Benzothiadiazine derivatives as MRGX2 antagonists

Abstract

Disclosed herein are chemical compounds of Formula (I) which are antagonists of MRGX2 and therefore useful in the treatment of MRGX2-mediated diseases and disorders. Also disclosed are pharmaceutical compositions comprising chemical compounds of Formula (I), methods of using such compounds and methods of making the same.

Description

[0001] 70311W001

[0002] COMPOUNDS

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to compounds which are antagonists of Mas- related G- protein coupled receptor member X2 (MRGPRX2 or MRGX2), compositions containing such compounds, and to their use in the treatment of various disorders.

[0005] BACKGROUND TO THE INVENTION

[0006] Mature mammalian mast cells are implicated in the progression and / or maintenance of many diseases (Nature Immunology, 6, 135-142 (2005)). Recently work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation (Nature, 519, 237-241 (2015)). Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2 (Adv. Immunol., 136, 123-62 (2017)). To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells (Nature Immunology, 17, 878- 887 (2016); Annu. Rev. Immunol., 38, 49-77 (2020)). This knowledge provides the opportunity to target mast cell degranulation in a very precise manner.

[0007] Natural endogenous ligands of Mrgprb2 / MRGPRX2 have been reported and are mostly neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), Cortistatin- 14, and pituitary adenylate cyclase activating polypeptide (PACAP). Others include p-defensin, cathelicidin (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP9-20) (Journal of Allergy and Clinical Immunology, 138, 700-710 (2016); J. Immunol., 191 , 345-352 (2013); BBRC, 349, 1322-28 (2006)). Given the close proximity between mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 could contribute to symptoms of neurogenic inflammation including pain, swelling and pruritus. Various observations using knock-out (KO) mice are consistent with the Mrgprb2 / MRGPRX2 receptors playing a role in mast cell-mediated neurogenic inflammation. For instance, Mrgprb2 / MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice (Nature, 519, 237-241 (2015); Immunity, 50, 1163-1171 (2019)). Mrgprb2-deficent mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models (Neuron, 101 , 412-420 (2019); Immunity, 50, 1163-1171 (2019); Nature Immunology, 20, 1435- 1443 (2019)). An important and relevant observation was the demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKR1 (canonical Substance P receptor) KO mice whereas the response was substantially blunted in Mrgprb2 null mice (Neuron, 101 , 412-420 (2019)). This observation extends the role of Mrgprb2 / MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain (Neuron, 101 , 353-355, (2019)). Indeed, a Substance P / Mrgprb2 sensory cluster was demonstrated to be 70311W001 critical in driving the clinical score of a severe preclinical model of atopic dermatitis (Nature Immunology, 20, 1435-1443 (2019)).

[0008] In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of MRGPRX2-expressing mast cells being significantly increased in severe chronic urticaria (Clinical and Molecular Allergy 16, 24 (2018)), PACAP nerve fibers were demonstrated to be in close proximity to tryptase-positive mast cells, providing the morphological basis for increased mast cell - sensory interactions (J. Allergy Clin. Immunol., 134, 622-633 (2014)). In support of this, patients with urticaria exhibit enhanced wheal reactions vs healthy individuals to MRGPRX2 agonists (e.g., Substance P) when injected intradermally (Allergy, 54, 46-56 (1999)). In addition, PACAP and the antimicrobial peptide, LL-37, which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea (J. Invest. Dermatol., 15, 53-62, (2011)). Indeed, mast cell-deficient mice do not develop inflammation / flushing following LL-37 injection (J. Inv. Derm., 134, 2728 (2014)) thus inferring a role for Mrgprb2.

[0009] In addition to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis (Immunol. Rev., 217, 38-52 (2007); Pharmacology and Therapeutics, 116, 207-235 (2007)) as well as asthma (Respiratory Research, 19, 1 (2018)) and migraine. In patients with rheumatoid arthritis (RA), the number of degranulated mast cells is increased in synovial tissue and is correlated with disease activity, as it is for patients with IBD. A positive correlation between serum Substance P levels and chronic pain intensity has been noted in both osteoarthritic and RA patients (PLOS ONE, 10, e0139206 ((2015)) and a recent article suggested that the SP-MRGPRX2 axis may play a role in the pathogenesis of RA, especially in the regulation of inflammation and pain (Allerg. Intern., 26, S9-S20 (2017)). Finally, there is a growing body of evidence for a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells (Frontiers in Cellular Neuroscience, 13, 1-11 (2019)).

[0010] In summary, there exists a need to develop novel chemical compounds which are capable of therapeutic targeting of MRGPRX2.

[0011] SUMMARY OF THE INVENTION

[0012] In a first aspect, the present invention provides compound of Formula (I) or a pharmaceutically acceptable salt thereof, 70311W001 wherein:

[0013] R1is a C3-7 cycloalkyl optionally substituted by 1 or 2 groups independently selected from halo or C1-5 alkyl, or R1is a C1-5 alkyl optionally substituted by a C3-7 cycloalkyl;

[0014] X1, X2, and X3are each independently N or CR2wherein each R2is independently selected from the group consisting of hydrogen, halo, cyano, Ci-3alkyl, and halo(Ci-3)alkyl;

[0015] L1is selected from the group consisting of a bond,-O-, -OCi-3alkylene-, -Ci-3alkyleneO-, - Ci-salkyleneNH-, -NHCi-salkylene-, and -NH-;

[0016] Ring A is a C3-10 cycloalkyl ring or a 4- to 10- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S; n is 0, 1 , 2, 3, or 4; each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-e)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-e)alkyl, halo(Ci-6)alkyl, halo(C2-e)alkenyl, halo(Ci-e)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-6)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)C(O)R4, -NR3CO2R4,- NR3SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci.3alkyleneNHCi.3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4, - C(O)SR3, -C(O)OR3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-2alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, -OSO2R3, and -L2-Y;

[0017] R3, R4and R5are each independently selected from hydrogen, Ci-4alkyl, and halo(Ci- 4)alkyl;

[0018] L2is selected from the group consisting of a bond, -NR3-, -NR3C(O)-, -CH2-, -C(O)NR3-, - C(O)O-, -C(O)OCH2-, and -SO2-;

[0019] Y is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl containing one, two or three heteroatoms independently selected from N, O, and S, C3-8 cycloalkyl and a 4- to 8- membered heterocycloalkyl ring containing one, two or three heteroatoms independently 70311W001 selected from N, O, and S, wherein Y is optionally substituted by one, two or three groups independently selected from halo, Ci-3alkoxy, Ci-3alkyl and halo(Ci-3)alkyl.

[0020] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable excipient.

[0021] In a third aspect, the present invention provides a compound of the invention as disclosed herein for use in therapy.

[0022] In a fourth aspect, the present invention provides a method of treatment of an MRGX2- mediated disease or disorder in a human in need thereof comprising administering to said human a therapeutically effective amount of a compound of the invention as disclosed herein.

[0023] In a fifth aspect, the present invention provides the use of a compound of the invention disclosed herein in the manufacture of a medicament for use in the treatment of an MRGX2- mediated disease or disorder.

[0024] DETAILED DESCRIPTION

[0025] Definitions

[0026] As used herein, the term “halo” refers to chloro, fluoro, bromo, or iodo substituents.

[0027] As used herein, the term “cyano” refers to the group -CN.

