4-substituted indole and indazole sulfonamido derivatives as PARG inhibitors

Abstract

To provide cell permeable PARG inhibitors.SOLUTION: Provided herein are a compound having the following formula, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, Ar, X1, X2, and ring B have the meanings as provided herein. The provided compounds are useful Poly ADP-ribose glycohydrolase (PARG) inhibitors.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 USC 119(e) of U.S. Provisional Application No. 62 / 903,438, filed September 20, 2019, the entirety of which is incorporated herein by reference for all purposes.

[0002] STATEMENT REGARDING RIGHTS TO INVETIONS RESULTING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable.

[0003] Reference to a "Sequence Listing," table, or computer program listing attachment submitted on a compact disc Not applicable. [Background technology]

[0004] 2. Background of the Invention Cancer is caused by uncontrolled and unregulated cell proliferation. This rapid proliferation often results in high levels of oxidative stress in tumors, damaging DNA and resulting in a greatly increased mutation rate. Therefore, tumor cells engage and are highly dependent on DNA damage repair mechanisms.

[0005] Single-strand breaks (SSBs) are the most common type of lesion occurring in cells, and PARG (poly ADP-ribose glycohydrolase), together with PARP, is involved in alternative repair mechanisms called single-strand break repair (SSBR) and base excision repair (BER) together with many other proteins.

[0006] One of the earliest events during single-strand DNA repair is the binding of PARP (poly ADP-ribose polymerase) to the break and the rapid synthesis of poly ADP-ribose (PAR) to itself. This molecular structure acts as a signal to bring in other DNA repair proteins, initially XRCC1, which then repair the break (Mortusewicz, Fouquerel et al. 2011). The signal initiated by these PAR chains is short-lived, as it is rapidly degraded by an enzyme called PAR glycohydrolase (PARG). The binding of PARP to PAR reduces its catalytic activity, thus facilitating the return of PARP to its catalytically active form by the activity of PARG (Curtin and Szabo 2013).

[0007] PARG exists as a single gene with isoforms present in the nucleus, mitochondria and cytoplasm. The only other protein with glycohydrolase activity is ARH3, which is localized to mitochondria (Mashimo, Kato et al. 2014). PARG is primarily known for its direct role in DNA repair, but it also influences PAR signaling in splicing, transcription and epigenetic pathways (Ji and Tulin 2009) (Le May, Iltis et al. 2012) (Dahl, Maturi et al. 2014) (Guastafierro, Catizone et al. 2013) (Caiafa, Guastafierro et al. 2009).

[0008] Cancer cells can become dependent on specific DNA repair pathways when other DNA repair mechanisms fail. Tumors with mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of SSBR. There is already some evidence that PARG depletion inhibits SSBR and reduces the viability of BRCA2-deficient cells (Fathers, Drayton et al. 2012). However, mutations in other tumors can result in defects in double-strand DNA repair mechanisms (so-called "BRCA-ness"), thereby sensitizing tumor cells to PARG inhibition.

[0009] PARG depletion has been studied in many mouse and human model systems. Mouse cells lacking or lacking PARG show increased sensitivity to experimental and clinical DNA damaging agents. However, PARG deficiency does not result in sensitivity to all agents (e.g., gemcitabine, camptothecin), suggesting that PARG functions specifically in certain DNA damage repair pathways, chemo- and radiotherapy (Fujihara, Ogino et al. 2009) (Shirai, Fujimori et al. 2013) (Zhou, Feng et al. 2010) (Zhou, Feng et al. 2011).

[0010] In humans, PARG depletion sensitizes lung, cervical and pancreatic cancer cells to γ-radiation or experimental DNA damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate) (Ame, Fouquerel et al. 2009) (Nakadate, Kodera et al. 2013) (Shirai, Poetsch et al. 2013).

[0011] PARP inhibitors are currently undergoing numerous clinical trials exploring the concept of synthetic lethality or chemosensitivity. Clinical resistance to PARP inhibitors has already been described (Drost and Jonkers 2014) (Barber, Sandhu et al. 2013), and therefore there is a need to find alternative inhibitors targeting DNA damage repair mechanisms. PARG inhibition may provide a therapeutic advantage in PARP inhibitor-resistant cells, as depletion of PARG results in a similar reduction in the percentage of SSBR as depletion of PARP1 (Fisher, Hochegger et al. 2007). Moreover, it has been reported that depletion of PARG results in a significantly different gene expression pattern than depletion of PARP in breast cancer cells (Frizzell, Gamble et al. 2009).

[0012] Although current models suggest that PARG depletion leads to PARP-dependent DNA repair effects, recent studies have demonstrated a different mechanism than PARP inhibition. Following genotoxic stimulation, PARG depletion, in contrast to PARP depletion, leads to a decrease in NAD levels, which leads to lung cancer cell death, which may be the result of energy failure (Erdelyi, Bai et al. 2009).

[0013] Cell-permeable PARG inhibitors are limited to compounds such as tannic acid or gallotannins, which have questionable specificity for PARG and limited bioavailability.

[0014] An object of the present invention is to provide a cell-permeable PARG inhibitor. Summary of the Invention

[0015] overview In one aspect, the present disclosure provides a compound of formula (I): [ka] (In the formula:X 1 is N or CR 8 where R 8is hydrogen, halo, C 1-2 Alkyl, and C 1-2 is haloalkyl; X 2 is selected from the group consisting of N, CH, and CF; R 1 are hydrogen, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1-2 Alkyl, C 1-2 Alkyl, and C 1-2 haloalkyl; R 2 and R 3 is C 1-2 is alkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl; Ar is a 5-membered heteroaryl; R 4 is C 1-3 Alkyl, C 1-3 Haloalkyl, Hydroxy C 1-3 selected from the group consisting of alkyl, -C(O)H and cyano; R 5 and R 6 are each independently absent or hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; R 7 are hydrogen, deuterium, halo, C 1-6 Alkyl, and C 1-6 haloalkyl; and Ring B is C 3-6 Cycloalkyl, phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl, where the phenyl, heteroaryl, heterocyclyl, fused heterocyclyl, spiroheterocyclyl, and bridged heterocyclyl of ring B are R a , R b , and / or Rc where R a is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy C 1-6 Alkyl, heteroaryl, heterocyclyl, -C(O)R d (R d is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is hydrogen or C 1-6 alkyl), -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl; or R f and R g together with the nitrogen atom to which they are attached form a heterocyclyl), or -S(O)NR h R i (R h and R i is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl or hydroxy C 1-6 alkyl; or R h and R i together with the nitrogen atom to which they are attached form a heterocyclyl, and R b and R c is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; or Ring B is Ra , R b , and / or R c 5-6 membered heterocyclyl substituted with R b and R c are on adjacent ring vertices and are joined to form a 4-6 membered heterocyclyl having 0-2 additional heteroatom ring vertices selected from N, O, and S, and R a is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy C 1-6 Alkyl, heteroaryl, heterocyclyl, -C(O)R d (R d is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is hydrogen or C 1-6 alkyl), -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl; or R f and R g together with the nitrogen atom to which they are attached form a heterocyclyl), and -S(O)NR h R i (R h and R i is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl or hydroxy C 1-6 alkyl; or R h and R itogether with the nitrogen atom to which they are attached form a heterocyclyl; and Furthermore, here R a Heteroaryl and heterocyclyl; R d phenyl, heteroaryl, and heterocyclyl, R f and R g And R h and R i The heterocyclyl formed by is unsubstituted or 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 substituted with 1, 2, or 3 substituents independently selected from haloalkoxy; or Pharmaceutically acceptable salts thereof are provided.

[0016] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0017] In another aspect, there is provided herein a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in therapy.

[0018] In another aspect, provided herein is a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in treating cancer. In one embodiment, the cancer is a human cancer.

[0019] In another aspect, provided herein is a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in producing a PARG inhibitory effect.

[0020] In another aspect, there is provided herein the use of a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer.Suitably, the medicament is for use in the treatment of cancer in humans.

[0021] In another aspect, provided herein is a compound of Formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in producing a PARG inhibitory effect.

[0022] In another aspect, provided herein is a method for inhibiting PARG in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof.

[0023] In another aspect, provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof.

[0024] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) (or any embodiment thereof), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein.

[0025] In another aspect, provided herein is a method for identifying PARG activity in a test compound for PARG inhibitory activity, the method comprising: (i) contacting the test compound with an isolated PARG enzyme, a biotinylated-PARYlated PARP substrate to form a PARG reaction premix; (ii) contacting the PARG reaction premix with a detection antibody and streptavidin-europium to form a PARG reaction mixture; and (iii) measuring the fluorescence intensity of the PARG reaction mixture, wherein the method further comprises performing steps (i)-(iii) using a positive control sample represented by formula (I) (or any embodiment thereof).

[0026] In another aspect, there is provided a method for synthesizing a compound of formula (I) (or any embodiment thereof) as described herein, or a pharma- ceutically acceptable salt thereof.

[0027] In another aspect, provided herein is a compound as described herein, or a pharma- ceutically acceptable salt thereof, obtainable, obtained, or directly obtained by the synthetic methods described herein.

[0028] In another aspect, provided herein are novel intermediates, as described herein, suitable for use in any one of the synthetic methods presented herein.

[0029] The preferred, appropriate, and optional features of any one particular embodiment of the present invention are also preferred, appropriate, and optional features of any other embodiment.

[0030] BRIEF DESCRIPTION OF THE DRAWINGS Not applicable.

[0031] Detailed Description of the Invention Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0032] Where a range of values ​​is provided, unless the context requires otherwise, it is understood that each intervening value between the upper and lower limit of that range, to the nearest tenth of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the invention. The lower and upper limits of these smaller ranges may be independently included in the smaller ranges and are also encompassed within the invention, subject to any specific excluded limit in the stated range. Where a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0033] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended to serve as a precondition for using exclusive terminology such as "solely," "only," and the like, or for using a "negative" limitation in connection with the recitation of claim elements.

[0034] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates which may need to be independently confirmed.

[0035] overview Provided herein are, for example, compounds and compositions for inhibiting PARG, and pharmaceutical compositions comprising the same.Also provided herein are, for example, methods for treating or preventing diseases, disorders or conditions, or symptoms thereof, mediated by the inhibition of PARG.

[0036] definition Unless otherwise stated, the following terms shall have the meanings set forth below. Other terms are defined elsewhere within this specification.

[0037] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, an alkyl group having a specified number of carbon atoms (i.e., C 1-8 means a saturated straight or branched chain hydrocarbon radical having 1 to 8 carbons. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0038] The term "alkylene" refers to a straight or branched chain saturated hydrocarbon radical having the indicated number of carbon atoms and which is attached to at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties attached to the alkylene can be attached to the same atom or to different atoms of the alkylene group. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0039] A "bridged heterocyclyl" is a heterocyclic ring structure formed from (X) n means a 5-7 membered saturated monocyclic heterocycle having two non-adjacent ring atoms linked by a group, n is 1-3, and each X is CRR', NR, S(O) n1 or O, where one or more X is NR, S(O) n1 or O, and R and R' are independently H or methyl (sometimes referred to herein as "bridging" groups). N, O, and S(O) n1 and the remaining ring atoms are carbon, where n1 is an integer from 0 to 2. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like. Further examples include 3,8-diazabicyclo[3.2.1]octane, and the like.

[0040] The term "cycloalkyl" refers to the alkyl group having the indicated number of ring atoms (e.g., C 3-6 Cycloalkyl refers to a saturated hydrocarbon ring having a carbon atom, unless otherwise specified. 1-6 Alkyl, halo, hydroxy, C 1-6 Haloalkyl, C 1-6 Optionally substituted with 1, 2 or 3 substituents independently selected from haloalkoxy, or cyano. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0041] The term "fused heterocyclyl," as used herein, means a saturated monocyclic ring of 4 to 7 ring atoms having 1 to 3 heteroatoms independently selected from N, N(oxide), O, S, SO, and SO2, with the remaining ring atoms being carbon, further wherein the heterocyclyl ring is selected from phenyl, 5- or 6-membered heteroaryl, or C, each as described herein, unless otherwise indicated. 3-6 The fused heterocyclyl may be attached to the remainder of the molecule through any ring atom. For clarity, the number of ring atoms in a saturated monocyclic ring does not include the number of ring vertices that are shared with the fused group (e.g., phenyl, 5- or 6-membered heteroaryl, or C 3-6 In addition, the cycloalkyl portion of the fused heterocyclyl group is substituted as described in the claims. Non-limiting examples of fused heterocyclyl include 2,3-dihydrobenzo[b][1,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, and the like.

[0042] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0043] The term "haloalkyl" means an alkyl, as defined above, substituted with one to five halo atoms, and includes monohaloalkyl and polyhaloalkyl. For example, "C 1-4 The term "haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0044] The terms "alkoxy" and "haloalkoxy" refer to an alkyl group and a haloalkyl group, respectively, each as described herein, that is attached to the remainder of the molecule via an oxygen atom.

[0045] The term "aminoalkyl" means an alkyl, as described above, substituted with one NRR', where R and R' are independently hydrogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, or -COC 1-6 For example, "amino C 1-6 The term "alkyl" is meant to include NH2 methyl, methylaminoethyl, diethylaminoethyl, dimethylaminoethyl, acetylaminoethyl and the like.

[0046] The term "aryl", unless otherwise indicated, means an aromatic, hydrocarbon group, which may be monocyclic or heterocyclic (up to three rings), which are fused or covalently linked to each other. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl.

[0047] The term "heteroaryl" refers to a 5-10 membered aromatic ring containing 1-5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like.

[0048] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated 4-10 membered monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. The nitrogen and sulfur atoms are optionally oxidized, the nitrogen atom(s) are optionally quaternized, and one or two ring carbon atoms of the heterocycle may be replaced by a -C=(O) group. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or heteroatom. Non-limiting examples of heterocycloalkyl groups include pyridin-2(H)-one.

[0049] The term "spiroheterocyclyl" as used herein means a saturated or partially unsaturated bicyclic ring of 5 to 12 ring atoms, where 1 to 3 ring atoms are heteroatoms independently selected from N, N(oxide), O, S, SO, and SO2, the remaining atoms are carbon, and the two rings are bonded together at one common atom. Non-limiting examples of spiroheterocyclyl include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octan-6-yl, 4-oxaspiro[2.4]heptanyl, spiro[3.5]non-6-ene, and 2,7-diazaspiro[4.4]nonanyl.

[0050] The term "hydroxyalkyl" refers to an alkyl substituted with one or two hydroxy groups, as described above. For example, "hydroxyC 1-4The term "alkyl" is meant to include hydroxymethyl, 1- or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, and the like.

[0051] As used herein, a wavy line "" that crosses a single bond, double bond, or triple bond in any chemical structure shown herein is "TIFF2025016684000002.tif5161" represents the point of attachment of that single, double, or triple bond to the remainder of the molecule. Additionally, a bond extending into the center of a ring (e.g., a phenyl ring) is meant to show a bond at any available ring vertex. One of skill in the art will understand that multiple substituents shown as attached to a ring will provide a stable compound and occupy any ring vertex that is otherwise sterically compatible.

[0052] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[0053] The term "pharmaceutical acceptable salts" is meant to include salts of compounds of formula (I) prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of formula (I) contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutical acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When a compound of formula (I) contains a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogen phosphate, dihydrogen phosphate, sulfuric, monohydrogen sulfate, hydridic, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.Also included are salts of amino acids, such as arginic acid, and organic acids, such as glucuronic acid and galactunoric acids (see, e.g., Berge, SM et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the present invention contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts.

[0054] The neutral form of the compound of formula (I) can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this invention. In addition to salt forms, compounds of formula (I) are provided herein in prodrug form. Prodrugs of compounds of formula (I) are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of formula (I). In addition, prodrugs can be converted to compounds of formula (I) by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds of formula (I) when placed in a reservoir of a transdermal patch with the aid of suitable enzymes or chemical reagents. Prodrugs are described in more detail elsewhere herein.

[0055] Certain compounds of formula (I) can exist in solvated forms, including hydrated forms, as well as nonsolvated forms. In general, solvated forms are equivalent to nonsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of formula (I) can exist in polycrystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated by the present invention and are intended to be included within the scope of the present invention.

[0056] Certain compounds of formula (I) have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical depiction is shown, it is meant to refer to a compound in which one of the isomers is present and the other isomer is substantially free. "Substantially free" of the other isomer indicates that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0057] The compounds of formula (I) may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to the amount consisting of 100% of that atom. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 Non-radioactive isotopes such as 1,2-dichlorophenyl isotopes (C) may be incorporated. Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of compounds of formula (I) may alter pharmacokinetic and pharmacodynamic properties that may contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variants of compounds of formula (I), whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0058] The terms "patient" or "subject" are used interchangeably to refer to a human or a non-human animal (e.g., a mammal). In one embodiment, the patient or subject is a human.

[0059] The terms "administration," "administering," and the like, when applied to, for example, a subject, cell, tissue, organ, or bodily fluid, refer to contacting, for example, a PARG inhibitor, a pharmaceutical composition containing same, or a diagnostic agent with a subject, cell, tissue, organ, or bodily fluid. In the case of a cell, administration includes contacting the reagent with the cell (e.g., in vitro or ex vivo), as well as contacting the reagent with a fluid where the fluid is in contact with the cell.

[0060] The terms "treat," "treating," "treatment," and the like refer to a course of action (such as administration of a PARG inhibitor or a pharmaceutical composition comprising same) initiated after a disease, disorder, or condition, or a symptom thereof, has been diagnosed or observed, to temporarily or permanently eliminate, reduce, inhibit, alleviate, or ameliorate at least one of the underlying causes of the disease, disorder, or condition afflicting the subject, or at least one of the symptoms associated with the disease, disorder, or condition afflicting the subject. Thus, treatment includes inhibiting an active disease (e.g., preventing the onset or further progression of a disease, disorder, or condition, or clinical symptoms associated therewith).

[0061] As used herein, the term "in need of treatment" refers to the judgment by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are within the physician's or caregiver's expertise.

[0062] The terms "prevent", "preventing", "prevention", and the like generally refer to a course of action (such as administration of a PARG inhibitor or a pharmaceutical composition comprising the same) that is initiated (e.g., prior to the onset of a disease, disorder, condition, or symptoms thereof) to temporarily or permanently prevent, suppress, inhibit, or reduce the subject's risk of developing a disease, disorder, condition, or the like (e.g., as defined by the absence of clinical symptoms), or to delay the onset of the disease, disorder, condition, or the like, in the context of a subject prone to having a particular disease, disorder, or condition. In some cases, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state.

[0063] As used herein, the term "prophylaxis is necessary" refers to the judgment by a physician or other caregiver that a subject needs or would benefit from preventative care. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0064] The terms "inhibiting" and "reducing" in relation to PARG, or any variation of these terms, include any measurable reduction or complete inhibition to achieve a desired result. For example, there may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more reduction in PARG activity compared to normal. As used herein, about means within ±10%, preferably within ±5% of a given value.

[0065] The phrase "therapeutically effective amount" means that an agent is administered to a subject in an amount that, alone or as part of a pharmaceutical composition, and in a single dose or as part of a series of doses, can have any detectable, positive effect on any symptom, aspect or characteristic of a disease, disorder or condition when administered to a subject. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect, and can be adjusted in conjunction with dosing regimens and diagnostic analysis of the subject's condition, and the like. As an example, measuring the serum level of a PARG inhibitor (or, for example, its metabolite) at a particular time after administration can indicate whether a therapeutically effective amount has been used.

[0066] The term "substantially pure" indicates that a component constitutes greater than about 50% of the total content of the composition, and typically greater than about 60% of the total content. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, at least 90% or more of the total composition is the component of interest. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] 1. In embodiment 1, the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is as described in the Summary.

[0068] 2. In embodiment 2, the compound of formula (I) according to embodiment 1, or a pharma- ceutically acceptable salt thereof, is 1 is N.

[0069] 3. In embodiment 3, the compound of formula (I) according to embodiment 1, or a pharma- ceutically acceptable salt thereof, is X 1 CR 8 In a first subembodiment of embodiment 3, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 8 is hydrogen, fluoro, methyl, ethyl, difluoromethyl, or trifluoromethyl. In a second subembodiment of embodiment 3, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is8 is hydrogen, fluoro, or methyl. In a third subembodiment of embodiment 3, the compound of formula (I) or a pharma- ceutically acceptable salt thereof comprises R 8 In a fourth subembodiment of embodiment 3, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 8 Halo, C 1-2 Alkyl, or C 1-2 It is haloalkyl.

[0070] 4. In embodiment 4, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 3 and subembodiments therein may comprise X 2 is CH or CF. In a first subembodiment of embodiment 4, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2 is CH.

[0071] 5. In embodiment 5, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 3 and subembodiments therein may comprise X 2 is N.

[0072] 6. In embodiment 6, the compound of formula (I) according to any one of embodiments 1 to 5 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 1 is hydrogen, cyano, methyl, or ethyl. In a first subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 In a second subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has R 1 In a third subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 In a fourth subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 C 1-2In a fifth subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 1 In a sixth subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 Cyano or C 1-2 In a sixth subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 1 Cyano, C 1-2 In a seventh subembodiment of embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 1 is cyano or -CONH2.

[0073] 7. In embodiment 7, the compound of formula (I) according to any one of embodiments 1 to 6 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 7 is hydrogen, deuterium, fluoro, chloro, methyl, difluoromethyl, or trifluoromethyl. In a first subembodiment of embodiment 7, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 7 is hydrogen, chloro, or fluoro. In a second subembodiment of embodiment 7, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 7 In a second subembodiment of embodiment 7, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has R 7 In a third subembodiment of embodiment 7, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 7 C 1-6 Alkyl, and C 1-6 It is haloalkyl.

