted Ci-6 alkyl, unsubstituted or substituted Ci-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, Ci-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 Y ’ and 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 Ci-4 alkoxy, and C(O)NRR’; each R7is independently selected from the group consisting of halogen, OR, CN, unsubstituted or substituted Ci-6 alkyl, and unsubstituted or substituted Ci-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 Ci-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, 4 or 5; and k is 0, 1, 2, 3, 4 or 5, provided that the compound of formula (I) is characterized by a binding affinity to cyclin- dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM.

61. Use of a compound in the manufacture of a medicament for the treatment of a cannabinoid receptor type 2 (CB2R)-mediated disease or condition, wherein the compound has the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 alkyl, and C3-C.6 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 R ' is 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 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 Ci-6 alkyl, and unsubstituted or substituted C 1-4 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 C1-6 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, 4 or 5; and Hs O, 1, 2, 3, 4 or 5, provided that the compound of formula (I) is characterized by a binding affinity to cyclin- dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM.

62. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is selected from pain, inflammatory' pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic pain, visceral pain, migraine, cluster headache, cancer related pain, complex regional pain syndrome, neuralgias (e.g. trigeminal neuralgia), multiple sclerosis, autoimmune disorders, CNS inflammation, Alzheimer's disease, Parkinson's disease, dementia, amyotrophic lateral sclerosis, epilepsy, diabetes neuropathy, human immunodeficiency virus (HIV) polyneuropathy, psychiatric diseases, psychosis, autistic spectrum disorder, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, gastroesophageal reflux disease (GERD), constipation, diarrhoea, functional gastrointestinal disorder, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriatic arthritis disease, spondylitides, asthma, allergy, psoriasis, dermatitis, seasonal allergic rhinitis, systemic lupus erythematosus (SLE), acute allograft rejection, gingivitis, encephalitis, cutaneous T cell lymphoma, pancreatic cancer, systemic fibrosis, systemic sclerosis (SSc), vasculitis liver fibrosis, lung fibrosis, kidney fibrosis, keloids, hypertrophic scars, acute respiratory distress syndrome ( ARDS), reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis, bronchitis, glaucoma, age-related macular degeneration (AMD) and geographic atrophy, diabetic retinopathy, uveitis, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, glomerulonephritis, renal ischemia, nephritis, diabetic nephropathy, chronic allograft nephropathy, hepatitis, acute liver failure, livercirrhosis, non-alcoholic steatohepatitis (NASH), myocardial infarction, cerebral ischemia, ischemia-reperfusion injury, heart failure, stroke, myocardial ischemia, cardiomyopathy, transient ischemic attack, diabetes, osteoporosis, regulation of bone mass, non-alcoholic fattyliver (NAFL), attention-deficit hyperactivity disorder (ADHD), anxiety, autistic spectrum disorder, depression, insomnia / sleep disorders, obsessive compulsive disorder (OCD), post- traumatic stress disorder (PTSD), Tourette’s syndrome, malaria, and pyrexia, or a related disease or condition.

63. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is chronic pain.

64. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is osteoarthritis.

65. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

66. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is anxiety and / or depression.

67. Use of a compound according to claim 61, wherein the CB2R-mediated disease or condition is addiction.

68. A compound for use in treating a cannabinoid receptor type 2 (CB2R)-mediated disease or condition, wherein the compound has the structural Formula (I):or a pharmaceutically acceptable form or an isotope derivative thereof, whereinRing A is a 4- to 7-membered carbocyclic ring; each of R1and R2is independently selected from the group consisting of H, unsubstituted or substituted C1-C6 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 Ci-6 alkyl, unsubstituted or substituted Ci-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, Ci-4alkyl, 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 Ci-6 alkyl, and unsubstituted or substituted C 1-4 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 Ci-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; z is 0, 1, 2, 3, 4 or 5; and k is 0, 1, 2, 3, 4 or 5, provided that the compound of formula (I) is characterized by a binding affinity to cyclin- dependent kinase 2 (CDK2) as measured by IC50 of greater than 100 nM.

69. A compound for use of claim 68, wherein the CB2R-mediated disease or condition is chronic pain.

70. A compound for use of claim 68, wherein the CB2R-mediated disease or condition is osteoarthritis.

71. A compound for use of claim 68, wherein the CB2R-mediated disease or condition is a neuroinfl ammatory and / or neurodegenerative disease or condition.

72. A compound for use of claim 68, wherein the CB2R-mediated disease or condition is anxiety and / or depression.

73. A compound for use of claim 68, wherein the CB2R-mediated disease or condition is addiction.

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