[0028] As used herein, the term “oxo” refers to a double-bonded oxygen moiety, for example if attached directly to a carbon atom oxo forms a carbonyl moiety (C=O).

[0029] As used herein, the term “hydroxyl” refers to the group -OH.

[0030] As used herein, the term “alkyl” refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms. For example, the term “C1-6 alkyl” refers to an alkyl group having 1 to 6 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, sec-butyl, isobutyl and tert-butyl), and pent-1 -yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2- trim ethyl eth-1 -yl. The term “C1-4 alkyl” refers to an alkyl group having 1 to 4 carbon atoms. When the term "alkyl" is used in combination with other substituent groups, such as "halo(Ci-6)alkyl" and “hydroxy(Ci-6)alkyl” the term “alkyl” is intended to encompass a divalent straight or branched chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.

[0031] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated, monocyclic, hydrocarbon ring containing the specified number of carbon atoms, and includes bicycloalkyl groups such as bridged, fused, or spiro, bicyclic groups. For example, “Cs- cycloalkyl” refers to a cycloalkyl group containing 3 to 10 carbon atoms. For example, “Cs-ycycloalkyl” refers to a cycloalkyl group containing 3 to 7 carbon atoms. Exemplary groups include cyclopropyl, 70311W001 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.1.1]hexyl, bicyclo[2.1 .1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[4.3.1]decyl, bicyclo[2.2.0]hexyl bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, octahydropentalenyl bicyclo[4.2.0]octyl, decahydronaphthalenyl, spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[4.5]decyl.

[0032] As used herein, the term “alkylene” refers to a divalent radical derived from a straight or branched, saturated hydrocarbon group of, for example, 1 to 3 carbon atoms (C1-3 alkylene). Exemplary groups include, but are not limited to, -CH2- (methylene), -CH2CH2- (ethylene), and - CH2CH2CH2- (propylene).

[0033] As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon radical containing the specified number of carbon atoms and at least 1 double bond. For example, “C2-6 alkenyl” has 2 to 6 carbon atoms. Exemplary groups include, but are not limited to, ethenyl, 1- propen-1-yl, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, l-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2- buten-1-yl, 2-buten-2-yl, 2-methyl-1 -propen-1 -yl, 2-methy1-2-propen- 1-yl, 1 ,3-butadien-l-yl, 1 ,3- butadien-2-yl, and pentenyl.

[0034] As used herein, the term “alkoxy” refers to an -O-alkyl group, i.e. an alkyl group which is attached through an oxygen linking atom, wherein “alkyl” is defined above. For example, the term “C1-4 alkoxy” refers to an alkoxy group having 1 to 4 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy.

[0035] As used herein, the term “halo(Ci-6)alkyl” is intended to mean a radical having one or more halogen atoms (e.g., 1 , 2 or 3), which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 6 carbon atoms, which is a straight or branched chain carbon radical. Exemplary groups include, but are not limited to, -CF3 (trifluoromethyl), -CCI3 (trichloromethyl), 1 ,1 -difluoroethyl, 2,2,2-trifluoroethyl, hexafluoroisopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1 -fluoroethyl, 1 ,1- difluoroethyl, 1 -chloroethyl, 1 ,1 -dichloroethyl, 1-fluoro-1 -methylethyl, and 1-chloro-1 -methylethyl.

[0036] As used herein, the term “halo(Ci-6)alkoxy” refers to a straight or branched chain hydrocarbon radical, having at least 1 and up to 6 carbon atoms with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms, which radical is attached through an oxygen linking atom. Exemplary groups include, but are not limited to, - OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).

[0037] As used herein, the term “thio(Ci-6)alkyl” refers to refers to an -S-alkyl group, i.e. an alkyl group which is attached through a sulfur linking atom, wherein “alkyl” is defined above. For example, the term “thio(Ci-4)alkyl” refers to a thioalkyl group having 1 to 4 carbon atoms. 70311W001

[0038] Exemplary groups include, but are not limited to, thiomethyl, thioethyl, thiopropyl, thio-isopropyl, and so on.

[0039] As used herein, the term “hydroxy(Ci-6)alkyl” is intended to mean a radical having one or more hydroxy groups at one or more carbon atoms of an alkyl moiety containing from 1 to 6 carbon atoms, which is a straight or branched chain carbon radical. Exemplary groups include, but are not limited to, hydroxymethyl (-CH2OH), 2-hydroxyethyl (-CH2CH2OH), and hydroxyisopropyl.

[0040] As used herein, the term “cyano(Ci-4)alkyl” is intended to mean a radical having one or more cyano groups at one or more carbon atoms of an alkyl moiety containing 1 to 4 carbon atoms, which is a straight or branched chain carbon radical.

[0041] As used herein, the term “halo(C2-6)alkenyl” refers to a straight or branched chain hydrocarbon radical, having at least 2 and up to 6 carbon atoms and at least one double bond, with one or more halogen atoms, which may be the same or different, attached to one or more carbon atoms. Exemplary groups include, but are not limited to, -CH=CHF, -CH=CF2 and - CF=CF2.

[0042] As used herein, the term “5- or 6-membered heteroaryl” refers to a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one (e.g., one, two or three) heteroatom independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Exemplary groups include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0043] As used herein, the term “member atoms” refers to the atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. Atoms that make up a substituent group attached to a chain or ring are not member atoms in the chain or ring.

[0044] As used herein, the term “heterocycloalkyl” refers to a non-aromatic, saturated or unsaturated, monocyclic or bicyclic (including spiro, fused or bridged) radical containing the specified number of atoms and including one to four heteroatoms independently selected from nitrogen, oxygen and sulfur. Both the monocyclic and bicyclic groups have a specified number of atoms in their ring or rings. For example, the term “4- to 10-membered heterocycloalkyl” refers to a heterocycloalkyl group having 4 to 10 atoms. As with bicyclic cycloalkyl groups, bicyclic 70311W001 heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound. Examples of heterocyclyl groups include oxetanyl, thietanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, 1,4-azathianyl, oxepanyl, thiepanyl, azepanyl, 1,4- dioxepanyl, 1 ,4-oxathiepanyl, 1,4-oxaazepanyl, 1 ,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 3.4-dihydro-2H-pyranyl, 3.6- dihydro-2H-pyranyl. 2H-pyranyl. 1 ,2-dihydropyridinyl, 1 , 2,3,4- tetrahydropyridinyl, 1.2.5.6- tetrahydropyridinyl, 1 ,6-dihydropyrimidinyl, 1,2, 3, 4- tetrahydropyrimidinyl, and 1 ,2-dihydropyrazolo[1 , 5-d][1 ,2 ,4]triazi nyl .

[0045] As used herein, the term “optionally substituted” indicates that a group may be unsubstituted or substituted with one or more substituents as defined herein. The term “substituted” in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced by one of the defined substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

[0046] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.

[0047] As used herein, the term “treatment” refers to ameliorating or stabilising the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject. The term “prevention” refers to avoidance of the stated disease in a subject who is not suffering from the stated disease.

[0048] As used herein, the term “therapeutically effective amount” refers to the quantity of a compound of the invention, which will elicit the desired biological response in a human body. It may vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated.