[0074] 8. In embodiment 8, the compound of formula (I) according to any one of embodiments 1 to 7 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 2 and R 3 C1-2 In a first subembodiment of embodiment 8, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 and R 3 are independently methyl or ethyl, preferably methyl.

[0075] 9. In embodiment 9, the compound of formula (I) according to any one of embodiments 1 to 7 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl.

[0076] 10. In embodiment 10, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9 and subembodiments therein, wherein Ar is imidazolyl, isoxazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl. In a first subembodiment of embodiment 10, the compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein Ar is 1,3,4-thiadiazol-2-yl. In a second subembodiment of embodiment 10, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Wherein Ar is imidaZolyl, isoxaZolyl, pyraZolyl, 1,2,3-triaZolyl, 1,2,4-triaZolyl, thiaZolyl, 1,2,4-thiadiaZolyl, or 1,3,4-thiadiaZolyl. In a third subembodiment of embodiment 10, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Wherein Ar is 1,2,4-thiadiaZolyl, or 1,3,4-thiadiaZolyl.

[0077] 11. In embodiment 11, the compound of formula (I) according to any one of embodiments 1 to 10 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 4is attached to a carbon atom of Ar that is meta to the atom of Ar that is attached to a nitrogen atom of the remainder of the molecule. In a first subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof comprises R 4 is methyl, ethyl, difluoromethyl, trifluoromethyl, cyano, or C(OH). In a second subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 4 is difluoromethyl, cyano, or C(O)H. In a third subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 4 In a fourth subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is selected from the group consisting of R 4 In a fifth subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 4 C 1-3 In a sixth subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 4 C 1-3 Alkyl, Hydroxy C 1-3 In a sixth subembodiment of embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 4 C 1-3 Alkyl or Hydroxy C 1-3 It is an alkyl.

[0078] 12. In embodiment 12, the compound of formula (I) according to any one of embodiments 1 to 11 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, may comprise R 5 and R 6 is each independently hydrogen or absent. In a first subembodiment of embodiment 12, the compound of formula (I) according to any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, comprises R 5 and R 6In a second subembodiment of embodiment 12, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 11 is absent. 5 and R 6 is hydrogen.

[0079] 13. In embodiment 13, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 12 and subembodiments therein, wherein ring B is C 3-6 In a first subembodiment of embodiment 13, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is wherein Ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0080] 14. In embodiment 14, the compound of formula (I) according to any one of embodiments 1 to 12 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, wherein ring B is R, as described in the Summary section. a , R b , and / or R c In a first subembodiment of embodiment 14, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring B is phenyl substituted with R a , R b , and / or R c phenyl substituted with, where R a is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, Hydroxy C 1-6 Alkyl, heteroaryl, -C(O)R d (R d is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is hydrogen or C 1-6 alkyl), -C(O)NR f Rg (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; and further wherein R a Heteroaryl of R d The phenyl, heteroaryl, and heterocyclyl are unsubstituted or 1-6 Alkyl, and C 1-6 In a second subembodiment of embodiment 14, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is substituted with one, two, or three substituents independently selected from haloalkyl. a phenyl substituted with, where R a -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl).

[0081] 15. In embodiment 15, the compound of formula (I) according to any one of embodiments 1 to 12 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, wherein ring B is R, as described in the Summary section. a , R b , and / or R cIn a first subembodiment of embodiment 15, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein Ring B is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, each ring being substituted with R a , R b , and / or R c where R a is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, Hydroxy C 1-6 Alkyl, heteroaryl, -C(O)R d (R d is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is hydrogen or C 1-6 alkyl), -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl or hydroxy C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; and further wherein R a Heteroaryl of R d The phenyl, heteroaryl, and heterocyclyl are unsubstituted or 1-6 Alkyl, and C 1-6In a second subembodiment of embodiment 15, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is substituted with one, two, or three substituents independently selected from haloalkyl, ... a where R a is hydrogen, C 1-6 Alkyl, or C 1-6 In a third subembodiment of embodiment 15, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein ring B is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, each ring being independently selected from the group consisting of R a where R a C 1-6 Alkyl, or C 1-6 It is an alkoxy.

[0082] 16. In embodiment 16, the compound of formula (I) according to any one of embodiments 1 to 12 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, wherein ring B is R, as described in the Summary section. a , R b , and / or R c In a first subembodiment of embodiment 16, the compound of Formula (I), or a pharma- ceutically acceptable salt thereof, is a compound wherein Ring B is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl, and each ring is substituted with R a , R b , and / or R c where R a is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, Hydroxy C 1-6 Alkyl, heteroaryl, -C(O)R d (R d is hydrogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is hydrogen or C 1-6 alkyl), -C(O)NR f R g (where R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 Alkyl, Hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; and further, R a Heteroaryl of R d The phenyl, heteroaryl, and heterocyclyl are unsubstituted or 1-6 Alkyl, and C 1-6 In a first subembodiment of the first subembodiment of embodiment 16, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein Ring B is morpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, azetin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, 6-oxo-1,6-dihydropyridin-3-yl, or piperazin-1-yl, and R a is attached at the para position to the ring atom connecting each ring to the remainder of the molecule. In a second subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a is hydrogen, C 1-6 Alkyl, hydroxy, halo, C 1-6 Haloalkyl, Hydroxy C 1-6 alkyl, heteroaryl, -C(O)R d (Rd is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl or heterocyclyl), -C(O)OR e (R e C 1-6 alkyl), -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and Amino C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 alkyl, and halo; and further, R a Heteroaryl of R d The heterocyclyl of is unsubstituted or 1-6 Alkyl, and C 1-6 In a third subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is substituted with one, two, or three substituents independently selected from haloalkyl. a is hydrogen, C 1-6 Alkyl, hydroxy, halo, C 1-6 Haloalkyl, or hydroxy C 1-6 In a fourth subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R a is hydrogen, C 1-6 Alkyl, hydroxy, halo, C 1-6 Haloalkyl, or hydroxy C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 In a fourth subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is independently selected from R a -C(O)R d (R d is hydrogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e C 1-6 alkyl), -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and Amino C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 alkyl, and halo; and further R d The heterocyclyl of is unsubstituted or 1-6 Alkyl, and C 1-6 In a fifth subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is substituted with one, two, or three substituents independently selected from haloalkyl. a is heteroaryl, and R b and R c is hydrogen, C 1-6 alkyl, and halo; and further R a Heteroaryl of C 1-6 Alkyl, and C 1-6 In a sixth subembodiment of embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is substituted with one, two, or three substituents independently selected from haloalkyl. a -C(O)NR f R g (R f and R g is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and Amino C 1-6 alkyl), and R b and R c is hydrogen, C 1-6 alkyl, and halo.

[0083] 17. In embodiment 17, the compound of formula (I) according to any one of embodiments 1 to 12 and subembodiments therein, or a pharma- ceutically acceptable salt thereof, further comprises a compound in which ring B is a bicyclic heterocylyl, a fused heterocylyl, a spiroheterocyclyl, or a bridged heterocyclyl, each of which may be selected from the group consisting of R, R, R, and ... a , R b , and / or R c In some embodiments, ring B is substituted with R a , R b and R c and R is a 5-6 membered heterocyclyl having 1-3 heteroatom ring vertices selected from N, O, and S substituted with b and R c are on adjacent ring vertices and are linked to form a 4-6 membered heterocyclyl having 0-2 additional heteroatom ring vertices selected from N, O, and S. In a first subembodiment of embodiment 17, the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein Ring B is 2-oxaspiro[3.5]non-6-en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6-azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1-oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2 ... spiro[3.3]hept-2-yl, 2,8-diazaspiro[4.5]dec-8-yl, 7-oxa-3-azabicyclo[3.3.0]oct-3-yl, 8-oxa-3-azabicyclo[4.3.0]non-3-yl, 2-oxa-6-azaspiro[3.5]non-6-yl, 7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl, 3-pyrrolino[3,4-c]pyrazol-2-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, 2,7-diazaspiro[3.5]non-7-yl, each ring being R a Optionally replaced by R ais hydrogen or alkyl. In some embodiments, ring B has the formula: [ka] is selected from the group consisting of: 18. In embodiment 18, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 13, 16, and 17, and subembodiments therein, is characterized in that the compound of formula (I) has the following formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof. 19. In embodiment 19, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 13, 16, and 17, and subembodiments therein, is characterized in that the compound of formula (I) has the following formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof. 20. In embodiment 20, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 13, 16, and 17, and subembodiments therein, is characterized in that the compound of formula (I) is represented by the following formula (Ic), the following formula (Id), the following formula (Ie), or the following formula (If): [ka] or a pharma- ceutically acceptable salt thereof. 21. In embodiment 21, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9, and 11 to 20, and subembodiments therein, is such that Ar is not 1,3,4-oxadiazolyl. 22. In embodiment 22, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9, and 11 to 20, and subembodiments therein, is such that Ar is not 1,2,4-oxadiazolyl. 23. In embodiment 23, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9, and 11 to 20 and subembodiments therein, wherein Ar is not 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl. 24. In embodiment 24, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9 and 11 to 23 and subembodiments therein, wherein Ar is imidazolyl, isoxazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl. In a first subembodiment of embodiment 24, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 9 and 11 to 23 and subembodiments therein, wherein Ar is 1,3,4-thiadiazol-2-yl.

[0084] biological activity The PARG enzyme and cellular assays described in the accompanying Examples section can be used to measure the pharmacological effects of the compounds of the invention.

[0085] Although the pharmacological properties of the compounds of formula (I) vary with structural changes, as expected, the compounds of the invention show activity in these PARG assays.

[0086] Generally, compounds of the invention have an IC of 10 μM or less in the PARG enzyme assay described herein. 50 and preferred compounds of the invention have IC of 1000 nM or less, or 500 nM or less. 50 and the most preferred compounds of the present invention have an IC of 200 nM or less. 50 Demonstrate the following.

[0087] Generally, compounds of the invention have an IC of 1 μM or less in the PARG cellular assay described herein. 50 and preferred compounds of the invention have an IC of 500 nM or less. 50 and the most preferred compounds of the present invention have an IC of 200 nM or less. 50 Demonstrate the following.

[0088] Pharmaceutical Compositions There is also provided a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable diluent or carrier.

[0089] The compositions may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0090] The compositions can be obtained by conventional procedures using conventional pharmaceutical additives well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0091] An effective amount of a compound of formula (I) or a pharmaceutical salt thereof for use in the treatment of cancer is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0092] The amount of active ingredient that is combined with one or more excipients to produce a dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain from 0.5 mg to 0.5 g of a compound of formula (I) or a pharmaceutical salt thereof (more suitably from 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with appropriate and convenient amounts of excipients that may vary, for example, from about 5 to about 98% by weight of the total composition.

[0093] The size of an dose of a compound of formula (I) administered for therapeutic or prophylactic purposes will naturally vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0094] In using the compound of formula (I) or a pharmaceutical salt thereof for therapeutic or prophylactic purposes, it will generally be administered to receive a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg body weight, divided as necessary. In general, lower doses will be administered when administered parenterally. Thus, for example, for intravenous or intraperitoneal administration, generally, doses ranging, for example, from 0.1 mg / kg to 30 mg / kg body weight will be used. Similarly, for administration by inhalation, doses ranging, for example, from 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration is also suitable, particularly in the form of tablets. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compound of the invention.

[0095] Therapeutic Uses and Applications Provided herein are compounds that function as PARG inhibitors.

[0096] Thus, the present invention provides a method for inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutical salt thereof.

[0097] The present invention also provides a method for selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutical salt thereof.

[0098] The present invention also provides a method of treating a disease or disorder in which PARG activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition described herein.

[0099] The present specification also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutical salt thereof.

[0100] Provided herein is a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition as described herein.

[0101] Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition as described herein.

[0102] The present disclosure provides a compound of formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition as described herein for use in therapy.

[0103] The present disclosure provides a compound of formula (I), or a pharmaceutical salt thereof, or a pharmaceutical composition as described herein for use in the treatment of a proliferative condition.

[0104] The present disclosure provides a compound of formula (I) or a pharmaceutical salt thereof, or a pharmaceutical composition as described herein, for use in treating cancer. In certain embodiments, the cancer is a human cancer.

[0105] The present disclosure provides a compound of Formula (I) as described herein, or a pharmaceutical salt thereof, for use in inhibiting PARG enzyme activity.

[0106] Provided herein is a compound of Formula (I) as described herein, or a pharmaceutical salt thereof, for use in the treatment of a disease or disorder in which PARG activity is implicated.

[0107] Provided herein is the use of a compound of Formula (I) or a pharmaceutical salt thereof as described herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0108] The present specification provides the use of a compound of formula (I) or a pharmaceutical salt thereof as described herein in the manufacture of a medicament for the treatment of cancer, suitably the medicament is for use in the treatment of cancer in humans.

[0109] Provided herein is the use of a compound of formula (I) or a pharmaceutical salt thereof in the manufacture of a medicament for the inhibition of PARG enzyme activity.

[0110] Provided herein is the use of a compound of formula (I) or a pharmaceutical salt thereof in the manufacture of a medicament for selectively inhibiting PARG enzyme activity over PARP1 or ARH3 enzyme activity.

[0111] Provided herein is the use of a compound of formula (I) or a pharmaceutical salt thereof in the manufacture of a medicament for treating a disease or disorder in which PARG activity is implicated.

[0112] The term "proliferative disorder" is used interchangeably herein and refers to the undesired or uncontrolled proliferation of unwanted excess or abnormal cells, e.g., neoplastic or hyperplastic proliferation, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis, including, but not limited to, premalignant and malignant cell proliferation. Any cell type can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0113] The antiproliferative properties of the compounds of formula (I) or pharmaceutical salts thereof (through their inhibition of PARG enzyme activity) have particular application in the treatment of human cancer.

[0114] Anti-cancer effects may occur through one or more mechanisms, including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of tumors from the primary site), inhibition of invasion (spread of tumor cells into nearby normal structures), or promotion of apoptosis (programmed cell death).

[0115] In certain embodiments of the invention, the proliferative condition to be treated is cancer.

[0116] Route of administration The compounds of formula (I) or pharmaceutical salts thereof or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[0117] Routes of administration include, but are not limited to; oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, bandages, etc.); transmucosal (including, e.g., by patches, bandages, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, e.g., via aerosol, e.g., used through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; implantation of a depot or reservoir (e.g., subcutaneous or intramuscular).

[0118] Combination therapy The anti-proliferative treatments described herein above may be applied as monotherapy or may involve, in addition to the compound of formula (I) or a pharmaceutical salt thereof, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosoureas); antimetabolites (e.g., gemcitabine, and antifolates, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine, tetracycl ... antitumor antibiotics (e.g., anthracyclines such as 31ecarbonat, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbicine, and 31ecarbo- and polo-like kinases such as taxol and taxotere); and topoisomerase inhibitors (e.g. epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin); cell proliferation inhibitors such as antiestrogens (e.g. tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists. (e.g. goserelin, leuprorelin and buserelin), progestins (e.g. megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors such as finasteride; anti-infiltrative agents [e.g. 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530;c-Src kinase family inhibitors such as International Patent Application WO 01 / 94341), N-(2-chloro-6-methoxyphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (31ecarbona, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors such as marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies against heparanase]; growth factor function inhibitors: for example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin; TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody have been described by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp 11-29)); such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; platelet derived growth factor family inhibitors such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., farnesyltransferase inhibitors, e.g., sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell 32ecarbona via MEK and / or AKT kinases, Ras / Raf inhibitors such as c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors. 32ecarbona inhibitors); cyclin-dependent kinase inhibitors such as Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and CDK2 and / or CDK4 inhibitors; anti-angiogenic agents such as those that inhibit the action of vascular endothelial growth factor, [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM) and for example vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO VEGF receptor tyrosine kinase inhibitors, such as those compounds disclosed in WO 98 / 13354, and compounds acting by other mechanisms (e.g., linomide, inhibitors of integrin αvβ3 function and angiostatin); vascular damaging agents, such as combretastatin A4 and the compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; antisense therapies, such as ISIS 2503, those that act directly on the targets listed above, such as anti-ras-antisense; gene therapy approaches, including approaches that replace mutant genes, such as mutant p53 or mutant BRCA1 or BRCA2, GDEPT (gene targeted enzyme prodrug therapy) approaches, such as those that use cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches that increase a patient's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy;and other anti-proliferative / antineoplastic agents and combinations thereof used in medical oncology, such as ex vivo and in vivo approaches to increase the immunogenicity of the patient's tumor cells, such as transfection of cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and immunotherapeutic approaches such as anti-idiotypic antibodies;

[0119] In certain embodiments, the antiproliferative treatments described herein above may comprise, in addition to a compound of formula (I) or a pharmaceutical salt thereof, conventional surgery or radiation therapy or chemotherapy.

[0120] Such combination treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the dosage ranges set forth hereinabove and the other pharma- ceutical active agent(s) within their approved dosage ranges.

[0121] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancer involving solid tumours) comprising a compound of formula (I) or a pharmaceutical salt thereof, and another anti-tumour agent.

[0122] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition such as cancer (e.g. cancer involving solid tumours), comprising a compound of formula (I) or a pharmaceutical salt thereof and any one of the anti-tumour agents described herein above.

[0123] In a further aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutical salt thereof for use in the treatment of cancer in combination with another anti-tumour agent optionally selected from those listed herein above.

[0124] In this specification, when the term "combination" is used, it should be understood that it refers to simultaneous, separate or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0125] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutical salt thereof, in combination with an anti-tumour agent (optionally selected from those listed herein above), in association with a pharma- ceutically acceptable diluent or carrier. EXAMPLES

[0126] Working Example The following references (intermediates) and examples (final compounds) are presented to provide one of ordinary skill in the art with a complete disclosure and description of how to make and use the invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments have been performed or that they are all of the experiments that may be performed. It should be understood that the exemplary descriptions written in the present tense have not necessarily been performed, but rather may be performed to generate data of the nature described therein, etc. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0127] Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including: μg = microgram; μl or μL = microliter; mM = millimolar; μM = micromolar; aa = amino acid(s); Ac2O = acetic anhydride; AcCl = acetyl chloride; ACN = acetonitrile; AIBN = 2,2'-azobis(2-methylpropionitrile); BID = twice daily; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc2O or (Boc)2O = di-tert-butyl carbonate; bp = base pair(s); BSA = bovine serum albumin; BW = body weight; d = doublet; dd = double doublet; DEAD = diethyl azodicarboxylate; DIBAL = diisobutylaluminum hydride. DIEA = N,N-diisopropylethylamine; DIPEA = N,N-diisopropylethylamine; dl or dL = deciliter; DMA = dimethylacetamide; DMAP = dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMEM = Dulbecco's modified Eagle's medium; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; DTT = dithiothreitol; EDTA = ethylene EDTA; ES = electrospray; EtOAc or EA = ethyl acetate; EtOH = ethanol; g = grams; h or hr = hour(s); HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPES = 4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acid; HOAc = acetic acid; HPLC = high performance liquid chromatography; HPLC = high pressure liquid chromatography; im = intramuscular; ip= intraperitoneal; IHC = immunohistochemistry; IPA = isopropyl alcohol; kb = kilobase(s); kDa = kilodalton; kg = kilogram; l or L = liter; LC = liquid chromatography; LCMS = liquid chromatography mass spectrometry; m / z = mass to charge ratio; M = molar; m = multiplet; MeCN = acetonitrile; MeOH = methanol; MeSO2Cl = methanesulfonyl chloride; mg = milligram; min = minute(s); min = minute; ml or mL = milliliter; mM = millimolar; MS = mass spectrometry; MsCl = methanesulfonyl chloride; N = normal; NADPH = nicotinamide adenine dinucleotide phosphate; NBS = N-bromosuccinimide; ng = nanogram; nm = nanometer; nM = nanomolar; NMP = N-methylpyrrolidone; NMR = nuclear magnetic resonance; ns = not statistically significant;nt = nucleotide(s);PBS = phosphate buffered saline;Pd / C = palladium on carbon;Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium;Pd(dppf)Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride;PE = petroleum ether;QD = daily;QM = monthly;QW = weekly;rac = racemic;Rt = retention time;s = singlet;s or sec = second(s);sat. = saturated;SC or SQ = subcutaneous (in);t = triplet;TBAB = tetra-n-butylammonium bromide;TEA = triethylamine;TFA = trifluoroacetic acid;THF = tetrahydrofuran;TLC = thin layer chromatography;TMSCl = trimethylsilyl chloride;TsOH = p-toluenesulfonic acid;U = units;wt = wild type.

[0128] Reference 1 Synthesis of 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride [ka] Step 1: Synthesis of 6-(benzylthio)-4-chloro-1H-indazole To a stirred mixture of 6-bromo-4-chloro-1H-indazole (15.00 g, 64.800 mmol, 1.00 equiv.) and phenylmethanethiol (24.14 g, 194.364 mmol, 3.00 equiv.) in 1,4-dioxane (150 mL) in a 500 mL 3-neck round bottom flask, Xantphos (3.75 g, 6.481 mmol, 0.10 equiv.) and DIEA (25.13 g, 194.440 mmol, 3.00 equiv.) were added portionwise at room temperature under nitrogen atmosphere. To the above mixture, Pd2(dba)3-CHCl3 (2.97 g, 3.243 mmol, 0.05 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for another 3 h. The residue was purified by silica gel column chromatography eluting with DCM:MeOH (100:1) to give the title compound (16.5 g).

[0129] Step 2: Synthesis of 2-(6-(benzylthio)-4-chloro-1H-indazol-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole To a stirred solution of 6-(benzylsulfanyl)-4-chloro-1H-indazole (5.1 g, 18.561 mmol, 1 equiv.) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (7.98 g, 37.122 mmol, 2 equiv.) in DMF (100 mL) in a 250 mL 3-neck round-bottom flask, Cs2CO3 (6.05 g, 18.569 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at 60° C. under nitrogen atmosphere for 1 h. The reaction was quenched by the addition of water and the aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluted with CH2Cl2 / MeOH (100 / 1)) to give the title compound (7 g).

[0130] Step 3: Synthesis of 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride To a stirred solution of 2-(6-(benzylthio)-4-chloro-1H-indazol-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (20.00 g, 48.915 mmol, 1.00 equiv.) and AcOH (2.5 mL) and HO (5.00 mL) in MeCN (200.00 mL) in a 500 mL 3-neck round bottom flask at 0° C. under nitrogen atmosphere was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (14.46 g, 73.394 mmol, 1.50 equiv.) in portions. The resulting mixture was stirred at 0° C. under nitrogen atmosphere for 2 h and then concentrated in vacuo to give the title compound (30 g, crude) as a brown solid. The crude product was used directly in the next step without further purification.

[0131] Reference 2 Synthesis of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide [ka] Into a 2 L 3-neck round bottom flask containing pyridine (300 mL), 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride (30.00 g, 77.886 mmol, 1.00 equiv.) and 1-aminocyclopropane-1-carbonitrile hydrochloride salt (17.14 g, 77.904 mmol, 1.00 equiv.) were added at 0° C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum, then the pH value of the solution was adjusted to 5 with HCl (1 mol / L), and then extracted with ethyl acetate. The organic layers were combined and concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH (50:1)) to give the title compound (17 g). LCMS (ES, m / z): [M+H] + 431

[0132] Reference 3 Synthesis of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indazole-6-sulfonamide [ka] To a stirred solution of 1-methylcyclopropan-1-amine hydrochloride (0.50 g, 4.648 mmol, 1.20 equiv.) and pyridine (22.5 mL) in a 50 mL 3-neck round-bottom flask, 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonyl chloride (1.50 g, 3.894 mmol, 1.00 equiv.) was added. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere and then concentrated under vacuum. The pH value of the solution was adjusted to 5 with HCl (1 mol / L) and the resulting solution was extracted with ethyl acetate. The combined organic layers were concentrated under vacuum and the residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 1)) to give the title compound (410 mg). LCMS (ES, m / z): [M+H] + 420

[0133] Reference 4 4-Chloro-N-(1-cyanocyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide [ka] The title compound was prepared according to the procedures described in References 2 and 3 above by substituting 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole for 2-bromo-5-methyl-1,3,4-thiadiazole in step 2 of Reference 2.

[0134] Reference 5 Synthesis of 4-chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indole-6-sulfonamide [ka] The title compound was prepared in step 2 of Reference 2 by proceeding as described in References 2 and 3 above, but substituting 6-bromo-4-chloro-1H-indazole with 6-bromo-4-chloro-1H-indole in step 2 of Reference 2.

[0135] Example 1 Synthesis of 1[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-phenyl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (100 mg, 0.232 mmol, 1 equiv.), phenylboronic acid (141.51 mg, 1.161 mmol, 5.00 equiv.) and K2CO3 (64.16 mg, 0.464 mmol, 2 equiv.) in dioxane (1.5 mL) in an 8 mL vial, Pd(DtBPF)Cl2 (15.13 mg, 0.023 mmol, 0.1 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere and then quenched with water. The aqueous layer was extracted with EtOAc and the combined EtOAc extracts were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=70:1) to give the crude product (60 mg). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column 30x150mm 5um; Mobile phase A: Water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 53% B in 7 min; 254; 220 nm; RT 5.67 min) to give the title compound (29.4 mg) as a white solid. LCMS (ES, m / z): [M+H] +473;1H-NMR(300MHz,DMSO-d6,ppm)δ1.29-1.51(m,4H),7.46-7.71(m,4H),7.7.83(d,2H),7.98(s,1H),8.93(s,1H),9.04(s,1H),9.50(brs,1H).

[0136] Example 2 Synthesis of 1-[({4-(1H-indazol-6-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 1 by substituting 1H-indazol-6-ylboronic acid for phenylboronic acid. LCMS (ES, m / z): [M+H] + 513; 1 H-NMR(300MHz,DMSO-d6,ppm)δ13.35(s,1H),9.54(s,1H),9.04(s,1H),8.97(s,1H) ,8.23(s,1H),8.01-8.04(m,2H),7.91(s,1H),7.46-7.82(m,2H),1.34-1.54(m,4H).

[0137] Example 3 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))phenyl]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 1 by substituting 4-(dimethylcarbamoyl)phenylboronic acid for phenylboronic acid. LCMS (ES, m / z): [M+H] + 544; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.52(s,1H),9.06(s,1H),8.98(s,1H),8.00(s,1 H),7.90-7.87(d,2H),7.82-7.46(m,3H),3.04-3.01(d,6H),1.52-1.34(m,4H).

[0138] Example 4 Synthesis of [3-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))phenyl]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described in Example 1 by substituting 3-(dimethylcarbamoyl)phenylboronic acid for phenylboronic acid. LCMS (ES, m / z): [M+H] + =544; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.52(s,1H),9.06(s,1H),8.92(s,1H),7.99(s,1H),7.90- 7.92(d,1H),7.51-7.81(m,4H),3.01-3.04(d,6H),1.47-1.51(m,2H),1.35-1.39(m,2H).

[0139] Example 5 Synthesis of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazole-6-sulfonamide [ka] The title compound was prepared as described above in Example 1 by substituting 1-methyl-6-oxopyridin-3-ylboronic acid for phenylboronic acid. LCMS (ES, m / z): [M+H] + 504; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.46(s,1H),9.08(d,1H),8.95(s,1H),8.30(d,1H), 7.90-7.91(m,2H),7.63-7.88(t,1H),6.64(d,1H),3.59(s,3H),1.23-1.49(m,4H).

[0140] Example 6 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-cyclopropyl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (100 mg, 0.232 mmol, 1 equiv.) and cyclopropylboronic acid (99.69 mg, 1.161 mmol, 5 equiv.), K2CO3 (64.16 mg, 0.464 mmol, 2 equiv.) in dioxane (1.5 mL) in an 8 mL vial under nitrogen atmosphere was added Pd(DtBPF)Cl2 (15.13 mg, 0.023 mmol, 0.1 equiv.). The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere and then quenched with water. The aqueous layer was extracted with EtOAc and the combined EtOAc extracts were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=80:1) to give the crude product (70 mg). The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C18 column 30x150mm 5um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35% B to 47% B in 7 min; 254; 220 nm; RT 5.68 min) to give the title compound (31.3 mg). LCMS (ES, m / z): [M+H] + 437; 1H-NMR(300MHz,DMSO-d6,ppm)δ0.95-1.01(m,2H),1.20-1.31(m,4H),1.42-1.48(d,2H),2. 62-2.70(m,1H),7.36(s,1H),7.51-7.79(t,1H),8.77(s,1H),9.10(s,1H),9.36(brs,1H).

[0141] Example 7 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-6-en-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] Step 1: Synthesis of 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate To a stirred solution of 2-oxaspiro[3.5]nonan-7-one (1.00 g, 7.134 mmol, 1.00 equiv) in THF (20 mL) was added dropwise LiHMDS (1432.36 mg, 8.560 mmol, 1.20 equiv) at −78° C. under nitrogen atmosphere. The mixture was stirred for 2 h, and then 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonyl methanesulfonamide (3822.60 mg, 10.700 mmol, 1.50 equiv) was added dropwise at −78° C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere and then quenched with saturated NH4Cl(aq). The product was extracted with EtOAc and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EtOAc (10 / 1)) to give the title compound (1.2 g).

[0142] Step 2: Synthesis of 4,4,5,5-tetramethyl-2-(2-oxaspiro[3.5]non-6-en-7-yl)-1,3,2-dioxaborolane In a 20 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was placed 2-oxaspiro[3.5]non-6-en-7-yl trifluoromethanesulfonate (200.00 mg, 0.735 mmol, 1.00 equiv), bis(pinacolato)diboron (223.87 mg, 0.882 mmol, 1.2 equiv), Pd(dppf)Cl2 (53.75 mg, 0.073 mmol, 0.10 equiv), KOAc (216.30 mg, 2.204 mmol, 3 equiv) and dioxane (5.00 mL). The resulting solution was stirred in an oil bath at 80 °C for 12 h, concentrated under vacuum and used directly in the next step without further purification.

[0143] Step 3: Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-6-en-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile Into an 8 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4,4,5,5-tetramethyl-2-(2-oxaspiro[3.5]non-6-en-7-yl)-1,3,2-dioxoborolane (200.00 mg, 0.800 mmol, 1.00 equiv), 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (344.46 mg, 0.800 mmol, 1 equiv), Pd(PPh3)4 (92.39 mg, 0.080 mmol, 0.10 equiv), KOAc (235.40 mg, 2.399 mmol, 3 equiv), dioxane (2.00 mL), and HO (2.00 mL). The resulting solution was stirred in an oil bath at 100° C. for 3 h and then quenched with water. The resulting solution was extracted with EtOAc, and the combined EtOAc extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 / 1). The crude product (170 mg) was purified by Prep-HPLC (column: XBridge Prep OBD C 18Column, 30×150 mm 5um; Mobile phase A: Water (0.05% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 29% B to 50% B in 10 min; 254; 220 nm; RT 8.28 min) to give the title compound (75 mg). LCMS (ES, m / z): [M+H] + 519;1H-NMR-(300MHz,DMSO-d6,ppm)δ9.43(brs,1H),8.97(s,1H),8.91(s,1H),7.76(s,1H) ,7.45-7.80(t,1H),6.31(s,1H),4.44(dd,4H),2.66(d,4H),2.08(t,2H),1.32-1.52(m,4H).

[0144] Example 8 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 25 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was placed 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-6-en-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile (110.00 mg, 0.212 mmol, 1.00 equiv), Pd / C (11.06 mg, 0.104 mmol, 0.49 equiv), and MeOH (11.00 mL). The resulting solution was stirred under hydrogen atmosphere at room temperature for 12 h, after which the solids were removed by filtration. The resulting mixture was concentrated and the residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 1). The crude product (75 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 50% B in 7 min; 254; 220 nm; RT 6.35 min) to give the title compound (2.9 mg). LCMS (ES, m / z): [M+H] + 521; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.29-9.44(brs,1H),9.05(s,1H),8.84(s,1H),7.69(s,1H),7.44-7.80(t,1H) ,4.46(s,2H),4.30(s,2H),3.17-3.25(m,1H),2.25(d,2H),1.90(d,2H),1.50-1.76(m,4H),1.22-1.42(m,4H).

[0145] Example 9 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-imidazol-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] Step 1: Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-(1-trityl-1H-imidazol-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (150 mg, 0.348 mmol, 1 equiv.) and 4-(tributylstannyl)-1-(triphenylmethyl)-1H-imidazole (417.42 mg, 0.696 mmol, 2 equiv.) in toluene (3 mL) in an 8 mL vial under nitrogen atmosphere was added Pd(PPh3)4 (80.47 mg, 0.070 mmol, 0.2 equiv.). The resulting mixture was stirred overnight at 110° C. under nitrogen atmosphere. The reaction was quenched by addition of water / ice and the aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (PE:EtOAc=2:1) ​​to give the title compound (200 mg).

[0146] Step 2: Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-imidazol-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile To a stirred solution of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-(1-trytyl-1H-imidazol-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile (190 mg, 0.270 mmol, 1 equiv.) in DCM (2 mL) and MeOH (2 mL) in an 8 mL vial was added HCl (gas) in 1,4-dioxane (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h and quenched with saturated NH4Cl (aq). The aqueous layer was extracted with DCM and the resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give the crude product (50 mg). The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C18 column 30 × 150 mm 5 um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 27% B in 7 min; 254; 220 nm; RT 6.08 min) to give the title compound (27.0 mg). LCMS (ES, m / z): [M+H] + 463; 1 H-NMR(300MHz,DMSO-d6,ppm)δ1.24-1.34(m,2H),1.44-1.49(m,2H),7.63(t,1H),7.97 (s,1H),8.17(s,1H),8.32(s,1H),8.84(s,1H),9.35(s,1H),9.48(s,1H),12.70(s,1H).

[0147] Example 10 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyridazin-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] A 5 mL sealed tube was charged with 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (200 mg, 0.464 mmol, 1 equiv.), DME (1.6 mL), HO (0.4 mL), 4-(tributylstannyl)pyridazine (342.72 mg, 0.928 mmol, 2 equiv.), and Pd(PPh3)4 (53.64 mg, 0.046 mmol, 0.1 equiv.). The final reaction mixture was microwaved under nitrogen at 140° C. for 2 h. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (CHCl2:MeOH=30:1) to give the crude product. The crude product (60 mg) was purified by Prep-HPLC (column: XBridge Prep OBD C18 column 30 × 150 mm 5 um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 26% B in 7 min; 254; 220 nm; RT 6.55 min) to give the title compound (15 mg). LCMS (ES, m / z): [M+H] + 475; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.73(d,1H),9.48(d,1H),9.15(s,1H),9.10( s,1H),8.15-8.18(m,2H),7.64(t,1H),1.45-1.50(m,2H),1.23-1.36(m,2H).

[0148] Example 11 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyridazin-3-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 10 by substituting 3-(tributylstannyl)pyridazine for 4-(tributylstannyl)pyridazine. LCMS (ES, m / z): [M+H] + 475;1 H-NMR(300MHz,DMSO-d6,ppm)δ9.71(s,1H),9.50(d,1H),9.15(s,1H),9.11( d,1H),8.13-8.19(m,2H),7.64(t,1H),1.46-1.50(m,2H),1.31-1.35(m,2H).

[0149] Example 12 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1-methylimidazol-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (200 mg, 0.464 mmol, 1 equiv.) and 1-methyl-4-(tributylstannyl)-1H-imidazole (344.60 mg, 0.928 mmol, 2 equiv.) in toluene (4 mL) in an 8 mL vial was added Pd(PPh3)4 (53.64 mg, 0.046 mmol, 0.1 equiv.). The resulting mixture was stirred overnight at 110° C. under nitrogen atmosphere, and the resulting mixture was concentrated under vacuum. The crude product was recrystallized with DCM / PE=1 / 4 (5 mL) to give the crude product (200 mg, crude). The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C18 column 19*250mm, 5um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B to 30% B in 11 min; 254; 220 nm; RT 9.08 min) to give the title compound (62.5 mg). LCMS (ES, m / z): [M+H] + 477; 1H-NMR(300MHz,DMSO-d6,ppm)δ1.22-1.43(m,4H),3.78(s,3H),7.64(t,1H),7. 87(s,1H),8.15(s,1H),8.24(s,1H),8.82(s,1H),9.26(s,1H),9.50(brs,1H).

[0150] Example 13 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1,3-thiazol-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (100 mg, 0.232 mmol, 1 equiv.) and 4-(tributylstannyl)-1,3-thiazole (173.70 mg, 0.464 mmol, 2 equiv.) in toluene (2 mL) in an 8 mL vial was added Pd(PPh3)4 (26.82 mg, 0.023 mmol, 0.1 equiv.). The resulting mixture was stirred at 110° C. overnight. The resulting mixture was concentrated under vacuum and the crude product was recrystallized from DCM / PE (1:1, 2 mL) to give the crude product (70 mg, crude). The crude product was purified by Prep-HPLC (Column: SunFire C18 OBD Prep Column, 100 Angstroms, 5 μm, 19x250 mm; Mobile phase A: Water (1% HAC), Mobile phase B: MeOH; Flow rate: 20 mL / min; Gradient: 75% B to 85% B in 7 min; 254 / 220 nm; RT 6.12 min) to give the title compound (36.1 mg). LCMS (ES, m / z): [M+H] + 480; 1 H-NMR(300MHz,DMSO-d6,ppm)δ1.20-1.60(m,4H),7.63(t,1H),8.46(s,1H),8.69(s,1H),9.02(s,1H),9.30(s,1H),9.43(s),9.51-9.62(brs,1H).

[0151] Example 14 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-pyridyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 12 by substituting 2-(tributylstannyl)pyridine for 1-methyl-4-(tributylstannyl)-1H-imidazole. LCMS (ES, m / z): [M+H] + 474; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.55(s,1H),9.30(s,1H),9.09(s,1H),8.89(d,1H), 8.40(d,1H),8.07-8.20(m,2H),7.64(t,1H),7.57-7.60(m,1H),1.35-1.47(m,4H).

[0152] Example 15 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyrimidin-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 12 by substituting 4-(tributylstannyl)pyrimidine for 1-methyl-4-(tributylstannyl)-1H-imidazole. LCMS (ES, m / z): [M+H] + 475; 1 H-NMR(300MHz,DMSO-d6,ppm)δ1.33-1.51(m,4H),7.64(t,1H),8.30(d,1H),8 .53(s,1H),9.09(d,1H),9.20(s,1H),9.36(s,1H),9.47(s,1H),9.60(s,1H).

[0153] Example 16 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-pyridyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 12 by substituting 4-(tributylstannyl)pyridine for 1-methyl-4-(tributylstannyl)-1H-imidazole. LCMS (ES, m / z): [M+H] + 474; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.10(s,1H),9.01(s,1H),8.83(s,2H),8.04(s,1H),7.46-7.84(m,3H),1.23-1.57(m,4H).

[0154] Example 17 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(3-pyridyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 15 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (200 mg, 0.464 mmol, 1 equiv.), 3-(tributylstannyl)pyridine (341.81 mg, 0.928 mmol, 2 equiv.), toluene (2 mL), and Pd(PPh3)4 (53.64 mg, 0.046 mmol, 0.1 equiv.) were placed under nitrogen atmosphere. The resulting solution was stirred overnight at 110° C. under nitrogen atmosphere and then concentrated under reduced pressure. The residue was dissolved in CHCl2 (5 mL) and purified by Prep-TLC (CHCl2:MeOH=50:1) to give the crude product (100 mg, crude) as a white solid. The crude product was purified by Prep-HPLC (Column: xbridge Prep OBD C18 column 19*250mm, 5um; Mobile phase A: water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 39%B to 46%B in 10min; 254; 220nm; rt: 8.38min) to give the title compound (15.1mg). LCMS (ES,m / z):[M+H] + 474; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.54(s,1H),9.08(s,1H),9.03-9.01(m,2H),8.79(d,1H),8.2 6(d,1H),8.02(s,1H),7.67-7.70(m,1H),7.65(t,1H),1.50-1.47(m,2H),1.37-1.34(m,2H).

[0155] Example 18 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyrazin-2-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (200 mg, 0.464 mmol, 1 equiv.) and 2-(tributylstannyl)pyrazine (342.72 mg, 0.928 mmol, 2 equiv.) in toluene (4 mL) in an 8 mL vial under nitrogen atmosphere was added Pd(PPh3)4 (53.64 mg, 0.046 mmol, 0.1 equiv.). The resulting mixture was stirred overnight at 110° C. under nitrogen atmosphere. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under vacuum and the residue was dissolved in DCM / hexane (1:9, 10 mL) to give the crude product (100 mg) as a crystalline solid. The crude product was purified by Prep-HPLC (Column: XSelect CSH Prep C18 OBD column, 5um, 19*150mm; Mobile phase A: Water (1% HAC), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 38%B to 63%B in 7min; 254 / 220nm; RT 6.83min) to give the title compound (54.7mg). LCMS (ES,m / z):[M+H] + 475; 1 H-NMR(300MHz,DMSO-d6,ppm)δ1.32-1.39(m,2H),1.43-1.52(m,2H),7.65(t,1H),8.51 (d,1H),8.85(d,1H),8.95(m,1H),9.16(s,1H),9.28(s,1H),9.46(d,1H),9.56(s,1H).

[0156] Example 19 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(6-methoxypyrimidin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarboxamide [ka] In a 15 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, 4-methoxy-6-(tributylstannyl)pyrimidine (1389.76 mg, 3.482 mmol, 3.00 equiv.), 1-[1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(2-methoxypyrimidin-4-yl)indazole-6-sulfonamido]cyclopropane-1-carboxamide (500 mg, 1.161 mmol, 1.00 equiv.), toluene (5 mL) and Pd(PPh3)4 (201.16 mg, 0.174 mmol, 0.15 equiv.) were placed. The resulting solution was stirred at 110° C. overnight and then quenched with water. The resulting solution was extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum, and the residue was purified by Prep-TLC (CH2Cl2:MeOH=50:1) to give the crude product. The crude product (20 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column 19*250 mm, 5 um; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 47% B to 57% B in 8 min; 254; 220 nm; RT 5.83 min) to give the title compound (3.3 mg). LCMS (ES, m / z): [M+H] + 523; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.28(s,1H),9.06(s,1H),8.92(brs,1H),8.41(s,1H),7. 86(d,1H),7.64(t,1H),7.08(d,2H),4.05(s,3H),1.14-1.18(m,2H),0.88-0.98(m,2H).

[0157] Example 20 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methoxypyrimidin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarboxamide [ka] The title compound was prepared as described above in Example 19, substituting 2-methoxy-4-(tributylstannyl)pyrimidine for 4-methoxy-6-(tributylstannyl)pyrimidine. LCMS (ES, m / z): [M+H] + 523; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.31(s,1H),9.09(s,1H),8.87(d,1H),8.42(s,1H),7.8 6(d,1H),7.64(t,1H),7.12(d,2H),4.10(s,3H),1.14-1.18(m,2H),0.88-0.98(m,2H).