[0049] As used herein, the term “independently selected” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. Thus, each substituent is separately selected from the entire group of recited possible substituents. 70311W001

[0050] Statement of Invention

[0051] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0052] R1is a C3-7 cycloalkyl optionally substituted by 1 or 2 groups independently selected from halo or C1-5 alkyl, or R1is a C1-5 alkyl optionally substituted by a C3-7 cycloalkyl;

[0053] X1, X2, and X3are each independently N or CR2wherein each R2is independently selected from the group consisting of hydrogen, halo, cyano, Ci-3alkyl, and halo(Ci-3)alkyl;

[0054] L1is selected from the group consisting of a bond,-O-, -OCi-3alkylene-, -Ci-3alkyleneO-, - Ci-salkyleneNH-, -NHCi-salkylene-, and -NH-;

[0055] Ring A is a C3-10 cycloalkyl ring or a 4- to 10- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S; n is 0, 1 , 2, 3, or 4; each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-e)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-e)alkyl, halo(Ci-6)alkyl (e.g., including 1 , 2, or 3 halo groups), halo(C2- e)alkenyl, halo(Ci-e)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene- NR3R4, -N(R3)C(O)R4, -NR3CO2R4,-NR3SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci.3alkyleneNHCi.3alkyl, -Ci.3alkyleneNR3R4, -C(O)NR3R4, -C(O)SR3, -C(O)OR3, -C(O)-hydroxy(Ci-3)alkyl, -CO2-halo(Ci-

[0056] 3)alkyl, -C(O)R3, -Ci-2alkylene-C(O)OR3, -S(O)R3, -S(O)2R3, -OSO2R3, and -L2-Y;

[0057] R3, R4and R5are each independently selected from hydrogen, Ci-4alkyl, and halo(Ci-

[0058] 4)alkyl;

[0059] L2is selected from the group consisting of a bond, -NR3-, -NR3C(O)-, -CH2-, -C(O)NR3-, - C(O)O-, -C(O)OCH2-, and -SO2-; 70311W001

[0060] Y is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl containing one, two or three heteroatoms independently selected from N, O, and S, C3-8 cycloalkyl and a 4- to 8- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S, wherein Y is optionally substituted by one, two or three groups independently selected from halo, Ci-3alkoxy, Ci-3alkyl and halo(Ci-3)alkyl.

[0061] In some embodiments, X1, X2, and X3are each independently CF or CH.

[0062] In some embodiments, X1is CH. In an alternate embodiment, X1is C(halo). In an alternate embodiment, X1is C(CN). In an alternate embodiment, X1is C(Ci-3alkyl). In an alternate embodiment, X1is N. In an alternate embodiment, X1is C(Ci-3haloalkyl).

[0063] In some embodiments, X2is CH or C(halo). In some embodiments, X2is CH or CF. In some embodiments, X2is CH. In some embodiments, X2is CF. In some embodiments, X1is CH and X2is CH or C(halo). In some embodiments, X1is CH and X2is CH or CF.

[0064] In some embodiments, X3is CH. In some embodiments, X1is CH and X3is CH. In some embodiments, X2is CH or C(halo) and X3is CH. In some embodiments, X1is CH, X2is CH or C(halo) and X3is CH.

[0065] In some embodiments, X1is CH, X2is CF, and X3is CH.

[0066] In some embodiments, R1is C3-6 cycloalkyl, methyl, ethyl, or propyl.

[0067] In some embodiments, R1is C3-6 cycloalkyl or ethyl.

[0068] In some embodiments, R1is a cyclopropyl group optionally substituted by one or two groups independently selected from halo (such as F) or C1-3 alkyl (such as methyl, ethyl or propyl).

[0069] In some embodiments, L1is selected from the group consisting of a bond, -NH-, -NHCH2- , -O-, and -OCH2-. In some embodiments, L1is selected from the group consisting of a bond, - NH-, -NHCH2-, -O-, and -OCH2-, and X1is CH, X2is CF, and X3is CH.

[0070] In some embodiments, L1is a bond.

[0071] In some embodiments, L1is a bond and Ring A is a 4- to 10-membered heterocyclic ring containing one nitrogen (N), and X1is CH, X2is CF, and X3is CH.

[0072] In some embodiments, L1is a bond and Ring A is a 4- to 10-membered heterocyclic ring containing one nitrogen (N), Z1is independently selected from the group consisting of hydroxy, halo(Ci-4)alkyl (e.g., -CF3), -NR3R4, -Ci-3alkyleneNR3R4, wherein R3and R4are independently selected from hydrogen, Ci-4alkyl, and halo(Ci-4)alkyl, n is 2 and X1is CH, X2is CF, and X3is CH. 70311W001

[0073] In some embodiments, Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-4alkyl, Ci-4alkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-4)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-4)alkyl, halo(Ci-4)alkyl, halo(C2-4)alkenyl, halo(Ci- 4)alkoxy, halo(C3-8cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, N(R3)CO2R4, -N(R3)SO2R4, -NR3-hydroxy(Ci.3)alkyl, -Ci.3alkyleneNHCi.3alkyl, -Ci-

[0074] 3alkyleneNR3R4, -C(O)NR3R4,-C(O)SR3, -CO2R3, -C(O)-hydroxy(Ci-3)alkyl, -CO2-halo(Ci-3)alkyl, - C(O)R3, -Ci.3alkylene-C(O)OR3, -S(O)R3, -S(O)2R3, and -OSO2R3.

[0075] In some embodiments, Z1is independently selected from the group consisting of oxo, cyano, -NH2, -CH2NH2, -CH2-NH-CH3, -CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -OCF2H, -OCF3, - CH3, -CH2CH3, -CH(CH3)2-F, -CH2CF3, -CHF2, -CF2CH3, -CF3, -CO2-CH2CF3, -CO2-C(CH3)3, - CONH2, -CON(CH3)2, -CONHCH3, -COCH(OH)CH3, -COCH3, -CH2OH, -CH2CH2OH, - C(CH3)2OH, -SO2CH3, -SO2CH2CH3, -N(CH2CH3)2, -NHCH3, -NHC(CH3)3, -NHCH(CH3)2, - N(CH3)CH2CH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH(CH3)2, -NHCH2CH2NH2, NHCH(CH3)CH2OH, -NHCO2C(CH3)3, -NHSO2CH3, -NHCH(CH3)CF3, and -L2-Y;

[0076] L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, and- NHCO-; and

[0077] Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCHs, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl.

[0078] In some embodiments, the compound of Formula (I) is a compound of Formula (II) as described above, and each Z1is independently selected from the group consisting of oxo, -NH2, -CH2NH2, -CH2-NH-CH3, -CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -CH3, -CH2CH3, -F, -CH2CF3, - CHF2, -CF2CH3, -CF3, -CO2-CH2CF3, -CO2-C(CH3)3, -CONH2, -CON(CH3)2, -CONHCH3, - COCH(OH)CH3, -COCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -SO2CH3, -SO2CH2CH3, -N(CH-2CH3)2, -NHCH3, -NHC(CH3)3, -NHCH(CH3)2, -N(CH3)CH2CH3, -N(CH3)2, -NHCH2CH3, -N(CH-3)CH(CH3)2, -NHCH2CH2NH2, -NHCH(CH3)CH2OH, -NHCO2C(CH3)3, -NHSO2CH3, - NHCH(CH3)CF3, cyclopropane, fluorocyclopropane, and -L2-Y;

[0079] L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, and - NHCO-; and

[0080] Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCHs, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl.