[0158] Example 21 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methoxypyrimidin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In an 8 mL sealed tube, 1-[1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(2-methoxypyrimidin-4-yl)indazole-6-sulfonamido]cyclopropane-1-carboxamide (14.00 mg, 0.033 mmol, 1.00 equiv.), piperidine (0.20 mL), and TFAA (20.50 mg, 0.098 mmol, 3 equiv.) were placed. The resulting solution was stirred at 0° C. under nitrogen atmosphere for 4 hours. The resulting mixture was concentrated under vacuum, and the residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to obtain the crude product. The crude product (12 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column 30×150 mm 5 um; Mobile phase A: Water (0.05% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B in 7 min; 254; 220 nm; RT 6.22 min) to give the title compound (2.1 mg). LCMS (ES, m / z): [M+H] + 505; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.48-9.70(brs,1H),9.35(s,1H),9.19(s,1H),8. 90(d,1H),8.50(s,1H),7.91(d,1H),7.65(t,1H),4.11(s,3H),1.32-1.50(m,4H).

[0159] Example 22 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(6-methoxypyrimidin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In an 8 mL sealed tube was placed 1-[1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-4-(6-methoxypyrimidin-4-yl)-1H-indazole-6-sulfonamido]cyclopropane-1-carboxamide (90.00 mg, 0.172 mmol, 1.00 equiv), DCM (0.90 mL), Et3N (104.3 mg, 1.033 mmol, 6 equiv), and TFAA (108.36 mg, 0.516 mmol, 3 equiv). The resulting solution was stirred at room temperature under nitrogen atmosphere for 3 h, and the resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give the crude product. The crude product (50 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 55% B to 68% B in 8 min; 254; 220 nm; RT 6.22 min) to give the title compound (3.2 mg, 4.14%) as a white solid. LCMS (ES, m / z): [M+H] + 505; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.32(s,1H),9.17(s,1H),9.06(s,1H),8.49(s,1H),7.46-7.81(m,2H),4.06(s,3H),1.30-1.53(m,4H).

[0160] Example 23 Synthesis of ({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-7-azaspiro[3.5]non-7-yl)(1H-indazol-6-yl)}sulfonyl)(methylcyclopropyl)amine [ka] To a stirred solution of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indazole-6-sulfonamide (250.00 mg, 0.595 mmol, 1.00 equiv) and 2-oxa-7-azaspiro[3.5]nonane oxalate (258.69 mg, 1.191 mmol, 2.00 equiv) in dioxane (2.50 mL) in an 8 mL vial was added BINAP (185.39 mg, 0.298 mmol, 0.5 equiv), CsCO (873.04 mg, 2.680 mmol, 4.5 equiv), and Pd(AcO) (53.47 mg, 0.238 mmol, 0.4 equiv). The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl (aq). The aqueous layer was extracted with EA and the resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 150 mg of crude product as a yellow solid. The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C). 18 Column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / l NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 54% B in 7 min; 254; 220 nm; RT 7.02 min) to give the title compound (9.4 mg). LCMS (ES, m / z): [M+H] + :511; 1H-NMR(300MHz,DMSO-d6,ppm)δ8.86(s,1H),8.43(s,1H),8.30(s,1H),7.61(t,1H),7.16(s,1 H),4.10(s,4H),3.34-3.36(m,4H),2.02-2.08(m,4H),1.07(s,3H),0.65(t,2H),0.40(t,2H).

[0161] Example 24 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(methylcyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide [ka] To a stirred solution of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-N-(1-methylcyclopropyl)indazole-6-sulfonamide (500.00 mg, 1.191 mmol, 1.00 equiv) and N,N-dimethylpiperazine-1-carboxamide (374.46 mg, 2.382 mmol, 2.00 equiv) in THF (3.00 mL) in an 8 mL vial under a nitrogen atmosphere was added Pd(OAc)2 (106.95 mg, 0.476 mmol, 0.4 equiv), Ruphos (222.29 mg, 0.476 mmol, 0.4 equiv) and t-BuONa (286.12 mg, 2.977 mmol, 2.5 equiv). The resulting mixture was stirred at 70° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl(aq). The aqueous layer was extracted with EA and the organics were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 100 mg of crude product as a yellow solid. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; Mobile phase A: (sater 10 mmol / l NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 55% B in 7 min; 254; 220 nm; RT 6.38 min) to give the title compound (2.4 mg). LCMS (ES, m / z): [M+H] + :541; 1 H-NMR(300MHz,DMSO-d6,ppm)δ8.94(s,1H),8.47(s,1H),8.32(s,1H),7.61(t,1H), 7.18(s,1H),3.35-3.50(m,8H),2.81(s,6H),1.08(s,3H),0.66(t,2H),0.41(t,2H).

[0162] Example 25 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (200.00 mg, 0.464 mmol, 1.00 equiv.) and 2-oxa-7-azaspiro[3.5]nonane; formic acid (160.82 mg, 0.928 mmol, 2.00 equiv.) in dioxane (2.00 mL) in an 8 mL vial was added Cs2CO3 (605.01 mg, 1.857 mmol, 4.00 equiv.), RuPhos (43.32 mg, 0.093 mmol, 0.20 equiv.) and RuPhos Palladacycle Gen.3 (38.83 mg, 0.046 mmol, 0.10 equiv.) under nitrogen atmosphere. The resulting mixture was stirred at 100°C under nitrogen atmosphere for 4 hours and then quenched with saturated NH4Cl(aq). The aqueous layer was extracted with EtOAc and the organics were concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=30:1). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBDC18 column 19*250mm, 5um; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 50%B to 65%B in 8min; 254; 220nm; RT 6.88min) to give the title compound (13.1mg). LCMS (ES,m / z): [M+H] + 522; 1 H-NMR(400MHz,DMSO-d6,ppm)δ1.30-1.33(m,2H),1.43-1.46(m,2H),2.04-2.05(m,4H),3.34 -3.37(m,4H),4.40(s,4H),7.17(s,1H),7.61(t,1H),8.46(s,1H),8.90(s,1H),9.34(s,1H).

[0163] Example 26 Synthesis of 1-[({4-((2R)-2-methylmorpholin-4-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] A 15 mL sealed tube was charged with 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (500.00 mg, 1.161 mmol, 1.00 equiv), (2R)-2-methylmorpholine (234.78 mg, 2.321 mmol, 2 equiv), dioxane (5.00 mL), CsCO (756.26 mg, 2.321 mmol, 2 equiv), RuPhos (108.31 mg, 0.232 mmol, 0.2 equiv), and RuPhos Palladacycle Gen.3 (97.06 mg, 0.116 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting solution was stirred at 100°C under nitrogen atmosphere overnight and then quenched with saturated NH4Cl (aq). The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give the crude product. The crude product (60 mg) was purified by Prep-HPLC (Column: Xbridge Prep OBD C18 column 30×150 mm 5um; Mobile phase A: Water (0.05% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 37% B in 7 min; 254; 220 nm; rt: 6.50 min) to give the title compound (19.3 mg). LCMS (ES, m / z): [M+H] + 496; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.34(brs,1H),9.00(s,1H),8.52(s,1H),7.61(t,1H),7.18(s,1H),3.96-4. 02(m,1H),3.68-3.84(m,4H),3.04(t,1H),2.73(t,1H),1.50-1.41(m,2H),1.36-1.28(m,2H),1.21(d,3H).

[0164] Example 27 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-hydroxypiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described in Example 26 by substituting piperidin-4-ol for (2R)-2-methylmorpholine. LCMS (ES, m / z): [M+H] + 496; 1 H-NMR(300MHz,DMSO-d6,ppm)δ1.31(t,2H),1.41-1.46(m,2H),1.62-1.68(m,2H),1.90-1.98(m,2H),3.12-3 .23(m,2H),3.70-3.79(m,3H),4.82(d,1H),7.15(d,1H),7.61(t,1H),8.44(s,1H),8.89(s,1H),9.32(s,1H).

[0165] Example 28 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylpropanoyl)piperazinyl]indol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indole-6-sulfonamide (600.00 mg, 1.396 mmol, 1.00 equiv.) and 2-methyl-1-(piperazin-1-yl)propan-1-one TFA salt (709.81 mg, 2.792 mmol, 2.00 equiv.) in 1,4-dioxane (10 mL) in a 20 mL vial under nitrogen atmosphere was added RuPhos (260.54 mg, 0.558 mmol, 0.40 equiv.), RuPhos Palladacycle Gen.3 (466.98 mg, 0.558 mmol, 0.40 equiv.) and Cs2CO3 (1591.81 mg, 4.886 mmol, 3.50 equiv.) were added. The resulting mixture was stirred at 90° C. overnight, then quenched with saturated NH4Cl(aq) (6 mL) and extracted with EtOAc. The combined extracts were concentrated under vacuum and the residue was purified by Prep-TLC (CH2Cl2:MeOH=25:1) to give the crude product (95 mg). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 50% B in 7 min; 254 / 220 nm; RT: 6.22 min) to give the title compound (2.5 mg). LCMS (ES, m / z): [M+H] + 550; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.10(s,1H),8.62(s,1H),8.17(d,1H),7.64(t,1H),7.22(s,1H), 7.13(d,1H),3.76(d,4H),3.21(d,4H),2.96(sep,1H),1.39(dd,2H),1.26(dd,2H),1.06(d,6H).

[0166] Example 29 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-8-azaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (400.00 mg, 0.928 mmol, 1.00 equiv.) and 2-oxa-8-azaspiro[4.5]decane hydrochloride (329.91 mg, 1.857 mmol, 2.00 equiv.) in 1,4-dioxane (4 mL) in an 8 mL vial under nitrogen atmosphere was added Cs2CO3 (1058.76 mg, 3.250 mmol, 3.50 equiv.) RuPhos Palladacycle Gen.3 (155.30 mg, 0.186 mmol, 0.2 equiv.) and RuPhos (43.32 mg, 0.093 mmol, 0.10 equiv.). The solution was stirred at 90° C. overnight and then quenched with saturated NH4Cl(aq). The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2:MeOH=20:1) to give the crude product. The crude product (60 mg) was purified by Prep-HPLC (Column: XBridge Phenyl OBD column, 5 um, 19*150 mm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 42% B to 52% B in 8 min; 254; 220 nm; rt: 8.13 min) to give the title compound (10.7 mg). LCMS (ES, m / z): [M+H] + 536; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.34(s,1H),8.90(s,1H),8.46(s,1H),7.61(t,1H),7.18(d,1 H),3.80(t,2H),3.43-3.55(m,6H),1.77-1.84(m,6H),1.40-1.50(m,2H),1.28-1.35(m,2H).

[0167] Example 30 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(9-oxa-3-azaspiro[5.5]undec-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 15 mL sealed tube was placed 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (500.00 mg, 1.161 mmol, 1.00 equiv), 3-oxa-9-azaspiro[5.5]undecane (360.33 mg, 2.321 mmol, 2 equiv), dioxane (5 mL), CsCO (756.26 mg, 2.321 mmol, 2 equiv), RuPhos Palladacycle Gen. 3 (97.06 mg, 0.116 mmol, 0.1 equiv), and RuPhos (108.31 mg, 0.232 mmol, 0.2 equiv). The resulting solution was stirred at 90° C. overnight and then quenched with saturated NH4Cl(aq). The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2:MeOH=40:1) to give the crude product. The crude product (18 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column 19*250mm, 5um; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: MeOH-HPLC; Flow rate: 20mL / min; Gradient: 65%B to 79%B in 8min; 254; 220nm; rt: 6.87min) to give the title compound (2.1 mg). LCMS (ES,m / z):[M+H] + 550; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.31(brs,1H),8.89(s,1H),8.42(s,1H),7.60(t,1H),7.16(s,1H),3.56-3 .62(m,4H),3.41-3.49(m,4H),1.69-1.81(m,4H),1.45-1.55(m,4H),1.40-1.42(m,2H),1.25-1.37(m,2H).

[0168] Example 31 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))(1,4-diazaperhydroepynyl)]-N-methylcarboxamide [ka] The title compound was prepared as described above in Example 30 by substituting N-methyl-1,4-diazepane-1-carboxamide TFA salt for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + 555; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.28(brs,1H),8.85(s,1H),8.27(s,1H),7.60(t,1H),6.96(s,1H),6.30 -6.32(d,1H),3.84(s,4H),3.68(s,2H),3.32(s,2H),2.51-2.52(m,3H),1.93(s,2H),1.24-1.44(m,4H).

[0169] Example 32 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-ethyl-N-methylcarboxamide [ka] The title compound was prepared as described above in Example 30 by substituting N-ethyl-N-methylpiperazine-1-carboxamide TFA salt for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + 566; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.32(s,1H),8.96(s,1H),8.50(s,1H),7.60(t,1H),7.18(d,1H),3.4 47(d,4H),3.39(d,4H),3.18(q,2H),2.80(s,3H),1.43-1.46(m,2H),1.23-1.29(m,2H),1.10(t,3H).

[0170] Example 33 Synthesis of 1-[({4-[4-(azetidinylcarbonyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 30 by substituting azetidin-1-yl(piperazin-1-yl)methanone TFA salt for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + =564; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.32(brs,1H),8.95(s,1H),8.49(s,1H),7.60(t,1H),7.15 (s,1H),3.95(t,4H),3.73-3.45(m,8H),2.18(p,2H),1.40-1.47(m,2H),1.28-1.35(m,2H).

[0171] Example 34 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 30 by substituting 2-oxa-6-azaspiro[3.4]octane oxalate for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + 508; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.27(s,1H),8.90(s,1H),8.20(s,1H),7.60(t,1H),6.77(d,1H) ),4.64(dd,4H),3.95(s,2H),3.69(t,2H),2.37(t,2H),1.42-1.51(m,2H),1.20-1.32(m,2H).

[0172] Example 35 Synthesis of [(2R)-4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))-2-methylpiperazinyl]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 30 by substituting (R)-N,N,2-trimethylpiperazine-1-carboxamide TFA salt for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + :566; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.31(s,1H),8.86(s,1H),8.49(s,1H),7.62(t,1H),7.17(s,1H),3.97(dd,1H),3.69(d,1H) ,3.60(d,1H),3.42-3.44(m,2H),3.30-3.32(m,1H),3.18-3.24(m,1H),2.81(s,6H),1.46-1.47(m,2H),1.28-1.39(m,5H).

[0173] Example 36 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(4-methyl(1,2,4-triazol-3-yl))piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 30 by substituting 1-(4-methyl-1,2,4-triazol-3-yl)piperazine for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + :562; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.26(brs,1H),9.03(s,1H),8.55(s,1H),8.27(s,1H),7.62(t,1H),7 .25(s,1H),3.56-3.62(m,4H),3.55(s,3H),3.37-3.38(m,4H),1.43-1.46(m,2H),1.30-1.33(m,2H).

[0174] Example 37 Synthesis of 1-[({4-[(1S,5R)-8-(2-methylpropanoyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 30 by substituting 1-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methylpropan-1-one TFA salt for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + 577; 1 H-NMR(400MHz,DMSO-d6,ppm)δ8.91(s,1H),8.42(s,1H),7.60(t,1H),7.12(s,1H),4.71(s,1H),4.58(s,1H),3.78(t ,2H),3.23(d,1H),3.15(d,1H),2.86(p,1H),1.84-2.00(m,4H),1.22-1.32(m,2H),1.12-1.21(m,2H),1.06(dd,6H).

[0175] Example 38 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 30 by substituting 2-methyl-1-(piperazin-1-yl)propan-1-one for 3-oxa-9-azaspiro[5.5]undecane. LCMS (ES, m / z): [M+H] + 551; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.34(s,1H),8.98(s,1H),8.50(s,1H),7.61(t,1H),7.17(s,1H ),3.77(d,4H),3.48(brs,4H),2.95(p,1H),1.39-1.47(m,2H),1.29-1.34(m,2H),1.06(d,6H).

[0176] Example 39 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2,2-dimethylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 25 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (400.00 mg, 0.928 mmol, 1.00 equiv.), 2,2-dimethyl-1-(piperazin-1-yl)propan-1-one hydrochloride (575.75 mg, 2.785 mmol, 3 equiv.), RuPhos (173.30 mg, 0.371 mmol, 0.4 equiv.), CsCO (1210.02 mg, 3.714 mmol, 4 equiv.), dioxane (8.00 mL), and RuPhos Palladacycle were added. Gen.3 (310.61 mg, 0.371 mmol, 0.4 equiv) was charged. The resulting solution was stirred in an oil bath at 90° C. for 12 h and then quenched with water. The resulting solution was extracted with ethyl acetate, and the organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography [silica gel, ethyl acetate / petroleum ether (1 / 1)] to give the title compound (14 mg). LCMS (ES, m / z): [M+H] + 565; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.28(brs,1H),8.98(s,1H),8.51(s,1H),7.62(m,1H),7. 18(s,1H),3.84(s,4H),3.47(s,4H),1.46-1.40(m,2H),1.33-1.29(m,2H),1.26(s,9H).

[0177] Example 40 Synthesis of [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)(4-piperidyl)]-N-methylcarboxamide [ka] In a 15 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was placed 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv), N-methylpiperidine-4-carboxamide (197.81 mg, 1.393 mmol, 2.00 equiv), Cs2CO3 (680.63 mg, 2.089 mmol, 3 equiv), dioxane (3.00 mL), RuPhos (32.49 mg, 0.070 mmol, 0.1 equiv), and RuPhosPdG3 (232.96 mg, 0.279 mmol, 0.40 equiv). The resulting solution was stirred at 90 °C overnight. The reaction was quenched with water at room temperature and extracted with EtOAc. The organics were concentrated under vacuum and the residue was purified by Prep-TLC (CH2Cl2:MeOH=20:1) to give the crude product. The crude product (150mg) was purified by Prep-HPLC (Column: Ultimate XB-C4 21.2*250mm 5um; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 38%B to 46%B in 7min; 254 / 220nm; RT 6.33min) to give the title compound (41.7mg, 11.16%). LCMS (ES,m / z):[M+H] + 537; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(brs,1H),8.89(s,1H),8.45(s,1H),7.81(d,1H),7.60(t,1H),7.16(s,1H),3.97 (d,2H),3.03-3.09(m,2H),2.60(d,3H),2.36-2.41(m,1H),1.78-1.82(m,4H),1.39-1.47(m,2H),1.26-1.34(m,2H).

[0178] Example 41 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1-oxa-7-azaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution / mixture of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (400 mg, 0.928 mmol, 1.00 equiv) and bis(1-oxa-7-azaspiro[3.5]nonane) and oxalic acid (319.76 mg, 0.928 mmol, 1.00 equiv) in 1,4-dioxane (4 mL) in an 8 mL vial under nitrogen atmosphere was added CsCO (1058.76 mg, 3.250 mmol, 3.50 equiv), RuPhos Palladacycle Gen.3 (77.65 mg, 0.093 mmol, 0.10 equiv) and RuPhos (86.65 mg, 0.186 mmol, 0.20 equiv). The solution was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was quenched with saturated NH4Cl(aq) and the resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified by Prep-TLC (CH2Cl2:EtOAc=30:1) to give the crude product. The crude product (120 mg) was recrystallized from PE / EtOAc (4:15 mL) to give the title compound (61.6 mg). LCMS (ES, m / z): [M+H] + 522; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.35(s,1H),8.92(s,1H),8.46(s,1H),7.61(t,1H),7.18(s,1H),4.46(t,2H),3. 46-3.50(m,2H),3.37-3.42(m,2H),2.43-2.45(m,2H),2.00-2.08(m,4H),1.44-1.49(m,2H),1.27-1.31(m,2H).

[0179] Example 42 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1,4-oxazaperhydroepin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a 20 mL vial was added 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv), dioxane (5.00 mL), 1,4-oxazepane hydrochloride (191.64 mg, 1.393 mmol, 2.00 equiv), Cs2CO3 (680.63 mg, 2.089 mmol, 3.00 equiv), RuPhos (129.97 mg, 0.279 mmol, 0.40 equiv), and RuPhos Palladacycle Gen.3 (232.96 mg, 0.279 mmol, 0.40 equiv). The resulting solution was stirred overnight at 90 °C under nitrogen atmosphere. The resulting mixture was washed with H2O and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by PrepTLC (CH2Cl2:MeOH=30:1) to give the title compound (40.7 mg). LCMS (ES, m / z): [M+H] + 496; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.29(s,1H),8.83(s,1H),8.28(s,1H),7.60(t,1H),6.97-6.96( d,1H),3.92-3.89(m,6H),3.69(t,2H),2.04-2.01(m,2H),1.46-1.41(m,2H),1.38-1.31(m,2H).

[0180] Example 43 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide [ka] Into a 15 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv), CsCO (680.63 mg, 2.089 mmol, 3 equiv), dioxane (3.00 mL), N,N-dimethylpiperazine-1-carboxamide (131.37 mg, 0.836 mmol, 1.2 equiv), RuPhos (32.49 mg, 0.070 mmol, 0.1 equiv), and RuPhos Palladacycle Gen. 3 (58.24 mg, 0.070 mmol, 0.1 equiv). The resulting solution was stirred at 90° C. overnight. The reaction was quenched with water at room temperature, and the aqueous layer was extracted with EtOAc. The resulting mixture was concentrated under vacuum, and the residue was purified by Prep-TLC (CH2Cl2:MeOH=20:1) to give the crude product. The crude product (150 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: Water (0.05% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 7 min; 254; 220 nm; RT 6.77 min) to give the title compound (57.4 mg). LCMS (ES, m / z): [M+H] + 552; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(brs,1H),8.94(s,1H),8.48(m,1H),7.59(t,1H) ,7.16(s,1H),3.31-3.43(m,8H),2.79(s,6H),1.39-1.44(t,2H),1.26-1.36(m,2H).

[0181] Example 44 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 1-oxa-8-azaspiro[4.5]decane for N,N-dimethyl-piperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 536; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.90(s,1H),8.45(s,1H),7.61(t,1H),7.17(d,1 H),3.78(t,2H),3.41-3.56(m,4H),1.68-1.97(m,8H),1.40-1.50(m,2H),1.20-1.36(m,2H).