[0081] In one embodiment, each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or-CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. 70311W001

[0082] In some embodiments, n is 2. In some embodiments, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., - CH2NH2, -CH2NHCH3, or -CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy.

[0083] In an alternate embodiment, n is 1.

[0084] In some embodiments, the group represented Formula (I) is selected from the group consisting of

[0085] 70311W001 where * indicates the binding site; n is 0, 1 , 2, 3, or 4; each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano,

[0086] Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-e)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-e)alkyl, halo(Ci-6)alkyl, halo(C2-e)alkenyl, halo(Ci-e)alkoxy, halo(C3.8)cycloalkyl, hydroxy(C2-6)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)C(O)R4, -NR3CO2R4,- NR3SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci-3alkyleneNHCi-3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4, - 70311W001

[0087] C(O)SR3, -C(O)OR3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-2alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, -OSO2R3, and -L2-Y;

[0088] R3, R4and R5are each independently selected from hydrogen, Ci-4alkyl, and halo(Ci- 4)alkyl;

[0089] L2is selected from the group consisting of a bond, -NR3-, -NR3C(O)-, -CH2-, -C(O)NR3-, - C(O)O-, -C(O)OCH2-, and -SO2-;

[0090] Y is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl containing one, two or three heteroatoms independently selected from N, O, and S, C3.3cycloalkyl and a 4- to 8- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S, wherein Y is optionally substituted by one, two or three groups independently selected from halo, Ci-3alkoxy, Ci-3alkyl and halo(Ci-3)alkyl; and

[0091] X4is selected from the group consisting of NH, O, and CH2; and X5is selected from the group consisting of NH and O.

[0092] In one aspect of this embodiment, X1, X2, and X3are each independently CF or CH. In one aspect of this embodiment, X1is CH. In one aspect of this embodiment, X2is CH or CF. In one aspect of this embodiment, X3is CH. In one aspect of this embodiment, X1is CH, X2is CF, and X3is CH. In one aspect of this embodiment, R1is C3-6cycloalkyl or ethyl. In one aspect of this embodiment, R1is C3-6cycloalkyl or ethyl, X1is CH, X2is CF, and X3is CH. In one aspect of this embodiment, R1is a cyclopropyl group. In one aspect of this embodiment, R1is cyclopropyl group, or ethyl, X1is CH, X2is CF, and X3is CH. In one aspect of this embodiment, L1is selected from the group consisting of a bond, -NH-, -NHCH2-, -CH2NH-, -O-, -CH2O-and -OCH2-. In one aspect of this embodiment, R1is cyclopropyl group, or ethyl, X1is CH, X2is CF, and X3is CH, and L1is selected from the group consisting of a bond, -NH-, -NHCH2-, -CH2NH-, -O-, -CH2O-and -OCH2-. In one aspect of this embodiment, L1is a bond. In one aspect of this embodiment, R1is cyclopropyl group, or ethyl, X1is CH, X2is CF, and X3is CH, and L1is a bond. In one aspect of this embodiment, each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-4alkyl, Ci-4alkoxy, C3-8cycloalkyl, Cs-scycloalkenyl, C2-6alkenyl, C2-6alkynyl, thio(Ci- 4)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-4)alkyl, halo(Ci-4)alkyl, halo(C2-4)alkenyl, halo(Ci-4)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)CO2R4, - N(R3)SO2R4, -NR3-hydroxy(Ci.3)alkyl, -Ci-3alkyleneNHCi-3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4,-C(O)SR3, -CO2R3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-3alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, and -OSO2R3. In one aspect of this embodiment, each Z1is independently selected from the group consisting of oxo, -NH2, -CH2NH2, -CH2-NH-CH3, - CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -CH3, -CH2CH3, -F, -CH2CF3, -CHF2, -CF2CH3, -CF3, -CO2- CH2CF3, -CO2-C(CH3)3, -CONH2, -CON(CH3)2, -CONHCH3, -COCH(OH)CH3, -COCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -SO2CH3, -SO2CH2CH3, -N(CH2CH3)2, -NHCH3, -NHC(CH3)3, - 70311W001

[0093] NHCH(CH3)2, -N(CH3)CH2CH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH(CH3)2, -NHCH2CH2NH2, - NHCH(CH3)CH2OH, -NHCO2C(CH3)3, -NHSO2CH3, -NHCH(CH3)CF3, cyclopropane, fluorocyclopropane, and -L2-Y;

[0094] L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, and - NHCO-; and Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCHs, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl. In one aspect of this embodiment, n is 2.

[0095] In another aspect of this embodiment, each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or - CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, n is 2. In another aspect of this embodiment, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., - CH2NH2, -CH2NHCH3, or -CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, X1, X2, and X3are each independently CF or CH, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -C1-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or -CH2NHCH(CH3)2), -NR3R4(e.g., - NHCH(CH3)CF3), and hydroxy.

[0096] In one embodiment, the compound of Formula (I) is a compound of Formula (II) wherein:

[0097] R1is a C3-7 cycloalkyl optionally substituted by 1 or 2 groups independently selected from halo or C1-5 alkyl, or R1is a C1-5 alkyl optionally substituted by a C3-7 cycloalkyl;

[0098] X1, X2, and X3are each independently N or CR2wherein each R2is independently selected from the group consisting of hydrogen, halo, cyano, Ci-3alkyl, and halo(Ci-3)alkyl; n is 0, 1 , 2, 3, or 4; 70311W001 each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-e)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-e)alkyl, halo(Ci-6)alkyl, halo(C2-e)alkenyl, halo(Ci-e)alkoxy, halo(C3.8)cycloalkyl, hydroxy(C2-6)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)C(O)R4, -NR3CO2R4,- NR3SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci-3alkyleneNHCi-3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4, - C(O)SR3, -C(O)OR3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-2alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, -OSO2R3, and -L2-Y;

[0099] R3, R4and R5are each independently selected from hydrogen, Ci-4alkyl, and halo(Ci- 4)alkyl;

[0100] L2is selected from the group consisting of a bond, -NR3-, -NR3C(O)-, -CH2-, -C(O)NR3-, - C(O)O-, -C(O)OCH2-, and -SO2-;

[0101] Y is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl containing one, two or three heteroatoms independently selected from N, O, and S, C3-s cycloalkyl and a 4- to 8- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S, wherein Y is optionally substituted by one, two or three groups independently selected from halo, Ci-3alkoxy, Ci-3alkyl and halo(Ci-3)alkyl; and p is 0, 1 , or 2, and X6is independently selected from the group consisting of CH2, NR6and O, and R6is independently selected from hydrogen and Ci-3alkyl which may be optionally substituted by one, two or three halo substituents (for example, fluoro).

[0102] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), and X1, X2, and X3are each independently CF or CH.

[0103] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (II), wherein X1is CH.

[0104] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (II), wherein X2is CH or CF.

[0105] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (II), wherein X3is CH.

[0106] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein X1is CH, X2is CF, and X3is CH.

[0107] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein R1is C3-6cycloalkyl or ethyl. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein R1is C3-6cycloalkyl or ethyl and X1, X2, and X3are each independently CF or CH. In some aspects of this embodiment, the 70311W001 compound of Formula (I) is a compound of Formula (II), wherein R1is Cs-ecycloalkyl or ethyl and X1is CH, X2is CF, and X3is CH.