[0182] Example 45 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(6-oxa-2-azaspiro[3.3]hept-2-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting bis(2-oxa-6-azaspiro[3.3]heptane)oxalate for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 494; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.30(brs,1H),8.71(s,1H),8.19(s,1H),7.59(t, 1H),6.58(s,1H),4.88(s,4H),4.47(s,4H),1.40-1.46(m,2H),1.25-1.33(m,2H).

[0183] Example 46 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 2-methyl-2,8-diazaspiro[4.5]decane hemioxalate salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 549; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.20-9.50(brs,1H),8.89(s,1H),8.45(s,1H),7.61(t,1H),7. 17(s,1H),3.25-3.47(m,6H),2.41(s,2H),2.26(s,3H),1.65-1.83(m,6H),1.29-1.46(m,4H).

[0184] Example 47 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(hydroxymethyl)piperidyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting piperidin-4-yl methanol for N,N-dimethylpiperazine-1-carboxamide. LCMS-PH(ES,m / z):[M+H] + 510; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.32(s,1H),8.87(s,1H),8.43(s,1H),7.60(t,1H),7.16(s,1H),4.56(t,1H),3. 89(d,2H),3.33-3.35(m,2H),3.04(t,2H),1.85(d,2H),1.63-1.66(m,1H),1.40-1.45(m,4H),1.32-1.37(t,2H).

[0185] Example 48 Synthesis of 1-[({4-((1S,5R)-7-oxa-3-azabicyclo[3.3.0]oct-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting cis-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 508; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.27(s,1H),8.90(s,1H),8.23(s,1H),7.60(t,1H),6.79(s,1H),3 .85-3.93(m,4H),3.73(dd,2H),3.61(dd,2H),3.17(s,2H),1.42-1.45(m,2H),1.28-1.30(t,2H).

[0186] Example 49 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-formylpiperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting piperazine-1-carbaldehyde for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + :509; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.27-9.42(brs,1H),8.98(brs,1H),8.52(brs,1H),8.13(br s,1H),7.49-7.74(m,1H),7.19(brs,1H),3.65(s,4H),3.39-3.58(m,4H),1.22-1.48(m,4H).

[0187] Example 50 Synthesis of 1-[({4-(4-acetylpiperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 1-(piperazin-1-yl)ethanone for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 509; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.43(s,1H),8.97(s,1H),8.50(s,1H),7.60(t,1H ),7.16(s,1H),3.73(s,4H),3.47(d,4H),2.08(s,3H),1.44(s,2H),1.32(s,2H).

[0188] Example 51 Synthesis of [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))(4-piperidyl)]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 43 by substituting N,N-dimethylpiperazine-1-carboxamide with N,N-dimethylpiperidine-4-carboxamide. LCMS (ES, m / z): [M+H] + 551; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.32(s,1H),8.91(s,1H),8.46(s,1H),7.60(t,1H),7.17(s,1H),3.89(d,2H),3.13- 3.17(m,2H),3.08(s,3H),2.90-2.97(m,1H),2.85(s,3H),1.81-1.90(m,4H),1.43-1.46(m,2H),1.25-1.30(m,2H).

[0189] Example 52 Synthesis of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(1,1-dioxidethiomorpholino)-1H-indazole-6-sulfonamide [ka] The title compound was prepared as described above in Example 43 by substituting thiomorpholine 1,1-dioxide for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 530; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.24(brs,1H),8.95(s,1H),8.56(s,1H),7.61(t, 1H),7.26(s,1H),3.92(s,4H),3.40(s,4H),1.40-1.44(t,2H),1.27-1.34(m,2H).

[0190] Example 53 Synthesis of [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))pyrrolidin-3-yl]-N-methylcarboxamide [ka] The title compound was prepared as described above in Example 43 by substituting N-methylpyrrolidine-3-carboxamide for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 523; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.26(s,1H),8.87(s,1H),8.20(s,1H),8.07(dd,1H),7.60(t,1H),6.76(s,1H) ,3.70-3.82(m,4H),3.19(p,1H),2.64-2.65(d,3H),2.15-2.38(m,2H),1.42-1.45(m,2H),1.29-1.30(m,2H).

[0191] Example 54 Synthesis of [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))pyrrolidin-3-yl]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 43 by substituting N,N-dimethylpiperazine-1-carboxamide with N,N-dimethylpyrrolidine-3-carboxamide. LCMS (ES, m / z): [M+H] + 537; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.25(s,1H),8.87(s,1H),8.19(s,1H),7.59(t,1H),6.75(d,1H),3.62-3.89( m,5H),3.12(s,3H),2.88(s,3H),2.27-2.37(m,1H),2.12-2.24(m,1H),1.39-1.48(m,2H),1.22-1.38(m,2H).

[0192] Example 55 Synthesis of [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))azetidin-3-yl]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 43 by substituting N,N-dimethylpiperazine-1-carboxamide with N,N-dimethylazetidine-3-carboxamide hydrochloride salt. LCMS (ES, m / z): [M+H] + 523; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.23(brs,1H),8.76(s,1H),8.21(s,1H),7.59(t,1H),6.62(d,1H),4.49 (t,2H),4.36(t,2H),3.95-4.10(m,1H),2.95(s,3H),2.89(s,3H),1.41-1.43(m,2H),1.27-1.29(m,2H).

[0193] Example 56 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(cis-8-oxa-3-azabicyclo-[4.3.0]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting octahydrofuro[3,4-c]pyridine hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 522; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.28(s,1H),8.86(s,1H),8.35(s,1H),7.60(t,1H),7.07(d,1H),3.84(dd,2H),3.69(dd,1H),3.58-3.63(m ,3H),3.42-3.51(m,2H),2.64-2.67(m,1H),2.50-2.51(m,1H),2.00- 2.04(m,1H),1.77-1.79(m,1H),1.42-1.45(m,2H),1.29-1.32(m,2H).

[0194] Example 57 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(pyrrolidinylcarbonyl)-piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 1-(pyrrolidine-1-carbonyl)piperazine hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 578; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.33(s,1H),8.96-8.97(d,1H),8.50(s,1H),7.61(t,1H),7.1 8(d,1H),3.47(s,8H),3.34-3.35(m,4H),1.79(t,4H),1.44-1.46(t,2H),1.22-1.30(m,2H).

[0195] Example 58 Synthesis of methyl 4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}-1H-indazol-4-yl)piperazinecarboxylate [ka] The title compound was prepared as described above in Example 43 by substituting methyl piperazine-1-carboxylate for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 539; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.95(s,1H),8.50(s,1H),7.60 (t,1H),7.17(s,1H),3.66(s,7H),3.47(d,4H),1.44(dd,2H),1.32(dd,2H).

[0196] Example 59 Synthesis of 1-[({4-((1S)-7-oxo-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting (S)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 535; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.35(s,1H),8.99(s,1H),8.52(s,1H),7.61(t,1H),7.22(d,1H),3.97(d,2H),3.85-3.89(m,2H) ,3.14(dt,1H),2.94(dt,1H),2.80(t,1H),2.29-3.33(m,2H),2.20-2.26(m,1H),1.65-1.70(m,1H),1.44(dd,2H),1.32(dd,2H).

[0197] Example 60 Synthesis of 1-[({4-((1R)-7-oxo-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting (R)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 535; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.35(s,1H),8.99(s,1H),8.53(s,1H),7.61(t,1H),7.22(d,1H),3.97(d,2H),3.85-3.89(m,2H) ,3.13(dt,1H),2.94(dt,1H),2.80(t,1H),2.29-2.35(m,2H),2.20-2.26(m,1H),1.67-1.70(m,1H),1.45(dd,2H),1.32(dd,2H).

[0198] Example 61 Synthesis of 1-[({4-((1R)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting (R)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 537; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.37(s,1H),8.99(s,1H),8.55(s,1H),7.62(t,1H),7.23(s,1H),4.47(t,1H),4.16-4. 23(m,1H),4.08(dd,1H),4.01(dd,1H),3.79(t,2H),3.35-3.40(m,1H),2.95-3.07(m,2H),1.46(dd,2H),1.32(dd,2H).

[0199] Example 62 Synthesis of 1-[({4-((1S)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting (S)-hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 537; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.36(s,1H),8.98(s,1H),8.55(s,1H),7.61(t,1H),7.22(s,1H),4.47(t,1H),4.16-4. 23(m,1H),4.08(dd,1H),4.01(dd,1H),3.79(t,2H),3.35-3.40(m,1H),2.95-3.07(m,2H),1.46(dd,2H),1.32(dd,2H)

[0200] Example 63 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-methyl(1,4-diazaperhydro-epynyl))-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting N-methylhomopiperazine for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + :509; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.28(s,1H),8.78(s,1H),8.25(s,1H),7.59(t,1H),6.93(s,1H),3.82(t,2H),3 .77(t,2H),2.79-2.81(m,2H),2.54-2.56(m,2H),2.33(s,3H),2.03-2.04(m,2H),1.443(dd,2H),1.26(dd,2H).

[0201] Example 64 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(difluoromethyl)piperidyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 4-(difluoromethyl)piperidine hydrochloride salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + :535; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.91(s,1H),8.47(s,1H),7.60(t,1H),7.18(d,1H),6.02(td,1H) ),3.93(d,2H),3.06(t,2H),2.13-2.28(m,1H),1.86-1.94(m,2H),1.67(qd,2H),1.43(dd,2H),1.32(dd,2H).

[0202] Example 65 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-6-azaspiro[3.5]non-6-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 2-oxa-6-azaspiro[3.5]nonane oxalate for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 522; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.36(s,1H),8.87(s,1H),8.51(s,1H),7.62(t,1H),7.24(s,1H),4.3 8(dd,4H),3.66(s,2H),3.29-3.38(m,2H),1.91(t,2H),1.75(brs,2H),1.47(dd,2H),1.34(dd,2H).

[0203] Example 66 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclopentylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 43 by substituting 1-cyclopentanecarbonylpiperazine TFA salt for N,N-dimethylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 577; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.29(brs,1H),8.97(s,1H),8.50(s,1H),7.61(t,1H),7.16(s,1H),3.75-3.86(m, 4H),3.46(s,4H),3.01-3.11(m,1H),1.72-1.90(m,4H),1.57-1.70(m,4H),1.45-1.51(m,2H),1.20-1.30(m,2H).

[0204] Example 67 Synthesis of N-(2,2-difluoroethyl)[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-methylcarboxamide [ka] In a 20 mL vial was added 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (250.00 mg, 0.580 mmol, 1.00 equiv), dioxane (5.00 mL), N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide (144.30 mg, 0.696 mmol, 1.20 equiv), CsCO (283.60 mg, 0.870 mmol, 1.50 equiv), RuPhos (108.31 mg, 0.232 mmol, 0.40 equiv), and RuPhos Palladacycle Gen. 3 (194.13 mg, 0.232 mmol, 0.40 equiv). The resulting solution was stirred at 90°C overnight under nitrogen atmosphere and then washed with H2O. The resulting solution was extracted with ethyl acetate, and the organic layers were combined and concentrated under vacuum. The crude product was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give the crude product, which was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 5um, 19*150mm; Mobile phase A: water (10mmol / L NH4HCO3+0.1%NH3 .H2O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 43% B to 47% B in 10 min; 254 / 220 nm; RT 9.32 min) to give the title compound (55.6 mg). LCMS (ES, m / z): [M+H] + 602; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.97(s,1H),8.51(s,1H),7.61(t,1H),7.18(s,1 H),6.21(tt,1H),3.62(td,2H),3.47-3.45(m,8H),2.99(s,3H),1.44(dd,2H),1.33(dd,2H).

[0205] Example 68 Synthesis of 1-{[(4-{4-[((3S)-1-methylpyrrolidin-3-yl)carbonyl]piperazinyl}-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 67 by substituting (S)-(1-methylpyrrolidin-3-yl)(piperazin-1-yl)methanone TFA salt for N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 592; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.33(brs,1H),8.96(s,1H),8.49(s,1H),7.61(t,1H),7.16(d,1H),3.76(d,4H),3.44( d,4H),2.78(t,1H),2.51-2.60(m,3H),2.30-2.38(m,1H),2.24(s,3H),1.95-2.01(m,2H),1.40(dd,2H),1.27(dd,2H).

[0206] Example 69 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(1-methylimidazol-2-yl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 67 by substituting 1-(1-methylimidazol-2-yl)piperazine hydrochloride salt for N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide. LCMS (ES, m / z): [M+H] + 561; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.36(s,1H),9.02(s,1H),8.54(s,1H),7.62(t,1H),7.25(s,1H) ,6.93(d,1H),6.65(d,1H),3.58(t,4H),3.53(s,3H),3.27(t,4H),1.46(dd,2H),1.33(dd,2H).

[0207] Example 70 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(7-oxa-3,9-diazabicyclo-[3.3.1]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] Step 1: Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(N-Boc-7-oxa-3,9-diazabicyclo[3.3.1]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile A stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-indazole-6-sulfonamide (400.00 mg, 0.929 mmol, 1.00 equiv.) and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]-nonane-9-carboxylate (423.91 mg, 1.858 mmol, 2.00 equiv.) in dioxane (4.00 mL) in an 8 mL vial was stirred under nitrogen with RuPhos (173.30 mg, 0.372 mmol, 0.40 equiv.), Cs2CO3 (756.26 mg, 2.322 mmol, 2.50 equiv.), RuPhos Palladacycle (1.00 mg, 0.00 mmol, 0.00 equiv.), and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]-nonane-9-carboxylate (1.00 mg, 0.00 mmol, 0.00 equiv.) in dioxane (4.00 mL) in an 8 mL vial was stirred under nitrogen with RuPhos (1.00 mg, 0.00 mmol, 0.00 equiv.), Cs2CO3 (1.00 mg, 0.00 mmol, 0.00 equiv.), and tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]-nonane-9-carboxylate (1.00 mg, 0.00 mmol, 0.00 equiv.). Gen.3 (310.61 mg, 0.372 mmol, 0.40 equiv). The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl(aq). The aqueous layer was extracted with EA and the combined fractions were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 100 mg of crude product as a yellow solid. The crude product (150 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 19*250 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 56% B to 66% B in 7 min; 254; 220 nm; RT 5.83 min) to give the title compound (15 mg) as a pale yellow solid.

[0208] Step 2: Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(7-oxa-3,9-diaza-bicyclo[3.3.1]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile To a stirred solution of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(N-Boc-7-oxa-3,9-diazabicyclo[3.3.1]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile (15 mg, 0.024 mmol, 1 equiv) in an 8 mL vial was added DCM (0.3 mL) and TFA (0.1 mL) under nitrogen atmosphere. The resulting mixture was stirred overnight for 12 h under nitrogen atmosphere. The reaction was quenched with saturated NaCl(aq) and the aqueous layer was extracted with EA. The resulting mixture was concentrated under vacuum and the crude product (20 mg) was purified by Prep-HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 40% B in 7 min; 254; 220 nm; RT 5.63 min) to give the title compound (5.2 mg). LCMS (ES, m / z): [M+H] + 523; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.22(brs,1H),8.98(s,1H),8.35(s,1H),7.61(t,1H),7.07 (s,1H),3.98(dd,4H),3.80(d,2H),3.51(dd,2H),3.04(s,2H),1.44(dd,2H),1.28(dd,2H).

[0209] Examples 71 and 72 Synthesis of 1-[({4-(8-methyl-7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (700.00 mg, 1.625 mmol, 1.00 equiv) and 2-methyl-hexahydroimidazo[1,5-a]pyrazin-3-one hydrochloride (622.81 mg, 3.250 mmol, 2.00 equiv) in dioxane (7.00 mL) in a 20 mL vial was added RuPhos (303.27 mg, 0.650 mmol, 0.40 equiv), Cs2CO3 (1852.84 mg, 5.687 mmol, 3.50 equiv) and RuPhos Palladacycle Gen.3 (543.56 mg, 0.650 mmol, 0.40 equiv) was added under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was quenched with saturated NH4Cl(aq) and the aqueous layer was extracted with EA. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (DCM:MEOH=25:1) to give 220 mg of crude product as a yellow solid. The crude product was purified by Prep-SFC (column: CHIRALPAK IA-3, 4.6*50mm, 3um; mobile phase A: Hex (0.1% DEA), mobile phase B: EtOH; flow rate: 1mL / min; gradient: 50%B to 50%; enantiomer A RT 2.77min; enantiomer B RT 2.40min) to give 1-[({4-(8-methyl-7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile enantiomer A (37.7mg) and enantiomer B (33.4mg).

[0210] Characterization Example 71 (Enantiomer A): LCMS (ES, m / z): [M+H] + 550; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.38(brs,1H),8.98(s,1H),8.53(s,1H),7.61(t,1H),7.21(d,1H),3.73-3.98 (m,4H),3.46(t,1H),3.22(td,1H),3.09(dd,1H),2.85-2.95(m,2H),2.72(s,3H),1.44(dd,2H),1.32(dd,2H).

[0211] Characterization Example 72 (Enantiomer B): LCMS (ES, m / z): [M+H] + 550; 1 H-NMR(300MHz,DMSO-d6,ppm)9.35(s,1H),8.99(s,1H),8.53(s,1H),7.62(t,1H),7.21(d,1H),3.67-3.98(m ,4H),3.46(t,1H),3.31(td,1H),3.09(dd,1H),2.85-2.95(m,2H),2.72(s,3H),1.45(dd,2H),1.32(dd,2H).

[0212] Example 73 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(5-methyl(3-pyrrolino[3,4-c]pyrazol-2-yl))-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] A mixture of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (400.00 mg, 0.928 mmol, 1.00 equiv.) and 5-methyl-2H,4H,6H-pyrrolo[3,4-c]pyrazole (2 To a stirred solution of t-BuXPhos (28.69 mg, 1.857 mmol, 2.00 equiv.) was added Cs2CO3 (756.26 mg, 2.321 mmol, 2.50 equiv.), t-BuXPhos (78.85 mg, 0.186 mmol, 0.20 equiv.) and t-BuXPhosPd-G3 (73.72 mg, 0.093 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight under nitrogen atmosphere and then quenched with saturated NH4Cl (aq.). The aqueous layer was extracted with EtOAc and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give the crude product (300 mg). The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm 5 um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 33% in 7 min; 254; 220 nm; RT 5.33 min) to give the title compound (82 mg). LCMS (ES, m / z): [M+H] + 518; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.54(brs,1H),9.15(s,1H),8.86(s,1H),8.43(s,1H), 8.09(d,1H),7.62(t,1H),3.77(d,4H),2.52-2.60(m,3H),1.45(dd,2H),1.33(dd,2H).

[0213] Example 74 Synthesis of 4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv) and N-methylpiperazine-1-carboxamide TFA salt (335.93 mg, 1.393 mmol, 2.00 equiv) in dioxane (3.00 mL) in an 8 mL vial under nitrogen atmosphere was added RuPhos (129.97 mg, 0.279 mmol, 0.40 equiv), KCO (336.83 mg, 2.437 mmol, 3.50 equiv), and RuPhos Palladacycle Gen. 3 (232.96 mg, 0.279 mmol, 0.40 equiv). The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl(aq). The aqueous layer was extracted with EtOAc and the organic layer was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 100 mg of crude product as a yellow solid. The crude product was purified by Prep-HPLC (Column: Xbridge Phenyl OBD Column, 5 um, 19*150 mm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 42% B to 52% B in 8 min; 254; 220 nm; Rt: 8.13 min) to give the title compound (40.7 mg). LCMS (ES, m / z): [M+H] + 538; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.35(brs,1H),8.97(s,1H),8.51(d,1H),7.60(t,1H),7.16(d,1 H),6.57(d,1H),3.57-3.64(m,4H),3.43-4.44(m,4H),2.62(d,3H),1.44(dd,2H),1.32(dd,2H).

[0214] Example 75 Synthesis of 1-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methylazetidine-3-carboxamide [ka] The title compound was prepared as described above in Example 74 by substituting N-methylazetidine-3-carboxamide TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 509; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.24(s,1H),8.72(s,1H),8.20(s,1H),8.09(d,1H),7.60(t,1 H),6.59(s,1H),4.42(t,2H),4.29(t,2H),3.52-3.65(m,1H),2.65(d,3H),1.25-1.45(m,4H).

[0215] Example 76 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-[2-(dimethylamino)ethyl]-N-methylcarboxamide [ka] The title compound was prepared as described above in Example 74 by substituting N-[2-(dimethylamino)ethyl]-N-methylpiperazine-1-carboxamide TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 609; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.32(brs,1H),8.97(s,1H),8.50(s,1H),7.61(t,1H),7.18(s,1H) ,3.45(s,4H),3.38(s,4H),3.27(t,2H),2.86(s,3H),2.41(t,2H),2.17(s,6H),1.30-1.46(m,4H).

[0216] Example 77 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-methyl-N-propylcarboxamide [ka] The title compound was prepared as described above in Example 74 by substituting N-methyl-N-propylpiperazine-1-carboxamide TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 580; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.96(s,1H),8.50(s,1H),7.61(t,1H),7.18(s,1H),3.37 -3.47(m,8H),3.10-3.15(t,2H),2.82(s,3H),1.54(q,2H),1.44(dd,2H),1.33(dd,2H),0.84(t,3H).

[0217] Example 78 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]-sulfonyl}(1H-indazol-4-yl))(1,4-diazaperhydroepynyl)]-N,N-dimethylcarboxamide [ka] The title compound was prepared as described above in Example 74 by substituting N,N-dimethyl-1,4-diazepane-1-carboxamide TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 566; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.30(s,1H),8.86(s,1H),8.27(s,1H),7.60(t,1H),6.97(s,1H),3. 87-3.91(m,4H),3.59(s,2H),3.20-3.29(m,2H),2.65(s,6H),2.03-2.08(d,2H),1.26-1.45(m,4H).

[0218] Example 79 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(3-methyl(2-pyridyl))-piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 74 by substituting 1-(3-methylpyridin-2-yl)piperazine dihydrochloride hydrochloride salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 572; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.01(brs,1H),9.01(s,1H),8.53(s,1H),8.17(d,1H),7.62(t,1H),7.5 6(d,1H),7.26(s,1H),6.99(dd,1H),3.61(t,4H),3.38(t,4H),2.33(s,3H),1.45(t,2H),1.32(dd,2H).

[0219] Example 80 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclopropylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 74 by substituting 1-cyclopropanecarbonylpiperazine for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 549; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.34(s,1H),8.98(s,1H),8.50(s,1H),7.61(t,1H),7.17(d,1H),3.98(s,2H),3 .76(s,2H),3.48-3.55(m,4H),3.17(d,1H),2.02-2.08(m,1H),1.44(dd,2H),1.32(dd,2H),0.70-0.80(m,4H). Example 81 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclobutylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 74 by substituting 1-cyclobutanecarbonylpiperazine TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 563; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.33(s,1H),8.96(s,1H),8.50(s,1H),7.47-7.74(t,1H),7.16(s,1H),3.73(s,2H),3 .61(s,2H),3.41-3.47(m,5H),2.12-2.27(m,4H),1.89-1.96(m,1H),1.77-1.81(m,1H),1.44(dd,2H),1.32(dd,2H).

[0220] Example 82 Synthesis of 1-[({4-[(3R)-3-methyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 74 by substituting (R)-2-methyl-1-(2-methylpiperazin-1-yl)propan-1-one TFA salt for N-methylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 565; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.32(s,1H),8.86(s,1H),8.7(s,1H),7.60(t,1H),7.14(brs,1H),4.70(brs,1H),4.20-4.55(m,1H), 3.97(brs,1H),3.86(d,1H),33.73(d,2H),3.00-3.20(m,1H),2.91(p,1H),1.32-1.50(m,3H),1.20-1.30(m,4H),1.04-1.06(d,6H).

[0221] Example 83 Synthesis of [(2S)-4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))-2-methylpiperazinyl]-N,N-dimethylcarboxamide [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (250.00 mg, 0.580 mmol, 1.00 equiv) and (S)-N,N,2-trimethylpiperazine-1-carboxamide TFA salt (312.50 mg, 1.161 mmol, 2.00 equiv) in dioxane (2.50 mL) in an 8 mL vial under nitrogen atmosphere was added RuPhos (108.31 mg, 0.232 mmol, 0.40 equiv), KCO (280.69 mg, 2.031 mmol, 3.5 equiv) and RuPhos Palladacycle Gen.3 (194.13 mg, 0.232 mmol, 0.40 equiv). The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl (aq). The aqueous layer was extracted with EA and the combined extracts were concentrated in vacuo. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 30 mg of crude product as a yellow solid. The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C 18 Column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 45% B in 7 min; 254; 220 nm; RT: 5.92 min) to give the title compound (3.2 mg). LCMS (ES, m / z): [M+H] + 566; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.30(brs,1H),8.87(s,1H),8.49(s,1H),7.62(t,1H),7.16(s,1H),3.97(dd,1H),3.69 (d,1H),3.60(d,1H),3.44(d,2H),3.28-3.30(m,1H),3.18-3.24(m,1H),2.81(s,6H),1.44(d,2H),1.31-1.33(m,5H).

[0222] Example 85 Synthesis of 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(1-methyl(4-piperidyl))-carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 83 by substituting (1-methylpiperidin-4-yl)(piperazin-1-yl)methanone TFA salt for (S)-N,N,2-trimethylpiperazine-1-carboxamide TFA salt. LCMS (ES, m / z): [M+H] + 606; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.33(brs,1H),8.96(s,1H),8.49(s,1H),7.61(t,1H),7.16(s,1H),3.76(d,4H),3.4 6(d,4H),2.79(d,2H),2.55-2.64(m,1H),2.16(s,3H),1.92(td,2H),1.59-1.65(m,4H),1.40(dd,2H),1.29(dd,2H).

[0223] Example 84 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(4-methyl(3-pyridyl))piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] Into a 25 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (170.00 mg, 0.395 mmol, 1.00 equiv), 1-(4-methylpyridin-3-yl)piperazine TFA salt (210 mg, 1.184 mmol, 3 equiv), RuPhos Palladacycle Gen. 3 (132.01 mg, 0.158 mmol, 0.4 equiv), RuPhos (73.65 mg, 0.158 mmol, 0.4 equiv), and CsCO (514.26 mg, 1.578 mmol, 4 equiv), dioxane (3.40 mL). The resulting solution was stirred in an oil bath at 90°C for 12 hours and then quenched with water. The resulting solution was extracted with ethyl acetate, and the organics were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 1). The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 19*250mm, 10um; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 33%B to 50%B in 7min; 254 / 220nm; RT: 5.87min) to give the title compound (2.7mg). LCMS (ES,m / z):[M+H] + 572; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.00(s,1H),8.54(s,1H),8.33(s,1H),8.20(d,1H),7.62(t,1H) ,7.26(s,1H),7.24(d,1H),3.62(s,4H),3.24(s,4H),2.35(s,3H),1.43(dd,2H),1.33(dd,4H).

[0224] Example 86 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-methyl-N-(2,2,2-trifluoroethyl)carboxamide [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (250.00 mg, 0.580 mmol, 1.00 equiv.) and N-methyl-N-(2,2,2-trifluoroethyl)piperazine-1-carboxamide TFA salt (375.14 mg, 1.161 mmol, 2.00 equiv.) in 1,4-dioxane (3 mL) in a 20 mL sealed tube was added K2CO3 (280.69 mg, 2.031 mmol, 3.50 equiv.), RuPhos (108.31 mg, 0.232 mmol, 0.40 equiv.) and RuPhos Palladacycle under nitrogen atmosphere. Gen.3 (194.13 mg, 0.232 mmol, 0.40 equiv) was added. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq) and then diluted with water. The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give the crude product (50 mg), which was purified by crystallization from CH2Cl2:Hexane (1:10, 1 mL) to give the title compound (20.7 mg). LCMS(ES,m / z):[M+H]+620;1H-NMR(400MHz,DMSO-d6,ppm)δ9.35(s,1H),8.98(d,1H),8.52(s,1H ),7.61(t,1H),7.19(d,1H),4.12(q,2H),3.48(s,8H),3.05(s,3H),1.45(dd,2H),1.33(dd,2H).

[0225] Example 87 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-pyridylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL vial, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv.), dioxane (5.00 mL), 1-(pyridine-2-carbonyl)piperazine (266.32 mg, 1.393 mmol, 2.00 equiv.), K2CO3 (288.71 mg, 2.089 mmol, 3.00 equiv.), RuPhos (129.97 mg, 0.279 mmol, 0.40 equiv.), and RuPhos Palladacycle Gen.3 (232.96 mg, 0.279 mmol, 0.40 equiv.) were placed. The resulting solution was stirred overnight at 90 °C under nitrogen atmosphere. The resulting mixture was washed with 3x5 mL of H2O. The resulting solution was extracted with 2x5 mL of ethyl acetate and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=30:1) to give 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-pyridylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile (9.7 mg). LCMS (ES, m / z): [M+H] + 586; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.97(s,1H),8.64(d,1H),8.51(s,1H),7.98(td,1H),7.67(d,1H),7.61 (t,3H),7.53(dd,1H),7.19(d,1H),3.95(s,2H),3.75(s,2H),3.58(s,2H),3.48(s,2H),1.45(dd,2H),1.32(dd,2H).

[0226] Example 88 Synthesis of 1-[({4-[(3S)-3-methyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL sealed tube, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv.), K2CO3 (336.83 mg, 2.437 mmol, 3.5 equiv.), dioxane (3.00 mL) in an 8 mL vial were placed and (S)-2-methyl-1-(2-methylpiperazin-1-yl)propan-1-one TFA salt (373.62 mg, 1.393 mmol, 2 equiv.), RuPhos Pd Gen.3 (232.96 mg, 0.279 mmol, 0.4 equiv.) and RuPhos (129.97 mg, 0.279 mmol, 0.40 equiv.) were added. The mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl(aq) at room temperature. The aqueous layer was extracted with EtOAc and the resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=30:1) to give the crude product (120 mg). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 19*250 mm, 5 um; Mobile phase A: Water (10 mmol / L NH4HCO3+0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 45% B to 60% B in 7 min; 254 / 220 nm; RT: 9.50 min) to give the title compound (3.3 mg). LCMS (ES, m / z): [M+H] + 565; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.15(brs,1H),8.84(s,1H),8.46(s,1H),7.61(t,1H),7.13(s,1H),4.65-4.75(m,1H),4.20 -4.55(m,1H),3.88-3.95(m,1H),3.84(d,1H),3.72(d,2H),3.10-3.20(m,1H),2.91(p,1H),1.24-1.45(m,7H),1.04(d,6H).

[0227] Example 89 Synthesis of 1-[({4-[cis-3,5-dimethyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (600.00 mg, 1.393 mmol, 1.00 equiv.), 1-(cis-2,6-dimethyl-piperazin-1-yl)-2-methylpropan-1-one TFA salt (513.29 mg, 2.785 mmol, 2.00 equiv.), RuPhos (259.95 mg, 0.557 mmol, 0.40 equiv.), KCO (577.42 mg, 4.178 mmol, 3.00 equiv.), dioxane (10.00 mL), and RuPhos Pd Gen.3 (465.91 mg, 0.557 mmol, 0.40 equiv.) was charged. The resulting solution was stirred in an oil bath at 90° C. for 12 hours and then quenched with water. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with dichloromethane / methanol (20 / 1) to give the crude product (8 mg). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to 55% B in 7 min; 254; 220 nm; RT: 6.38 min) to give the title compound (1.3 mg). LCMS (ES, m / z): [M+H] + 579; 1H-NMR(300MHz,DMSO-d6,ppm)δ9.23(brs,1H),8.71(s,1H),8.50(s,1H),7.61(t,1H),7.20(s,1H),4.58-4.70(m,1H) ,4.25-4.40(m,1H),3.73(d,2H),3.05-3.30(m,2H),2.89(p,1H),1.30-1.54(m,8H),1.20-1.29(m,2H),1.07(d,6H).

[0228] Example 90 Synthesis of 1-{[(4-{4-[((2R)-1-methylpyrrolidin-2-yl)carbonyl]piperazinyl}-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 89 by substituting 1-(methyl-D-prolyl)piperazine TFA salt for 1-(cis-2,6-dimethylpiperazin-1-yl)-2-methylpropan-1-one TFA salt. LCMS (ES, m / z): [M+H] + 592; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.21(brs,1H),8.99(s,1H),8.50(s,1H),7.61(t,1H),7.17(s,1H),4.06-3.68(brt,4H),3.59-3.41( brd,4H),3.19(t,1H),2.97(s,1H),2.26(s,3H),2.23-2.18(m,1H),2.05-2.18(m,1H),1.87-1.79(m,3H),1.42(t,2H),1.30(t,2H).

[0229] Example 91 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[6-(2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound 1 was prepared as described above in Example 89 by substituting 1-(cis-2,6-dimethylpiperazin-1-yl)-2-methylpropan-1-one TFA salt with 1-(3,6-diaza-bicyclo[3.1.1]heptan-6-yl)-2-methylpropan-1-one TFA salt. LCMS (ES, m / z): [M+H] + 563;H- 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.28(s,1H),8.84(s,1H),8.30(s,1H),7.60(t,1H),6.86(d,1H),4.85(s,2H),4.13(brs,1H),3.78(obsbr s,1H),3.74(d,1H),3.49(d,1H),2.88(q,1H),2.60(p,1H),1.74(d,1H),1.32-1.42(m,2H),1.15-1.24(m,2H),0.92(d,3H),0.63(d,3H).

[0230] Example 92 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methyl-2,7-diazaspiro-[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (500.00 mg, 1.160 mmol, 1.00 equiv) and 2-methyl-2,7-diazaspiro[3.5]nonane (542.48 mg, 3.868 mmol, 2.00 equiv) in dioxane (5.00 mL) in an 8 mL vial was added RuPhos (361.03 mg, 0.773 mmol, 0.4 equiv), KPO (1847.60 mg, 8.703 mmol, 4.5 equiv), RuPhos Palladacycle Gen.3 (647.10 mg, 0.773 mmol, 0.4 equiv) under nitrogen atmosphere. The resulting mixture was stirred at 90°C under nitrogen atmosphere overnight for 12 hours and then quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc and the resulting organic layer was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 260 mg of crude product as a yellow solid. The crude product (260 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5um; Mobile phase A: Water (0.05% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 21% B to 37% B in 7 min; 254; 220 nm; RT: 6.73 min) to give the title compound (51.0 mg). LCMS (ES, m / z): [M+H] + : 1 H-NMR(300MHz,DMSO-d6,ppm)δ8.87(s,1H),8.45(s,1H),7.61(t,1H),7.16(d,1H),3 .35-3.38(m,4H),3.04(s,4H),2.28(s,3H),1.92(t,4H),1.43(dd,2H),1.30(dd,2H).

[0231] Example 93 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-(2-pyridyl)piperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] To a stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv.) and 1-(pyridin-2-yl)piperazine (227.32 mg, 1.393 mmol, 2.00 equiv.) in dioxane (3.00 mL) in an 8 mL vial under nitrogen atmosphere was added RuPhos (129.97 mg, 0.279 mmol, 0.4 equiv.), Pd(OAc) (62.53 mg, 0.279 mmol, 0.4 equiv.) and CSCO (567.20 mg, 1.741 mmol, 2.5 equiv.). The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched by the addition of saturated NH4Cl (aq). The aqueous layer was extracted with ethyl acetate and the combined extracts were concentrated in vacuo. The residue was purified by Prep-TLC (DCM:MEOH=25:1) to give the crude product (200 mg) as a yellow solid. The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C). 18 Column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 48% B to 58% B in 7 min; 254; 220 nm; RT1: 6.28 min) to give the title compound (30.6 mg). LCMS (ES, m / z): [M+H] + 558.2; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.33(s,1H),8.98(s,1H),8.48(s,1H),8.15(dd,1H),7.42-7.77(m,2H),7 .18(s,1H),6.89(d,1H),6.68(dd,1H),3.76-3.78(m,4H),3.58-3.59(m,4H),1.43(dd,2H),1.31(dd,2H).

[0232] Example 94 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-(3-pyridyl)piperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 93 by substituting 1-(pyridin-2-yl)piperazine with 1-(pyridin-3-yl)piperazine hydrochloride salt. LCMS (ES, m / z): [M+H] + :558; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.35(brs,1H),8.98(s,1H),8.50(s,1H),8.37(d,1H),8.03( d,1H),7.39-7.77(m,2H),7.19-7.28(m,2H),3.40-3.65(m,8H),1.39(dd,2H),1.27(dd,2H).

[0233] Example 95 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-pyridazin-3-yl piperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 93 by substituting 3-(piperazin-1-yl)pyridazine hydrochloride for 1-(pyridin-2-yl)piperazine. LCMS (ES, m / z): [M+H] + 559; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.34(s,1H),9.03(s,1H),8.62(d,1H),8.52(s,1H),7.62(obs t,1H),7.40(obsdd,2H),7.22(s,1H),3.91(s,4H),3.64(s,4H),1.44(dd,2H),1.33(dd,2H).

[0234] Example 96 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(phenylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 93 by substituting 1-benzoylpiperazine for 1-(pyridin-2-yl)piperazine. LCMS (ES, m / z): [M+H] + 585; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.33(s,1H),8.96(s,1H),8.51(s,1H),7.60(obst,1H), 7.49(s,5H),7.18(s,1H),3.51-3.90(m,8H),3.31(s,4H),1.43(dd,2H),1.32(dd,2H).

[0235] Example 97 Synthesis of 1-[({1-(5-methyl(1,3,4-thiadiazol-2-yl))-4-[4-(2-methylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 15 mL sealed tube, 4-chloro-N-(1-cyanocyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (300.00 mg, 0.696 mmol, 1.00 equiv.), dioxane (4.00 mL), 2-methyl-1-(piperazin-1-yl)propan-1-one TFA salt (265.57 mg, 1.044 mmol, 1.5 equiv.), K2CO3 (288.71 mg, 2.089 mmol, 3 equiv.), RuPhos (32.49 mg, 0.070 mmol, 0.1 equiv.), RuPhos Palladacycle Gen.3 (58.24 mg, 0.070 mmol, 0.1 equiv.) were added. The resulting solution was stirred at 90 °C overnight. The reaction was quenched with saturated NH4Cl(aq) at room temperature, the aqueous layer was extracted with EtOAc, and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=50:1) to give the crude product. The crude product (80 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: Water (0.05% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 37% B in 7 min; 254; 220 nm; RT: 5.88 min) to give the title compound (39.2 mg). LCMS (ES, m / z): [M+H] + 515; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.29(s,1H),8.87(s,1H),8.51(s,1H),7.13(s,1H),3.76-3. 79(m,4H),3.45(s,4H),2.96(p,1H),2.76(s,3H),1.44(dd,2H),1.33(dd,2H),1.05(d,6H).

[0236] Example 98 Synthesis of 1-[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(methylethyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-2-methylpropan-1-one [ka] Step 1: Synthesis of 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-isopropyl-1H-indazole-6-sulfonamide In a 10 mL round-bottom flask were placed 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonyl chloride (900.00 mg, 2.337 mmol, 1.00 equiv), propan-2-amine (151.93 mg, 2.570 mmol, 1.1 equiv), and pyridine (369.65 mg, 4.673 mmol, 2 equiv). The resulting product was stirred overnight at room temperature under nitrogen atmosphere, and the aqueous layer was extracted with EA. The resulting mixture was concentrated in vacuo, and the residue was purified by Prep-TLC (DCM:MeOH=25:1) to give the title compound (250 mg) as a pale yellow solid.

[0237] Step 2: Synthesis of 1-[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(methylethyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-2-methylpropan-1-one To a stirred solution of 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-isopropyl-1H-indazole-6-sulfonamide (240.00 mg, 0.588 mmol, 1.00 equiv) in an 8 mL vial under nitrogen atmosphere was added 2-methyl-1-(piperazin-1-yl)propan-1-one TFA salt (299.24 mg, 1.177 mmol, 2 equiv), RuPhos (219.68 mg, 0.471 mmol, 0.8 equiv), CsCO (671.07 mg, 2.060 mmol, 3.5 equiv), RuPhos Palladacycle Gen.3 (196.87 mg, 0.235 mmol, 0.40 equiv), and dioxane (3.00 mL). The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere and then quenched with saturated NH4Cl(aq). The aqueous layer was extracted with EA and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give the crude product (200 mg) as a yellow solid. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 36B% to 46%B in 8 min; 254; 220 nm; RT: 7.03 min) to give the title compound (30.7 mg). LCMS (ES, m / z): [M+H] + 528; 1 H-NMR(400MHz,DMSO-d6,ppm)δ8.93(s,1H),8.45(s,1H),7.83(s,1H),7.60(t,1H),7.17(s ,1H),3.77(d,4H),3.45(d,4H),3.30-3.27(m,1H),2.95(p,1H),1.04(d,6H),0.97(d,6H).

[0238] Example 99 Synthesis of 1-[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(tert-butyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-2-methylpropan-1-one [ka] Step 1: Synthesis of N-(tert-butyl)-4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide The title compound N-(tert-butyl)-4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide was prepared as 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-isopropyl-1H-indazole-6-sulfonamide by substituting tert-butylamine for propan-2-amine.

[0239] Step 2: Synthesis of 1-[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(tert-butyl)amino]-sulfonyl}(1H-indazol-4-yl))piperazinyl]-2-methylpropan-1-one To a stirred solution of 2-methyl-1-(piperazin-1-yl)propan-1-one TFA salt (492.99 mg, 1.939 mmol, 2.00 equiv.) and N-(tert-butyl)-4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazole-6-sulfonamide (400.00 mg, 0.969 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL) in a 20 mL vial under nitrogen atmosphere was added RuPhos (180.96 mg, 0.388 mmol, 0.40 equiv.), RuPhos Palladacycle Gen.3 (324.34 mg, 0.388 mmol, 0.40 equiv) and K2CO3 (468.96 mg, 3.393 mmol, 3.50 equiv) were added. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere, then quenched with saturated NH4Cl(aq), extracted with EtOAc, and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2 / MeOH=25 / 1) to give the crude product (230 mg). The crude product was dissolved in MeOH to give a precipitate, which was collected by filtration and then dried under vacuum to give the title compound (189.7 mg). LCMS (ES, m / z): [M+H] + 542; 1 H-NMR(400MHz,DMSO-d6,ppm)δ8.92(s,1H),8.48(s,1H),7.78(s,1H),7.60(m,1H),7.22(d ,1H),3.77(dd,4H),3.44(d,4H),3.46-3.42(d,4H),2.95(p,1H),1.11(s,9H),1.05(d,6H).

[0240] Example 100 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-morpholin-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL sealed tube purged and maintained with an inert atmosphere of nitrogen, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (500 mg, 1.161 mmol, 1 equiv.), t-BuONa (278.83 mg, 2.901 mmol, 2.50 equiv.), t-BuOH (5 mL), morpholine (1011.09 mg, 11.606 mmol, 10.00 equiv.), and t-BuXPhos-PdG3 (86.73 mg, 0.116 mmol, 0.10 equiv.) were placed. The resulting solution was stirred at 80° C. overnight, and the resulting solution was diluted with saturated NH4Cl(aq.). The resulting solution was extracted with DCM, and the DCM extract was washed with water and then concentrated under vacuum. The resulting residue (50 mg) was purified by Prep-TLC (DCM:MeOH=60:1) to give the title compound (12.5 mg). LCMS (ES, m / z): [M+H] + 482; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.35(s,1H),8.99(d,1H),8.52(s,1H),7.61 (t,1H),7.18(d,1H),3.87(t,4H),3.41(t,4H),1.44(dd,2H),1.32(dd,2H).