[0108] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein R1is a cyclopropyl group. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein R1is a cyclopropyl group and X1, X2, and X3are each independently CF or CH. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II), wherein R1is a cyclopropyl group and X1is CH, X2is CF, and X3is CH.

[0109] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II) and each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-4alkyl, Ci-4alkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci- 4)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-4)alkyl, halo(Ci-4)alkyl, halo(C2-4)alkenyl, halo(Ci-4)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)CC>2R4, - N(R3)SO2R4, -NR3-hydroxy(Ci.3)alkyl, -Ci.3alkyleneNHCi.3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4,-C(O)SR3, -CO2R3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-3alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, and -OSO2R3.

[0110] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II) and each Z1is independently selected from the group consisting of oxo, cyano, -NH2, -CH2NH2, -CH2-NH-CH3, -CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -OCF2H, -OCF3, -CH3, -CH2CH3, -CH(CH3)2-F, -CH2CF3, -CHF2, -CF2CH3, -CF3, -CO2-CH2CF3, -CO2-C(CH3)3, -CONH2, - CON(CH3)2, -CONHCH3, -COCH(OH)CH3, -COCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, - SO2CH3, -SO2CH2CH3, -N(CH2CH3)2, -NHCH3, -NHC(CH3)3, -NHCH(CH3)2, -N(CH3)CH2CH3, - N(CH3)2, -NHCH2CH3, -N(CH3)CH(CH3)2, -NHCH2CH2NH2, -NHCH(CH3)CH2OH, - NHCO2C(CH3)3, -NHSO2CH3, -NHCH(CH3)CF3, cyclopropane, fluorocyclopropane, and -L2-Y;

[0111] L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, -NHCO- ; and Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCHs, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl.

[0112] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II) and n is 2.

[0113] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (II) and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or -CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, n is 2. In another aspect of this embodiment, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or-CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, X1, X2, and X3are each independently CF or CH, n is 2 and each Z1is independently selected from the group 70311W001 consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or - CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy.

[0114] In some embodiments, the compound of Formula (I) is a compound of Formula (III) wherein

[0115] R1is a C3-7 cycloalkyl optionally substituted by 1 or 2 groups independently selected from halo or C1-5 alkyl, or R1is a C1-5 alkyl optionally substituted by a C3-7 cycloalkyl;

[0116] X1, X2, and X3are each independently N or CR2wherein each R2is independently selected from the group consisting of hydrogen, halo, cyano, Ci-3alkyl, and halo(Ci-3)alkyl; p is 0, or 1 ;

[0117] X7is independently selected from the group consisting of CR7R8, C=O, NR9, and O; wherein R7is H or CH3;

[0118] R8is selected from the group consisting of NHCH(CH3)2, C(CH3)2NH2, CH2NH2, CH2NHCH(CH3)2, NH2, N(CH3)CH2CH3, NHCH3, NHCH2CH2NH2, NHCH(CH3)CH2OH, C(O)NHCH3, C(O)NH2, NHCH2CH3, NH-cyclobutyl, pyrrolidinyl, NH-oxetanyl, NHSO2CH3, H, N(CH2CH3)2, OH, N(CH3)CH(CH3)2, and N(CH3)2; and

[0119] R9is selected from the group consisting of C(O)CH3, oxetanyl, CH2CH2OH, CH3, H, C(O)CH(OH)CH3, SO2CH3, and C(O)OC(CH3)3.

[0120] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), and X1, X2, and X3are each independently CF or CH.

[0121] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (III), wherein X1is CH. 70311W001

[0122] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (III), wherein X2is CH or CF.

[0123] In some aspects of this embodiment,, the compound of Formula (I) is a compound of Formula (III), wherein X3is CH.

[0124] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein X1is CH, X2is CF, and X3is CH.

[0125] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is Cs-ecycloalkyl or ethyl. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is Cs-ecycloalkyl or ethyl and X1, X2, and X3are each independently CF or CH. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is Cs-ecycloalkyl or ethyl and X1is CH, X2is CF, and X3is CH.

[0126] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is a cyclopropyl group. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is a cyclopropyl group and X1, X2, and X3are each independently CF or CH. In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III), wherein R1is a cyclopropyl group and X1is CH, X2is CF, and X3is CH.

[0127] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III) and each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-4alkyl, Ci-4alkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci- 4)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-4)alkyl, halo(Ci-4)alkyl, halo(C2-4)alkenyl, halo(Ci-4)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene-NR3R4, -N(R3)CC>2R4, - N(R3)SO2R4, -NR3-hydroxy(Ci.3)alkyl, -Ci.3alkyleneNHCi.3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4,-C(O)SR3, -CO2R3, -C(O)-hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-3alkylene- C(O)OR3, -S(O)R3, -S(O)2R3, and -OSO2R3.

[0128] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III) and each Z1is independently selected from the group consisting of oxo, cyano, - NH2, -CH2NH2, -CH2-NH-CH3, -CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -OCF2H, -OCF3, -CH3, - CH2CH3, -CH(CH3)2-F, -CH2CF3, -CHF2, -CF2CH3, -CF3, -CO2-CH2CF3, -CO2-C(CH3)3, -CONH2, -CON(CH3)2, -CONHCH3, -COCH(OH)CH3, -COCH3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, - SO2CH3, -SO2CH2CH3, -N(CH2CH3)2, -NHCH3, -NHC(CH3)3, -NHCH(CH3)2, -N(CH3)CH2CH3, - N(CH3)2, -NHCH2CH3, -N(CH3)CH(CH3)2, -NHCH2CH2NH2, -NHCH(CH3)CH2OH, - NHCO2C(CH3)3, -NHSO2CH3, -NHCH(CH3)CF3, cyclopropane, fluorocyclopropane, and -L2-Y; 70311W001

[0129] L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, -NHCO- ; and Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCH3, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl.

[0130] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III) and n is 2.

[0131] In some aspects of this embodiment, the compound of Formula (I) is a compound of Formula (III) and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or -CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, n is 2. In another aspect of this embodiment, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or-CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy. In another aspect of this embodiment, X1, X2, and X3are each independently CF or CH, n is 2 and each Z1is independently selected from the group consisting of halo(Ci-3)alkyl (e.g., CF3), -Ci-3alkyleneNR3R4(e.g., -CH2NH2, -CH2NHCH3, or - CH2NHCH(CH3)2), -NR3R4(e.g., -NHCH(CH3)CF3), and hydroxy.

[0132] In aspect of this embodiment, X7is selected from the group consisting of CH2, NH, and O.

[0133] In some embodiments, R7is H, and R8is -CH2NH2, -CH2NHCH(CH3)2, -OH, -CH2NHCH3and -NHCH(CH3)CF3. In some embodiments, R7is H, and R8is -CH2NH2, -CH2NHCH(CH3)2, - OH, -CH2NHCH3and -NHCH(CH3)CF3, and X7is selected from the group consisting of CH2, NH, and O.