[0241] Example 101 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyrrolidinyl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (500 mg, 1.161 mmol, 1 equiv.), t-BuONa (278.83 mg, 2.901 mmol, 2.5 equiv.), t-BuOH (5 mL), pyrrolidine (412.71 mg, 5.803 mmol, 5 equiv.), and tBuXPhos Pd G3 (92.19 mg, 0.116 mmol, 0.1 equiv.) were placed. The resulting solution was stirred at 80° C. overnight. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (CHCl:MeOH=20:1) to give the crude product. The crude product (20 mg) was purified by Prep-HPLC (Column: SunFire C18 OBD Prep Column, 100 Angstroms, 5 μm, 19x250 mm; Mobile phase A: Water (1% Acetic Acid), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 60% B to 74% B in 7 min; 254; 220 nm; RT: 6.95 min) to give the title compound (1.4 mg). LCMS (ES, m / z): [M+H] + 466; 1 H-NMR(300MHz,DMSO-d6,ppm)δ8.74(s,1H),8.04(s,1H),7.59(t,1H),6.72(s,1H),3.20-3.80(H2O obs peak),2.05(s,4H),1.71(s,5H),0.78-1.04(m,4H).

[0242] Example 102 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-methylpiperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] A solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (500.00 mg, 1.161 mmol, 1.00 equiv.), 1-methylpiperazine (581.23 mg, 5.803 mmol, 5 equiv.), t-BuONa (278.83 mg, 2.901 mmol, 2.5 equiv.) and t-BuXPhos Pd G3 (92.19 mg, 0.116 mmol, 0.1 equiv.) in t-BuOH (5.00 mL) in a 25 mL 3-neck round-bottom flask was stirred overnight at 80° C. under nitrogen atmosphere. The resulting mixture was concentrated under vacuum and the residue was then purified by Prep-TLC (CHCl:MeOH=20:1) to give the crude product (20 mg). The crude product was purified by Prep-HPLC (column: XBridge Prep OBD C18 column 30 × 150 mm 5 um; mobile phase A: water (0.05% NH . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 20% B to 40% B in 7 min; 254; 220 nm; Rt: 6.22 min) to give the title compound (4.5 mg). LCMS (ES, m / z): [M+H] + 495; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.44(brs,1H),9.00(s,1H),8.55(s,1H),7.62(t,1H),7 .23(s,1H),3.62(brs,4H),3.10(brs,4H),2.62(brs,3H),1.45(dd,2H),1.33(dd,2H).

[0243] Example 103 Synthesis of (S)-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(2-methylmorpholino)-1H-indazole-6-sulfonamide [ka] In a 15 mL sealed tube, 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoro-methyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (500.00 mg, 1.161 mmol, 1.00 equiv), (2S)-2-methylmorpholine (234.78 mg, 2.321 mmol, 2.00 equiv), t-BuOH (5.00 mL), t-BuONa (278.83 mg, 2.901 mmol, 2.50 equiv), and t-BuXPhos-Pd-G3 (129.01 mg, 0.162 mmol, 0.14 equiv) were placed under nitrogen atmosphere. The resulting solution was stirred overnight at 100 °C under nitrogen atmosphere and then quenched with saturated NH4Cl (aq). The resulting mixture was extracted with EtOAc and the combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2:MeOH=40:1) to give the crude product. The crude product (20 mg) was purified by Prep-HPLC (Column: Xbridge Prep OBD C18 column 19*250mm, 5um; Mobile phase A: Water (10mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 20mL / min; Gradient: 51%B to 61%B in 8min; 254; 220nm; rt: 7.77min) to give the title compound (1.6 mg). LCMS (ES,m / z): [M+H] + 496; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.35(s,1H),9.00(s,1H),8.52(s,1H),7.61(t,1H),7.17(d,1H),4 .00(d,1H),3.63-3.84(m,4H),3.05(t,1H),2.74(t,1H),1.45(dd,2H),1.33(dd,2H),1.21(d,3H).

[0244] Example 104 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-fluoropiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 103 by substituting 4-fluoropiperidine hydrochloride salt for (2S)-2-methylmorpholine. LCMS (ES, m / z): [M+H] + 498; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.35(brs,1H),8.95(s,1H),8.49(s,1H),7.62(t,1H),7.20(s,1H),4.86-5.23( m,1H),3.52-3.67(m,2H),3.41-3.51(m,3H),2.08-2.29(m,2H),1.88-2.02(m,2H),1.44(dd,2H),1.34(dd,2H).

[0245] Example 105 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4,4-difluoropiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 103 by substituting 4,4-difluoropiperidine for (2S)-2-methylmorpholine. LCMS (ES, m / z): [M+H] + 516; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.39(s,1H),8.99(s,1H),8.54(s,1H),7.62(t,1H), 7.24(s,1H),3.59(t,4H),2.21-2.30(m,4H),1.44-1.48(m,2H),1.32-1.37(m,2H).

[0246] Example 106 Synthesis of 1-({[4-((3R)-4-{[1-(2,2-difluoroethyl)(4-piperidyl)]carbonyl}-3-methylpiperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl]sulfonyl}amino)cyclopropanecarbonitrile [ka] Step 1: Synthesis of benzyl (R)-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-3-methyl-piperazine-1-carboxylate In a 100 mL round bottom flask purged and maintained under an inert atmosphere of nitrogen was placed benzyl (3R)-3-methylpiperazine-1-carboxylate (1.00 g, 4.268 mmol, 1.00 equiv), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.98 g, 4.268 mmol, 1 equiv), EDCI (1.23 g, 6.402 mmol, 1.5 equiv), HOBT (0.87 g, 6.402 mmol, 1.5 equiv), DIEA (1.65 g, 12.804 mmol, 3 equiv), and DMF (10.00 mL). The resulting solution was stirred at room temperature for 12 hours and then quenched with water. The resulting solution was extracted with ethyl acetate and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Flash-Prep-HPLC (Intel Flash-1: column 18, mobile phase, increasing from CH3CN:H2O=1:1 to CH3CN:H2O=2:1 within 30 min) to give the title compound (1.7 g).

[0247] Step 2: Synthesis of benzyl (R)-3-methyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed benzyl (R)-4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-3-methylpiperazine-1-carboxylate (1.65 g, 3.815 mmol, 1.00 equiv), TFA (5.00 mL), and DCM (20.00 mL). The resulting solution was stirred at room temperature for 12 h and then concentrated to give the title compound (2.4 g).

[0248] Step 3: Synthesis of benzyl (R)-4-(1-(2,2-difluoroethyl)piperidine-4-carbonyl)-3-methyl-piperazine-1-carboxylate In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, benzyl (R)-3-methyl-4-(piperidine-4-carbonyl)piperazine-1-carboxylate (2.35 g, 6.658 mmol, 1.00 equiv), 1,1-difluoro-2-iodoethane (2.56 g, 13.316 mmol, 2 equiv), K2CO3 (2.76 g, 19.970 mmol, 3.00 equiv), and DMF (30.00 mL) were placed. The resulting solution was stirred in an oil bath at 80° C. for 12 h and then quenched with water. The resulting solution was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 3) to give the title compound (1 g).

[0249] Step 4: Synthesis of (R)-(1-(2,2-difluoroethyl)piperidin-4-yl)(2-methylpiperazin-1-yl)methanone In a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed benzyl (R)-4-(1-(2,2-difluoroethyl)piperidine-4-carbonyl)-3-methyl-piperazine-1-carboxylate (1 g, 2.442 mmol, 1.00 equiv), Pd / C (200.00 mg, 1.879 mmol, 0.77 equiv), and THF (20 mL). The resulting solution was stirred under a hydrogen atmosphere at room temperature for 12 h. The solids were filtered and the resulting mixture was concentrated to give the title compound (560 mg) (83%) as a colorless oil.

[0250] Step 5: Synthesis of 1-({[4-((3R)-4-{[1-(2,2-difluoroethyl)(4-piperidyl)]carbonyl}-3-methyl-piperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl]sulfonyl}-amino}cyclopropanecarbonitrile Into a 25 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (400.00 mg, 0.928 mmol, 1.00 equiv), PH-IDE-B-0489-4 (383.46 mg, 1.393 mmol, 1.50 equiv), RuPhos (173.30 mg, 0.371 mmol, 0.40 equiv), CsCO (907.51 mg, 2.785 mmol, 3.00 equiv), dioxane (5.00 mL), and RuPhos Palladacycle Gen. 3 (310.61 mg, 0.371 mmol, 0.4 equiv). The resulting solution was stirred in an oil bath at 90°C for 7 hours and then concentrated. The residue was applied to a silica gel column with dichloromethane / methanol (15 / 1). The crude product (150 mg) was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30 x 150 mm 5um; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3 .HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 38% B to 50% B in 7 min; 254; 220 nm; RT: 7.05 min) to give the title compound (54.8 mg). LCMS (ES, m / z): [M+H] + 670; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.30(s,1H),8.85(s,1H),8.47(s,1H),7.60(t,1 H),7.13(s,1H),6.12(tt,1H),4.69(s,1H),4.45-4.23(m,1H),3.96-3.65(m,3H) ,3.34-3.20(m,1H),3.15-2.98(m,1H),2.92(d,2H),2.72(td,2H),2.61-2.50(m, 1H),2.26-2.20(m,2H),1.63-1.50(m,4H),1.46-1.37(m,3H),1.33-1.25(m,4H).

[0251] Example 107 Synthesis of 1-({[4-(4-{[1-(2,2-difluoroethyl)(4-piperidyl)]carbonyl}piperazinyl)-1-[5-(difluoro-methyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl]sulfonyl}amino)cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 106 by substituting benzyl piperazine-1-carboxylate for benzyl (3R)-3-methylpiperazine-1-carboxylate in step 1. LCMS (ES, m / z): [M+H] + 656; 1H-NMR(400MHz,DMSO-d6,ppm)δ9.23(brs,1H),8.96(s,1H),8.50(s,1H),7.60(t,1H),7.17(s,1H),6.12(tt,1H),3.77 (d,4H),3.46(brs,4H),2.93(d,2H),2.61-2.76(m,3H),2.24(td,2H),1.59-1.65(m,4H),1.43(dd,2H),1.31(dd,2H).

[0252] Example 108 Synthesis of 1-{[(4-{(3R)-3-methyl-4-[(methylcyclopropyl)carbonyl]piperazinyl}-1-[5-(difluoro-methyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] To a stirred mixture of (R)-(1-methylcyclopropyl)(2-methylpiperazin-1-yl)methanone TFA salt (400.00 mg, 1.427 mmol, 1.00 equiv) and 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]indazole-6-sulfonamide (307.42 mg, 0.714 mmol, 0.50 equiv) in DMF (6 mL) in a 20 mL vial under nitrogen atmosphere was added RuPhos (133.19 mg, 0.285 mmol, 0.20 equiv), RuPhos Palladacycle Gen.3 (238.71 mg, 0.285 mmol, 0.20 equiv) and CsCO (813.70 mg, 2.497 mmol, 1.75 equiv). The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq), extracted with EtOAc, and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2:MeOH=25:1) to give the crude product (100 mg). The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 um; Mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3 . HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 47% B in 9 min; 254; 220 nm; RT: 8.47 min) to give the title compound (11.1 mg). LCMS (ES, m / z): [M+H] + 577; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.23(brs,1H),8.86(s,1H),8.49(s,1H),7.60(t,1H),7.17(s,1H),4.65(s,1H),4.25(d,1H),3.86(d ,1H),3.73(d,1H),3.57(brs,1H),3.30-3.24(m,1H),3.10(s,1H),1.45-1.43(m,2H),1.35-1.28(m,8H),0.87(dd,2H),0.58(s,2H).

[0253] Example 109 Synthesis of 1-{[(4-{(3R)-3-methyl-4-[(methylcyclobutyl)carbonyl]piperazinyl}-1-[5-(difluoro-methyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 108 by substituting (R)-(1-methylcyclobutyl)(2-methylpiperazin-1-yl)methanone TFA salt for (R)-(1-methylcyclopropyl)(2-methylpiperazin-1-yl)methanone TFA salt. LCMS (ES, m / z): [M+H] + 591; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.25(brs,1H),8.84(s,1H),8.47(s,1H),7.60(m,1H),7.15(s,1H),4.67(s,1H),4.41-4.01(m,1H),3.82(d,1H) ),3.73(d,1H),3.57(s,1H),3.25-2.85(m,2H),2.50-2.42(m,2H),2.00 -1.78(m,3H),1.69-1.60(m,1H),1.50-1.43(m,6H),1.31-1.25(m,4H).

[0254] Example 110 Synthesis of 1-[({4-[(3R)-3-methyl-4-(2-methylbutanoyl)piperazinyl]-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] Step 1: Synthesis of tert-butyl (3R)-3-methyl-4-(2-methyl-butanoyl)piperazine-1-carboxylate In a 20 mL round bottom flask, tert-butyl (3R)-3-methylpiperazine-1-carboxylate (817.08 mg, 4.080 mmol, 1.00 equiv), 2-methylbutanoic acid (500.00 mg, 4.896 mmol, 1.2 equiv), EDCI (1173.11 mg, 6.119 mmol, 1.5 equiv), DIEA (790.90 mg, 6.119 mmol, 1.5 equiv), HOBT (826.88 mg, 6.119 mmol, 1.5 equiv), and DMF (10.00 mL) were placed. The resulting solution was stirred overnight at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EA, and the resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give the title compound (1.2 g, 77.46%) as a pale yellow solid.

[0255] Step 2: Synthesis of 2-methyl-1-((R)-2-methylpiperazin-1-yl)butan-1-one trifluoroacetate In a 20 mL round bottom flask was placed tert-butyl (3R)-3-methyl-4-(2-methyl-butanoyl)piperazine-1-carboxylate (1.2 g, 4.219 mmol, 1.00 equiv), DCM (6.00 mL), and TFA (2.00 mL). The resulting solution was stirred at room temperature for 2 h and concentrated in vacuo to give the title compound (1 g, 91.58%) as an orange oil.

[0256] Step 3: Synthesis of 1-[({4-[(3R)-3-methyl-4-(2-methylbutanoyl)piperazinyl]-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile A stirred solution of 4-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-1H-indazole-6-sulfonamide (381.52 mg, 0.886 mmol, 1.00 equiv.), 2-methyl-1-((R)-2-methylpiperazin-1-yl)butan-1-one trifluoroacetic acid (500 mg, 1.771 mmol, 2.00 equiv.), RuPhos (330.58 mg, 0.708 mmol, 0.80 equiv.), Cs2CO3 (1009.85 mg, 3.099 mmol, 3.50 equiv.), dioxane (4.00 mL), and RuPhos Palladacycle was added to an 8 mL vial under nitrogen atmosphere. Gen.3 (296.26 mg, 0.354 mmol, 0.40 equiv) was added. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was quenched by addition of saturated NH4Cl (aq), extracted with EA, and the combined extracts were concentrated under vacuum. The residue was purified by Prep-TLC (DCM:MeOH=25:1) to give 30 mg of crude product as a yellow solid. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 30*150 mm, 5 um; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 46% B in 8 min; 254; 220 nm; RT: 7.03 min) to give the title compound (2.4 mg). LCMS (ES, m / z): [M+H] + 579; 1 H-NMR(300MHz,DMSO-d6,ppm)δ8.87(s,1H),8.47(s,1H),7.61(t,1H),7.15(s,1H),4.73(s,1H),4.20-4.55(m,1H),3.60-4.10( m,3H),3.00-3.25(m,1H),2.68-2.82(m,1H),1.51-1.68(m,1H),1.35-1.49(m,4H),1.22-1.33(m,5H),1.04(d,3H),0.86(t,3H).

[0257] Example 111 Synthesis of 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(methylcyclopropyl)carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 108 by substituting (1-methylcyclopropyl)-(piperazin-1-yl)methanone TFA salt for (R)-(1-methylcyclopropyl)(2-methylpiperazin-1-yl)methanone TFA salt. LCMS (ES, m / z): [M+H] + 563; 1 H-NMR(400MHz,DMSO-d6,ppm)δ9.30(s,1H),8.98(s,1H),8.51(s,1H),7.60(t,1H),7.19(s ,1H),3.82(s,4H),3.48(s,4H),1.44(dd,2H),1.38-1.29(m,5H),0.87(t,2H),0.59(t,2H).

[0258] Example 112 Synthesis of 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(methylcyclobutyl)carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 108 by substituting (1-methylcyclobutyl)-(piperazin-1-yl)methanone TFA salt for (R)-(1-methylcyclopropyl)(2-methylpiperazin-1-yl)methanone TFA salt. LCMS (ES, m / z): [M+H] + 577; 1H-NMR(300MHz,DMSO-d6,ppm)δ8.88(s,1H),8.46(s,1H),7.56(t,1H),7.16(s,1H),3.62-3.56(m,3H),3.55-3.50(m,1H), 3.39(s,4H),2.46-2.41(m,2H),2.06-1.82(m,3H),1.70-1.60(m,1H),1.41(s,3H),1.22-1.18(m,2H),1.15-1.10(m,2H).

[0259] Example 113 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylbutanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] The title compound was prepared as described above in Example 108 by substituting 2-methyl-1-(piperazin-1-yl)butan-1-one TFA salt for (R)-(1-methyl-cyclopropyl)(2-methylpiperazin-1-yl)methanone TFA salt. LCMS (ES, m / z): [M+H] + 565; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.31(s,1H),8.98(s,1H),8.51(s,1H),7.61(t,1H),7.17(d,1H),3.78-3.82( m,4H),3.48(s,4H),2.79(q,1H),1.62(spt,1H),1.44(dd,2H),1.25-1.42(m,3H),1.03(d,3H),0.87(t,3H).

[0260] Example 114 Synthesis of 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-3-chloro-4-(2-oxa-7-aza-spiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile [ka] In a 20 mL vial was placed 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile (200.00 mg, 0.383 mmol, 1.00 equiv), DMF (4.00 mL), and NCS (76.81 mg, 0.575 mmol, 1.50 equiv). The resulting solution was stirred at room temperature overnight and then washed with H2O. The resulting solution was extracted with ethyl acetate, the combined extracts were concentrated under vacuum, and the residue was purified by Prep-TLC (CHCl2:MeOH=50:1) to give the crude product. The crude product was purified by Prep-HPLC (Column: Atlantis HILIC OBD column 19*150mm 5um; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 56%B to 58%B in 7min; 254 / 220nm; Rt: 6.2min) to give the title compound (8.6mg). LCMS (ES,m / z):[M+H] + =556; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.67(s,1H),9.05(s,1H),8.92(s,1H),7.61(t,1H),4.43(s,4H),3.31(s,4H),2.02-2.09(m,4H),1.25-1.46(m,4H).

[0261] Example 115 Synthesis of [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-3-chloro-6-{[(cyanocyclopropyl)-amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide [ka] In a 20 mL vial was placed [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide (300.00 mg, 0.544 mmol, 1.00 equiv), DMF (5.00 mL), and NCS (145.25 mg, 1.088 mmol, 2.00 equiv). The resulting solution was stirred at room temperature overnight and then washed with HO. The resulting solution was extracted with ethyl acetate and the combined extracts were concentrated under vacuum. The crude product was crystallized from DCM / PE (1 / 5, 3 mL) and then purified by Prep-HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm 5 um; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 7 min; 254; 220 nm; RT: 6.7 min) to give the title compound (79.9 mg). LCMS (ES, m / z): [M+H] + 586; 1 H-NMR(300MHz,DMSO-d6,ppm)δ9.61(s,1H),9.05(s,1H),8.96(s,1H),7.61(t,1H),3.44-3.31(m,8H),2.81(s,6H),1.45(t,2H),1.29(t,2H).

[0262] Biological Examples Example 1 PARG enzyme inhibition assay enzymological IC 50 Assay PARG enzyme was incubated in a microtiter plate with compound or carrier (DMSO) and biotinylated PAR-PARP substrate. Detection antibody and streptavidin-europium were added, followed by incubation and plate fluorescence reading. Low fluorescence control (DMSO) indicates no inhibition of the enzyme reaction, while high fluorescence control (no enzyme) indicates complete inhibition of the enzyme reaction. material: enzyme ·PARG o hPARG:250pM, His-tagged,PeakProteins, 0.96mg / mL (8.58μM) o Substrate: 30nM Reaction time: 70 minutes Substrate: hPARP1, His- and TEV-tagged, PeakProteins, 14 μM Detection antibody: Anti-His monoclonal antibody - ULight, PerkinElmer catalog #TRF0105-M Streproavidin-Europium: Perkin Elmer Catalog #AD0062 Assay buffer: 50 mM Tris-HCl pH 7.4, 50 mM KCl, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 0.01% BSA Temperature: 23℃ Total volume: 20μL control: 0% inhibitor control: DMSO 100% inhibition control: no enzyme Enzyme reaction and detection: Transfer 1.5 μL of 3× final concentration of test compound or DMSO to appropriate wells of the microtiter plate. 2. Centrifuge the plate at 1000 rpm for 1 minute. 3. Transfer 5 μL of 3× final concentration of enzyme in assay buffer or assay buffer alone to appropriate wells. 4. Centrifuge the plate at 1000 rpm for 1 minute. 5. Incubate the plate at room temperature for 1 hour. 6. Transfer 5 μL of 3× Substrate in Assay Buffer to all test wells. 7. Centrifuge the plate at 1000 rpm for 1 minute. 8. Incubate the plate at room temperature for 10 minutes. 9. Transfer 5 μL of 3× detection antibody and streptavidin-europium mixture in assay buffer to all test wells. 10. Centrifuge the plate at 1000 rpm for 1 minute. 11. Incubate the plate at room temperature for 1 hour. 12. Read the plate in a plate reader (e.g., Infinite M1000).