[0134] In one embodiment of the invention, there is provided a compound or pharmaceutically acceptable salt thereof selected from the group consisting of:

[0135] 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0136] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

[0137] 3-cyclopropyl-7-fluoro-5-((1S,3R,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

[0138] 3-cyclopropyl-7-fluoro-5-((1 R,5S)-2-(trifluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 1);

[0139] 3-cyclopropyl-7-fluoro-5-((1 R,5S)-2-(trifluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 2); 70311W001

[0140] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(2-hydroxyethyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0141] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-methyl-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0142] 3-cyclopropyl-7-fluoro-5-((1 R,3R,4R)-5-methyl-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0143] 3-cyclopropyl-5-((1S,3S,4S)-5-ethyl-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0144] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(oxetan-3-yl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0145] 3-cyclopropyl-7-fluoro-5-((1S,2S,5R)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; benzyl (1 R,4R,6R)-5-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0146] 3-cyclopropyl-7-fluoro-5-((1 R,3R,4R)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

[0147] 3-ethyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((1 R,5S,7R)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan- 6-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((1 R,5S,7S)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan- 6-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;

[0148] 3-cyclopropyl-7-fluoro-5-((1 R,3S,4S)-3-(trifluoromethyl)-2-azabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0149] (R)-3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; tert-butyl 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-3- (trifluoromethyl)piperazine-l -carboxylate; rac-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0150] (S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; 70311W001

[0151] (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0152] 3-cyclopropyl-7-fluoro-5-(4-(2-hydroxyethyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0153] 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-(4- methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one;

[0154] 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-5- (trifluoromethyl)piperazin-2-one;

[0155] 3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine

[0156] 1 ,1 -dioxide;

[0157] (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0158] (S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0159] (S)-3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0160] 3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)azetidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine

[0161] 1 ,1 -dioxide;

[0162] (R)-3-cyclopropyl-7-fluoro-5-(4-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0163] 3-cyclopropyl-7-fluoro-5-(4-hydroxy-2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0164] 3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine

[0165] 1 ,1 -dioxide;

[0166] 3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-(R)-3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0167] 3-cyclopropyl-7-fluoro-5-((2S,5R)-2-methyl-5-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide 70311W001

[0168] 3-cyclopropyl-7-fluoro-5-((2R,5S)-2-methyl-5-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0169] Trans-rac-5-((2S,4R)-4-amino-2-(trifluoromethyl)pyrrolidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0170] 3-cyclopropyl-7-fluoro-5-(7-(trifluoromethyl)-1 ,4-diazepan-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0171] (S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0172] (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0173] (R)-3-cyclopropyl-7-fluoro-5-(2-methylpyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide;

[0174] 3-cyclopropyl-7-fluoro-5-(piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,3R)-3-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0175] 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-ethyl-5- (trifluoromethyl)piperazin-2-one; rac-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); cis-rel-1-(3-cyclopropyl-7-fluoro-1,1-dioxo-4H-1A6,2,4-benzothiadiazin-5-yl)-2- (trifluoromethyl)pyrrolidine-3-carboxylic acid;

[0176] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);

[0177] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0178] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); 70311W001

[0179] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); trans-rel-3-cyclopropyl-7-fluoro-5-((2S,3S)-3-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);

[0180] Trans-rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-3-(2-hydroxypropan-2-yl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0181] 3-cyclopropyl-7-fluoro-5-(4-hydroxy-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-(R)-3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0182] 3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide; rel-(R)-3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0183] 3-cyclopropyl-7-fluoro-5-((2R,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0184] 3-cyclopropyl-7-fluoro-5-((2S,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0185] 3-cyclopropyl-7-fluoro-5-((2S,5R)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0186] 3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0187] (R)-3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0188] (S)-3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0189] 3-cyclopropyl-7-fluoro-5-((2S,5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide 70311W001

[0190] 3-cyclopropyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0191] 3-cyclopropyl-5-(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0192] 3-cyclopropyl-7-fluoro-5-(piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1 -dioxide;

[0193] (S)-3-cyclopropyl-7-fluoro-5-(3-methylpiperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;

[0194] 3-cyclopropyl-7-fluoro-5-(4-(isopropylamino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine

[0195] 1 ,1 -dioxide;

[0196] 5-(4-aminopiperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;

[0197] 3-ethyl-7-fluoro-5-((2R*,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0198] (S)-3-ethyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;

[0199] (S)-3-ethyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1,2,4]thiadiazine

[0200] 1 ,1 -dioxide;

[0201] (R)-3-ethyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H-benzo[e][1,2,4]thiadiazine

[0202] 1 ,1 -dioxide;

[0203] 3-ethyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide;

[0204] 3-ethyl-7-fluoro-5-(2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-ethyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-3-ethyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); rel-5-((2R,4R)-4-amino-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); rel-5-((2R,4R)-4-amino-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2); 70311W001 rac-5-((2R,4S)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0205] 5-((2S,4R)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-ethyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0206] 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0207] 5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0208] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0209] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((1-hydroxypropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0210] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R*)-1-hydroxypropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);

[0211] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R*)-1-hydroxypropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0212] 3-cyclopropyl-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0213] 3-cyclopropyl-5-((2R,4S)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0214] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((propan-2-yl-d7)amino)-2-(trifluoromethyl)piperidin-

[0215] 1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0216] 3-cyclopropyl-5-((2S,4R)-4-(ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0217] 3-cyclopropyl-5-((2S,4R)-4-(diethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0218] 3-cyclopropyl-5-((2S,4R)-4-(dimethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; 70311W001

[0219] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropyl(methyl)amino)-2-(trifluoromethyl)piperidin- 1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0220] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0221] 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0222] 5-((2S,4R)-4-((2-aminoethyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0223] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0224] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methyl-d3)amino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0225] 3-cyclopropyl-5-((2S,4R)-4-(ethyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0226] (R)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one;

[0227] (S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one;

[0228] 3-cyclopropyl-7-fluoro-5-((2S,4S)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0229] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0230] 5-((2S,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0231] 5-((2S,4S)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0232] 5-((2S,4R)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0233] 3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((R)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0234] 3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((S)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 70311W001

[0235] 3-cyclopropyl-7-fluoro-5-((2S,4S)-2-(trifluoromethyl)-4-(((S)-1 , 1 , 1 -trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0236] (R)-3-cyclopropyl-7-fluoro-5-(4-(methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0237] (S)-3-cyclopropyl-7-fluoro-5-(4-(methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0238] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(methylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0239] 3-cyclopropyl-7-fluoro-5-((1R,3R,4R)-5-(methylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0240] 3-cyclopropyl-5-((1S,3S,4S)-5-(ethylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0241] 3-cyclopropyl-5-((1S,3S,4S)-5-(cyclopropylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-yl)methanesulfonamide;

[0242] Cis-rel-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-2-(trifluoromethyl)piperidin-4-yl)methanesulfonamide (Isomer 1);

[0243] Cis-rel-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-2-(trifluoromethyl)piperidin-4-yl)methanesulfonamide (Isomer 2);

[0244] (R)-1-(4-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3- (trifluoromethyl)piperazin-1-yl)ethan-1-one;

[0245] (S)-1-((R)-4-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-3- (trifluoromethyl)piperazin-1-yl)-2-hydroxypropan-1-one; rac-cis-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-N,N- dimethyl-2-(trifluoromethyl)pyrrolidine-3-carboxamide; rac-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide; rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide (Isomer 1); rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide (Isomer 2); 70311W001 rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-N- methyl-2-(trifluoromethyl)piperidine-4-carboxamide (Isomer 1); rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-N- methyl-2-(trifluoromethyl)piperidine-4-carboxamide (Isomer 2);

[0246] (R)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0247] (S)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((isopropylamino)methyl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0248] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);