[0263] TR-FRET IC of compounds of formula (I) of Examples 1 to 115 50 The values ​​are provided in Table 1 below.

[0264] Example 2 Inhibition of PARG Cellular Assay The ability of the compounds disclosed herein to inhibit PARG was measured as described below. Briefly, HeLa cells were treated with the compounds disclosed herein for 1 hour, followed by an additional hour of treatment with the DNA alkylating agent methyl methanesulfonate (MMS), after which the cells were fixed with 3.7% formaldehyde. The cells were permeabilized with 0.5% Triton-X100, blocked with 5% goat serum, and incubated with a mouse monoclonal antibody against poly(ADP) ribose (PAR) polymers at 4°C overnight. The cells were washed and incubated with Alexafluor488-conjugated secondary antibody with a nuclear stain (Hoechst33342) for 1 hour at room temperature. After washing, images of the cells were captured and analyzed with a high content imaging microscope and software. Two measurements of PAR chains were obtained: PAR forcyte (PAR forcyte IC) and PAR forcyte IC. 50 The mean intensity over background of nuclear ForSci (fluorescence signal at 488 nm in the range 0.3-2.0 μm ForSci) was quantified as PAR% positive (PAR% positive IC). Cells with a PAR ForSci signal >1.3 were considered positive (PAR% positive IC). 50 ) and the percentage of positive cells was quantified. An increase in the percentage of PAR forcy or positive cells indicates the presence of more PAR chains and provides the magnitude of PARG inhibition. The PAR forcy IC of the compounds of formula (I) in Examples 1 to 115 50The values ​​are provided in Table 1 below.

[0265] Example 3 Cell viability assay HCC1806-XRCC1 KD (knockdown) cells were seeded at 2000 cells / well in a clear flat-bottom 96-well white plate. After 24 hours, compounds of the present disclosure were added starting at 30 μM to generate a 9-point dose-response curve at 1:3 dilution. Compounds of the present disclosure were added with a Tecan digital dispenser, except for the outermost wells of the plate. All treatments were performed in duplicate. After 4 days of incubation, 50ul of CellTiter-Glo (Promega) was added to each well. Luminescence was read using a plate reader (TECAN) after 15 minutes of incubation with the reagent. The average value of DMSO-treated wells within the plate was calculated. All data points were normalized to the average value of DMSO. The % control of each sample was compared to the DMSO-treated control sample. Curves were fitted using a 4-parameter inhibition model (Levenberg-Marquardt algorithm) as % control vs. log [compound concentration]. Fit=(A+((BA) / (1+((C / x)^D)))) Res=(y-fit)

[0266] The PARGi (HCC1806-shXRCC1) cell viability of the compounds of formula (I) in Examples 1 to 115 is provided in Table 1 below.

[0267] Table 1 TR-FRET and PAR Forcy assays ****<=0.1μM,0.1μM < *** <=0.3μM,0.3μM < ** <= 1μM,1μM <*< 10μM HCC1806-shXRCC1 PARGi survival rate ****< 1μM,1μM<= *** <10μM,10μM <=**<20μM,20μM<= * <=30μM

[0268]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0269] References [1] Ame, J. C., E. Fouquerel, L. R. Gauthier, D. Biard, F. D. Boussin, F. Dantzer, G. de Murcia and V. Schreiber (2009). "Radiation-induced mitotic catastrophe in PARG-deficient cells." J Cell Sci 122(Pt 12): 1990-2002. [2] Barber, L. J., S. Sandhu, L. Chen, J. Campbell, I. Kozarewa, K. Fenwick, I. Assiotis, D. N. Rodrigues, J. S. Reis Filho, V. Moreno, J. Mateo, L. R. Molife, J. De Bono, S. Kaye, C. J. Lord and A. Ashworth (2013). "Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor." J Pathol 229(3): 422-429. [3] Blenn, C., P. Wyrsch and F. R. Althaus (2011). "The ups and downs of tannins as inhibitors of poly(ADP-ribose)glycohydrolase." Molecules 16(2): 1854-1877. [4] Caiafa, P., T. Guastafierro and M. Zampieri (2009). "Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns." FASEB J 23(3): 672-678. [5] Curtin, N. J. and C. Szabo (2013). "Therapeutic applications of PARP inhibitors: anticancer therapy and beyond." Mol Aspects Med 34(6): 1217-1256. [6] Dahl, M., V. Maturi, P. Lonn, P. Papoutsoglou, A. Zieba, M. Vanlandewijck, L. P. van der Heide, Y. Watanabe, O. Soderberg, M. O. Hottiger, C. H. Heldin and A. Moustakas (2014). "Fine-tuning of Smad protein function by poly(ADP-ribose) polymerases and poly(ADP-ribose) glycohydrolase during transforming growth factor beta signaling." PLoS One 9(8): e103651. [7[ Drost, R. and J. Jonkers (2014). "Opportunities and hurdles in the treatment of BRCA1-related breast cancer." Oncogene 33(29): 3753-3763. [8] Erdelyi, K., P. Bai, I. Kovacs, E. Szabo, G. Mocsar, A. Kakuk, C. Szabo, P. Gergely and L. Virag (2009). "Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cell death in oxidatively stressed A549 cells." FASEB J 23(10): 3553-3563. [9] Fathers, C., R. M. Drayton, S. Solovieva and H. E. Bryant (2012). "Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells." Cell Cycle 11(5): 990-997.

[10] Fisher, A. E., H. Hochegger, S. Takeda and K. W. Caldecott (2007). "Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase." Mol Cell Biol 27(15): 5597-5605.

[11] Frizzell , KM , Gamble MJ , Berrocal JG , Zhang T , Krishnakumar R , Cen Y , Sauve AA and Kraus WL (2009). "Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells." J Biol Chem 284(49):33926–33938.

[12] Fujihara, H., H. Ogino, D. Maeda, H. Shirai, T. Nozaki, N. Kamada, K. Jishage, S. Tanuma, T. Takato, T. Ochiya, T. Sugimura and M. Masutani (2009). "Poly(ADP-ribose) Glycohydrolase deficiency sensitizes mouse ES cells to DNA damaging agents." Curr Cancer Drug Targets 9(8): 953-962.

[13] Guastafierro, T., A. Catizone, R. Calabrese, M. Zampieri, O. Martella, MG Bacalini, A. Reale, M. Di Girolamo, M. Miccheli, D. Farrar, E. Klenova, F. Ciccarone and P. Caiafa (2013). "ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement(1)." Biochem J 449(3):623–630.

[14] Ji, Y. and A. V. Tulin (2009). "Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins modulates splicing." Nucleic Acids Res 37(11): 3501-3513.

[15] Le May, N., I. Iltis, J. C. Ame, A. Zhovmer, D. Biard, J. M. Egly, V. Schreiber and F. Coin (2012). "Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression." Mol Cell 48(5): 785-798.

[16] Mashimo, M., J. Kato and J. Moss (2014). "Structure and function of the ARH family of ADP-ribosyl-acceptor hydrolases." DNA Repair (Amst).

[17] Mortusewicz, O., E. Fouquerel, J. C. Ame, H. Leonhardt and V. Schreiber (2011). "PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanisms." Nucleic Acids Res 39(12): 5045-5056.

[18] Nakadate, Y., Y. Kodera, Y. Kitamura, T. Tachibana, T. Tamura and F. Koizumi (2013). "Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cells to radiation through the abrogation of DNA damage checkpoint." Biochem Biophys Res Commun 441(4): 793-798.

[19] Shirai, H., H. Fujimori, A. Gunji, D. Maeda, T. Hirai, A. R. Poetsch, H. Harada, T. Yoshida, K. Sasai, R. Okayasu and M. Masutani (2013). "Parg deficiency confers radio-sensitization through enhanced cell death in mouse ES cells exposed to various forms of ionizing radiation." Biochem Biophys Res Commun 435(1): 100-106.

[20] Shirai, H., A. R. Poetsch, A. Gunji, D. Maeda, H. Fujimori, H. Fujihara, T. Yoshida, H. Ogino and M. Masutani (2013). "PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways." Cell Death Dis 4: e656.

[21] Sun, Y., T. Zhang, B. Wang, H. Li and P. Li (2012). "Tannic acid, an inhibitor of poly(ADP-ribose) glycohydrolase, sensitizes ovarian carcinoma cells to cisplatin." Anticancer Drugs 23(9): 979-990.

[22] Zhou, Y., X. Feng and D. W. Koh (2010). "Enhanced DNA accessibility and increased DNA damage induced by the absence of poly(ADP-ribose) hydrolysis." Biochemistry 49(34): 7360-7366.

[23] Zhou, Y., X. Feng and D. W. Koh (2011). "Synergistic cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine and absence of poly(ADP-ribose) glycohydrolase involves chromatin decondensation." Int J Oncol 39(1): 121-127.

Claims

1. A compound of formula (I): 【Chemical 1】 (In the formula: X 1 is N; X 2 is selected from the group consisting of CH, and CF; R 1 is cyano, C 1-2 Alkyl, and C 1-2 haloalkyl; R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl; Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl; R 4 is C 1-3 Alkyl, C 1-3 Haloalkyl, hydroxy C 1-3 selected from the group consisting of alkyl, —C(O)H and cyano; R 5 and R 6 are not present respectively; R 7 is hydrogen; Ring B is heterocyclyl, fused heterocyclyl, spiroheterocyclyl, or bridged heterocyclyl, where the heterocyclyl, fused heterocyclyl, spiroheterocyclyl, and bridged heterocyclyl of Ring B are R a , R b , and / or R c where R a is hydrogen, C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, Hydroxy C 1-6 Alkyl, heteroaryl, heterocyclyl, —C(O)R d (R d is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), —C(O)OR e (R e is hydrogen or C 1-6 alkyl), —C(O)NR f R g (R f and R g are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl, and hydroxy C 1-6 alkyl; or R f and R g together with the nitrogen atom to which they are attached form a heterocyclyl), or —S(O) 2 NR h R i (R h and R i are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, Amino C 1-6 Alkyl or hydroxy C 1-6 alkyl; or R h and R i together with the nitrogen atom to which they are attached form a heterocyclyl, and R b and R c are each independently hydrogen, C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 haloalkoxy; Furthermore, here R a heteroaryl and heterocyclyl of R d phenyl, heteroaryl, and heterocyclyl of R f and R g is bonded to the nitrogen to which it is attached, and R h and R i are bonded to the nitrogen to which they are attached, the heterocyclyl formed is each independently unsubstituted or 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, and C 1-6 substituted with 1, 2, or 3 substituents selected from haloalkoxy; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X 2 is CH or CF.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is cyano.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

5. The compound according to claim 1, wherein Ar is 1,3,4-thiadiazol-2-yl, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl, ethyl, difluoromethyl, trifluoromethyl, cyano, or C(O)H.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1-3 haloalkyl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 4 is difluoromethyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring B is heterocyclyl substituted with R a , R b , and / or R c .

10. Ring B is morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl, wherein the morpholinyl, 1,1-dioxothiomorpholinyl, azetinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl is each substituted with R a , R b , and / or R c ; R a is hydrogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo, C 1-6 haloalkyl, hydroxyC 1-6 alkyl, heteroaryl, —C(O)R d (R d is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), —C(O)OR e (R e is hydrogen or C 1-6 alkyl), or —C(O)NR f R g (R f and R g are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, aminoC 1-6 alkyl, and hydroxyC 1-6 alkyl); R b and R c are each independently selected from hydrogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy; The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl of R a ; the phenyl, heteroaryl, and heterocyclyl of R d are each independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

11. R a is hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, hydroxyC 1-6 alkyl, heteroaryl, -C(O)R d (R d is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, heteroaryl, or heterocyclyl), -C(O)OR e (R e is C 1-6 alkyl), or -C(O)NR f R g (R f and R g are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and aminoC 1-6 alkyl), R b and R c are each independently selected from hydrogen, C 1-6 alkyl, and halo; The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the heteroaryl of R a and the heterocyclyl of R d are each independently unsubstituted or each independently substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

12. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein ring B is piperazinyl substituted with R a , R b , and / or R c .

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R a is hydrogen, C 1-6 alkyl, hydroxy, halo, C 1-6 haloalkyl, or hydroxyC 1-6 alkyl, and R b and R c are each independently hydrogen, C 1-6 alkyl, or halo.

14. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R a is hydrogen or C 1-6 alkyl, and R b and R c are each independently hydrogen, C 1-6 alkyl, or halo.

15. The compound of claim 9, wherein R a is bonded to an atom of ring B that is para to the ring atom to which ring B is bonded to the remainder of the molecule, or a pharmaceutically acceptable salt thereof.

16. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is a bicyclic heterocylyl, a fused heterocyclyl, a spiroheterocyclyl, or a bridged heterocyclyl, wherein the bicyclic heterocylyl, the fused heterocyclyl, the spiroheterocyclyl, or the bridged heterocyclyl is each independently substituted with R a , R b , and / or R c .

17. Ring B is 2-oxaspiro[3.5]non-6-en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6-azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1-oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2-azaspiro[3.3]hept-2-yl, 2,8-di azaspiro[4.5]dec-8-yl, 7-oxa-3-azabicyclo[3.3.0]oct-3-yl, 8-oxa-3-azabicyclo[4.3.0]non-3-yl, 2-oxa-6-azaspiro[3.5]non-6-yl, 7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl, 3-pyrrolino[3,4-c]pyrazol-2-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, 2,7-diazaspiro[3.5]non-7-yl, Here, 2-oxaspiro[3.5]non-6-en-7-yl, 2-oxaspiro[3.5]non-7-yl, 2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6-azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1-oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2-azaspiro[3.3]hept-2-yl, 2,8-dia ...2-oxa-8-azaspiro[4.5]dec-8-yl, 9-oxa-3-azaspiro[5.5]undec-3-yl, 2-oxa-6-azaspiro[3.4]oct-6-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, 1-oxa-8-azaspiro[4.5]dec-8-yl, 6-oxa-2-azaspiro[3.3]hept-2-yl, 2,8-diazaspiro[3.5]non-7-yl, 2,8-diazaspiro[3.5]non-7-yl, 2,8-diazaspiro[3.5]non-7-yl, 2,8-diazaspiro[3.5]undec-3-yl, 2,8-diazaspiro[3.5]undec-3- 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein spiro[4.5]dec-8-yl, 7-oxa-3-azabicyclo[3.3.0]oct-3-yl, 8-oxa-3-azabicyclo[4.3.0]non-3-yl, 2-oxa-6-azaspiro[3.5]non-6-yl, 7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl, 3-pyrrolino[3,4-c]pyrazol-2-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, or 2,7-diazaspiro[3.5]non-7-yl is each optionally substituted with R a , wherein R a is C1-6 alkyl.

18. The compound according to claim 1, wherein X 2 is CH; R 1 is methyl; Ar is 1,3,4-thiadiazolyl; R 4 is difluoromethyl; Ring B is piperazinyl substituted with R a , R b , and / or R c ; R a is hydrogen or C 1-6 alkyl; R b and R c are each independently selected from hydrogen, C 1-6 alkyl, and halo; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18, wherein: 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-6-en-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; ({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-7-azaspiro[3.5]non-7-yl)(1H-indazol-6-yl)}sulfonyl)(methylcyclopropyl)amine; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(methylcyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-7-azaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-((2R)-2-methylmorpholin-4-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-hydroxypiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylpropanoyl)piperazinyl]indol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-8-azaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(9-oxa-3-azaspiro[5.5]undec-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)(1,4-diazaperhydroepynyl)]-N-methylcarboxamide; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-ethyl-N-methylcarboxamide; 1-[({4-[4-(azetidinylcarbonyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-6-azaspiro[3.4]oct-6-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [2R)-4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))-2-methylpiperazinyl]-N,N-dimethylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(4-methyl(1,2,4-triazol-3-yl))piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-[(1S,5R)-8-(2-methylpropanoyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2,2-dimethylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)(4-piperidyl)]-N-methylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1-oxa-7-azaspiro[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1,4-oxazaperhydroepin-4-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N,N-dimethylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(1-oxa-8-azaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(6-oxa-2-azaspiro[3.3]hept-2-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methyl-2,8-diazaspiro[4.5]dec-8-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(hydroxymethyl)piperidyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-((1S,5R)-7-oxa-3-azabicyclo[3.3.0]oct-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-formylpiperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-(4-acetylpiperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)(4-piperidyl)]-N,N-dimethylcarboxamide; N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(1,1-dioxidethiomorpholino)-1H-indazole-6-sulfonamide; [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))pyrrolidin-3-yl]-N-methylcarboxamide; [1-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))pyrrolidin-3-yl]-N,N-dimethylcarboxamide; [1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)azetidin-3-yl]-N,N-dimethylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(cis-8-oxa3-azabicyclo-[4.3.0]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(pyrrolidinylcarbonyl)-piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; Methyl 4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}-1H-indazol-4-yl)piperazinecarboxylate; 1-[({4-((1S)-7-oxo-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-((1R)-7-oxo-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-((1R)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-((1S)-7-oxo-8-oxa-3,6-diazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-methyl(1,4-diazaperhydro-epynyl))-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(difluoromethyl)piperidyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-oxa-6-azaspiro[3.5]non-6-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclopentylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; N-(2,2-difluoroethyl)[4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyano-cyclopropyl)amino]sulfonyl}(1H-indazol-4-yl)piperazinyl]-N-methylcarboxamide; 1-{[(4-{4-[((3S)-1-methylpyrrolidin-3-yl)carbonyl]piperazinyl}-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(1-methylimidazol-2-yl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(7-oxa-3,9-diazabicyclo-[3.3.1]non-3-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-(8-methyl-7-oxo-3,6,8-triazabicyclo[4.3.0]non-3-yl)-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(5-methyl(3-pyrrolino[3,4-c]pyrazol-2-yl))-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 4-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methylpiperazine-1-carboxamide; 1-(6-(N-(1-cyanocyclopropyl)sulfamoyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1H-indazol-4-yl)-N-methylazetidine-3-carboxamide; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-[2-(dimethylamino)ethyl]-N-methylcarboxamide; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-methyl-N-propylcarboxamide; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]-sulfonyl}(1H-indazol-4-yl)(1,4-diazaperhydroepynyl)]-N,N-dimethylcarboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(3-methyl(2-pyridyl))-piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclopropylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(cyclobutylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-[(3R)-3-methyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [2S)-4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))-2-methylpiperazinyl]-N,N-dimethylcarboxamide; 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(1-methyl(4-piperidyl))-carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(4-methyl(3-pyridyl))piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; [4-(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-6-{[(cyanocyclopropyl)amino]sulfonyl}(1H-indazol-4-yl))piperazinyl]-N-methyl-N-(2,2,2-trifluoroethyl)carboxamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-pyridylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-[(3S)-3-methyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({4-[cis-3,5-dimethyl-4-(2-methylpropanoyl)piperazinyl]-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-{[(4-{4-[((2R)-1-methylpyrrolidin-2-yl)carbonyl]piperazinyl}-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[6-(2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(2-methyl-2,7-diazaspiro-[3.5]non-7-yl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-(2-pyridyl)piperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-(3-pyridyl)piperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-pyridazin-3-ylpiperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(phenylcarbonyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-(5-methyl(1,3,4-thiadiazol-2-yl))-4-[4-(2-methylpropanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-morpholin-4-yl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-pyrrolidinyl-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-methylpiperazinyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; (S)—N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(2-methylmorpholino)-1H-indazole-6-sulfonamide; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4-fluoropiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-(4,4-difluoropiperidyl)-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-({[4-((3R)-4-{[1-(2,2-difluoroethyl)(4-piperidyl)]carbonyl}-3-methylpiperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl]sulfonyl}amino)cyclopropanecarbonitrile; 1-({[4-(1-(2,2-difluoroethyl)(4-piperidyl)]carbonyl}piperazinyl)-1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl]sulfonyl}amino)cyclopropanecarbonitrile; 1-{[(4-{(3R)-3-methyl-4-[(methylcyclopropyl)carbonyl]piperazinyl}-1-[5-(difluoro-methyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-{[(4-{(3R)-3-methyl-4-[(methylcyclobutyl)carbonyl]piperazinyl}-1-[5-(difluoro-methyl)(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-[({4-[(3R)-3-methyl-4-(2-methylbutanoyl)piperazinyl]-1-[5-(difluoromethyl)-(1,3,4-thiadiazol-2-yl)]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile; 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(methylcyclopropyl)carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; 1-{[(1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-{4-[(methylcyclobutyl)carbonyl]piperazinyl}-1H-indazol-6-yl)sulfonyl]amino}cyclopropanecarbonitrile; and 1-[({1-[5-(difluoromethyl)(1,3,4-thiadiazol-2-yl)]-4-[4-(2-methylbutanoyl)piperazinyl]-1H-indazol-6-yl}sulfonyl)amino]cyclopropanecarbonitrile 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of claim 21, wherein the subject is undergoing surgery, radiation therapy, or chemotherapy to treat cancer.

23. A combination pharmaceutical for use in the treatment of cancer, comprising: (a) the pharmaceutical composition of claim 21; and (b) antitumor agent wherein each component of the combination is administered simultaneously, sequentially, or by separate administration.

24. The pharmaceutical composition of claim 21 or 22, or the combination pharmaceutical of claim 23, wherein the cancer is cancer of the lung, colon, breast, ovary, prostate, liver, pancreas, brain, or skin.

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