[0249] 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0250] 5-((2S,4R)-4-(cyclobutylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0251] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(oxetan-3-ylamino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0252] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1);

[0253] 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2);

[0254] Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin- 1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2); trans- rel-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(hydroxymethyl)-2-

[0255] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); 70311W001

[0256] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); trans-rel-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(hydroxymethyl)-2- (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);

[0257] Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); rac-5-((2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,3S)-3-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0258] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)oxazole-4-carboxamide;

[0259] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)cyclopropane carboxamide;

[0260] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)benzamide;

[0261] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)nicotinamide;

[0262] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)-1 H-imidazole-5-carboxamide;

[0263] (S)-N-((1s,4R)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)-2,2-difluorocyclopropane-1 -carboxamide;

[0264] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)isoxazole-5-carboxamide;

[0265] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)isoxazole-3-carboxamide;

[0266] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)picolinamide;

[0267] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)thiazole-4-carboxamide;

[0268] N-((1s,4s)-4-((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)benzamide; 70311W001

[0269] N-((1 s,4s)-4-((3-cyclopropyl-1 , 1 -dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)cyclopropanecarboxamide;

[0270] N-((1s,4s)-4-((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)picolinamide; tert-butyl 3-(((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate;

[0271] 3-cyclopropyl-7-fluoro-5-(((1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; tert-butyl ((1R,3R)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate; tert-butyl (4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)bicyclo[2.1.1 ]hexan-1 -yl)carbamate; tert-butyl ((1S,3S)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate; tert-butyl ((1S,3R)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate; tert-butyl ((1r,4r)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)carbamate; rac-tert-butyl ((1R,3S)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)amino)cyclopentyl)carbamate;

[0272] 2,2,2-trifluoroethyl 3-(((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate;

[0273] Cyclopropyl(3-(((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholino)methanone;

[0274] (3-(((3-cyclopropyl-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thiadiazi n-5- yl)amino)methyl)morpholino)(2,2-difluorocyclopropyl)methanone;

[0275] 3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)piperidin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;

[0276] 3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;

[0277] 3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; 70311W001 benzyl 4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)oxy)piperidine-1 -carboxylate;

[0278] 3-cyclopropyl-7-fluoro-5-((2S,4S)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;

[0279] 3-cyclopropyl-5-((2S,4R)-4-(((R)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0280] 3-cyclopropyl-5-((2S,4S)-4-(((R)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0281] 3-cyclopropyl-5-((2S,4R)-4-(((S)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0282] 3-cyclopropyl-5-((2S,4S)-4-(((S)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0283] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R)-1-fluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0284] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((R)-2-methylaziridin-1-yl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0285] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((S)-1-fluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;

[0286] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((S)-2-methylaziridin-1-yl)-2- (trifluoromethyl)piperidin-l -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; and

[0287] (S)-3-cyclopropyl-7-fluoro-5-(4-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; or a pharmaceutically acceptable salt thereof.

[0288] In one aspect of the present invention, a compound is provided which is 5-((2S,4R)-4- (aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide as represented by the following structure: 70311W001 or a pharmaceutically acceptable salt thereof.

[0289] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-5- ((2S,4R)-4-(ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1 ,1-dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0290] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-7- fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((S)-1 ,1 ,1-trifluoropropan-2-yl)amino)piperidin-1-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0291] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-7- fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof. 70311W001

[0292] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-7- fluoro-5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0293] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-7- fluoro-5-((2S,4R)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0294] In one aspect of the present invention, a compound is provided which is 3-cyclopropyl-7- fluoro-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as represented by the following structure: or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the compound according to the invention as set out above is in its free base or free acid form. 70311W001

[0296] In an alternate embodiment, the compound according to the invention as set out above is in the form of a pharmaceutically acceptable salt.

[0297] Compounds of the invention may contain an acidic or basic functional group and, thus, a person of skill in the art will appreciate that pharmaceutically acceptable salts of the compounds of Formula (I) may be prepared.

[0298] Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in P H Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition 25 Stahl / Wermuth: Wiley- VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd- 3906390519.html).

[0299] Suitable pharmaceutically acceptable salts can include acid or base addition salts.

[0300] Such base addition salts can be formed by reaction of a compound of formula (I) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt.

[0301] Such acid addition salts can be formed by reaction of a compound of formula (I) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt.

[0302] Salts may be prepared in situ during the final isolation and purification of a compound of formula (I). If a basic compound of formula (I) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a compound of formula (I) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid. It will be understood that if a compound of Formula (I) contains two or more basic moieties, the stoichiometry of salt formation may include 1 , 2 or more equivalents of acid. Such salts would contain 1 , 2 or more acid counterions, for example, a dihydrochloride salt. Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of formula (I) are included within the scope of the invention, including substoichiometric salts. Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5- dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1 ,2-disulfonate (edisylate), 70311W001 ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5- di hydroxy benzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'- di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1 ,5-disulfonate (napadisylate), naphthalene-2 sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p- toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

[0303] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N’-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-T-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

[0304] The present invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention, is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.

[0305] Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as2H,3H,13C,14C,15N,17O,180,18F,19F and36CI, respectively. Certain isotopic variations of a compound of formula (I) or a salt or solvate thereof, for example, those in which a radioactive isotope such as3H or14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Thus, in one embodiment, the present invention includes a compound of the invention, wherein one or more hydrogen atoms attached to carbon atoms are replaced by deuterium. Isotopic variations of a compound of the invention, can generally be prepared by conventional procedures 70311W001 such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

[0306] In an embodiment, the present invention is a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms attached to carbon atoms are replaced by deuterium.

[0307] It is to be understood that the disclosed embodiments may be combined with any of the aspects and other embodiments.

[0308] It is also to be understood that the compounds of the invention may exist in tautomeric forms. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compound. For example, at least the following tautomer exists:

[0309] 70311W001

[0310] Statement of Use

[0311] Therapeutic targeting of the MRGPRX2 (also known as MRGX2) pathway with small molecule antagonists is expected to be beneficial in a broad range of MRGX2-mediated diseases or disorders.

[0312] Compounds of the invention may be useful in the prevention of an MRGX2-mediated diseases or disorders, such as Allergic rhinitis, Asthma (for example, acute or eosinophilic), Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis.

[0313] Compounds of the invention may be useful in the treatment of an MRGX2-mediated diseases or disorders, such as Allergic rhinitis, Asthma (for example, acute or eosinophilic), Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis.. 70311W001

[0314] In one embodiment, the present invention provides a compound of the present invention for use in therapy.

[0315] In one embodiment, the present invention provides a compound or pharmaceutically acceptable salt thereof as described herein for use in the treatment of an MRGX2-mediated disease or disorder.

[0316] In one embodiment, the present invention provides a compound or pharmaceutically acceptable salt thereof as described herein for use in the treatment of an MRGX2-mediated disease or disorder wherein the compound is selected from the group consisting of: or pharmaceutically acceptable salts thereof.

[0317] In one aspect, the present invention provides a compound or pharmaceutically acceptable salt thereof as described herein for use in the treatment of a the disease or disorder selected from the group consisting of Allergic rhinitis, Asthma (for example, acute or eosinophilic), Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis. 70311WG01

[0318] In one embodiment, the present invention provides a compound or pharmaceutically acceptable salt thereof (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) as described herein for use in the treatment of chronic spontaneous urticaria.

[0319] In one embodiment, the present invention provides a compound or pharmaceutically acceptable salt thereof (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) as described herein for use in the treatment of rosacea.

[0320] In one embodiment, the present invention provides a compound or pharmaceutically acceptable salt thereof (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) as described herein for use in the treatment of prurigo nodularis.

[0321] In one embodiment, the present invention provides a compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic spontaneous urticaria.

[0322] In one aspect of the invention, there is provided a method of treating an MRGX2-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the present invention or a pharmaceutical composition including such compound or pharmaceutically acceptable salt.

[0323] In one embodiment, the present invention provides a method of treating an MRGX2- mediated disease or disorder in a human in need thereof comprising administering to the human 70311W001 a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the present invention (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition including such compound or pharmaceutically acceptable salt, wherein the disease or disorder is selected from the group consisting of Allergic rhinitis, Asthma (for example, acute or eosinophilic), Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis..

[0324] In one embodiment, the present invention provides a method of treating an MRGX2- mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the present invention (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) wherein the disease or disorder is chronic spontaneous urticaria.

[0325] In one embodiment, the present invention provides a method of treating an MRGX2- mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound selected from the group consisting of 70311W001 or a pharmaceutically acceptable salt thereof wherein the disease or disorder is chronic spontaneous urticaria.

[0326] In one aspect of the present invention, the present invention provides the use of a compound or pharmaceutically acceptable salt thereof (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) of the present invention in the manufacture of a medicament for use in the treatment of an MRGX2-mediated disease or disorder.

[0327] In one embodiment, the present invention provides use of a compound or pharmaceutically acceptable salt thereof of the present invention (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in the treatment of an MRGX2-mediated disease or disorder wherein the disease or disorder is Allergic rhinitis, Asthma (e.g, acute or eosinophilic), Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis.

[0328] In one aspect of the present invention, the present invention provides the use of a compound or pharmaceutically acceptable salt thereof (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) of the present invention in the manufacture of a medicament for use in the treatment of chronic spontaneous urticaria.

[0329] Pharmaceutical Compositions / Routes of administration / Dosages

[0330] While it is possible that when used in therapy, the compounds of the invention may be administered as the raw chemical, it is common to present the active ingredient as a pharmaceutical composition.

[0331] In one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to the present invention (e.g., a compound of Example 1-192 or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.

[0332] The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral 70311W001

[0333] (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), ocular (including topical, intraocular, subconjunctival, episcleral, sub-Tenon), parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the excipient(s). In one embodiment, the pharmaceutical composition is presented for oral administration, for example as a tablet or capsule. Other suitable compositions for oral administration may be powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.

[0334] 70311W001

[0335] Examples

[0336] General Synthetic Methods

[0337] The compounds of this invention may be prepared using synthetic procedures illustrated in the reaction schemes below and knowledge of a skilled organic chemist. The syntheses provided in these schemes are applicable for producing compounds of the invention having a variety of different substituent groups employing appropriate precursors, which are suitably protected if needed, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needed, affords compounds of the nature generally disclosed. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in “Greene’s Protective Groups in Organic Synthesis’ (Peter G. M. Nuts, 5th edition, J. Wiley and Sons, 2014). Intermediates (compounds used in the preparation of the compounds of the invention) may also be present as salts.

[0338] The chemical reactions described herein may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Generally, the reactions disclosed herein may be carried out at about room temperature (RT) and ambient pressure, but depending on reaction kinetics, yields, and so on, some reactions may be run at elevated pressures or employ higher temperatures (for example, reflux conditions) or lower temperatures (for example, -78°C to 0°C). The reactions described herein may also employ one or more solvents which may influence the reaction rate and yield. The one or more solvents may be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination depending on the desired chemical reaction. Representative solvents include saturated aliphatic hydrocarbons (for example, n-pentane, n- hexane, n-heptane, n-octane, cyclohexane, and methylcyclohexane); aromatic hydrocarbons (for example, benzene, toluene, and xylenes); halogenated hydrocarbons (for example, methylene chloride, chloroform, and carbon tetrachloride); aliphatic alcohols (for example, methanol, ethanol, propan-1 -ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-ol, 2-methyl-propan- 2-ol, pentan-1 -ol, 3-methyl-butan-1-ol, hexan-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2- butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2-(2-butoxy-ethoxy)- ethanol); ethers (for example, diethyl ether, di-isopropryl ether, dibutyl ether, 1 ,2-dimethoxy- ethane, 1 ,2-diethoxy-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethox-2-(2-ethoxy- ethoxy)-ethane, tetra hydrofuran, 1 ,4-dioxane); ketones (for example, acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (for example, formamide, N,N-dimethylformamide, acetonitrile, N-methyl-pyrrolidione, pyridine, quinoline, nitrobenzene; sulfur-containing solvents (for example, carbon disulfide, dimethyl sulfoxide, tetrahydro-thiophene-1 , 1 ,-dioxide)l; and phosphorous-containing solvents (for example, hexamethylphosphoric triamide). 70311W001

[0339] In the generic schemes below, substituent identifiers R1, X1, X2, X3, Z1, A and n are as defined are as defined previously. As mentioned earlier, however, some of the starting materials and intermediates may include protecting groups, which are removed prior to the final product. In such cases, the substituent identifier refers to moieties defined in Formula (I) and to those moieties with appropriate protecting groups. For example, a starting material or intermediate in the schemes may include a reactant having a potentially reactive amine. In such cases, the reactant may include the moiety with or without a protecting group such as Boc or Cbz group attached to the amine depending on the desired reaction. LG means Leaving Group and can be routinely selected by the person skilled in the art using ordinary skill.

[0340] Scheme A shows a general method for preparing compounds of Formula (I).

[0341] Scheme A

[0342] In accordance with this method, a 2-haloaniline (A-1 , LG=bromo) is reacted with sulfurisocyanatidic chloride in the presence of a polar solvent (nitromethane) at reduced temperature (e.g., -40 to 0°C) to give a urea intermediate (not shown) which is subsequently treated with aluminium trichloride at reduced temperature (e.g., -20 to 0°C) and then at elevated temperature (e.g., 75°C) to give a 3-hydroxy-4H-benzo[e][l,2,4]thiadiazine 1 ,1-dioxide intermediate (A-2), which may exist as a corresponding tautomer, a 2H-benzo[ e ][l ,2,4]thiadiazin- 3( 4H)-one 1 ,1-dioxide derivative. Following ring closure, the 2H-benzo[e][l,2,4]thiadiazin-3(4H)- one 1 ,1-dioxide derivative (A-2) is reacted with acid (H2SO4) at elevated temperature (e.g., 110°C) to give a N-(2-bromo-4-fluoro-6-sulfamoylphenyl)acetamide intermediate (A-3) which is 70311W001 subsequently reacted with an R1-substituted acid chloride (A-4) in an appropriate solvent (dioxane) at elevated temperature (e.g. 60-150 °C) to give a substituted 2-halo-6- sulfamoylphenyl)alkylcarboxamide intermediate (A-5). The substituted 2-halo-6- sulfamoylphenyl)alkylcarboxamide intermediate (A-5) is reacted with a non-nucleophilic base (e.g., Na2CC>3, NaOH) in a suitable solvent (water) at elevated temperature (90-120°C) to give a 5-halo-3-alkyl-4H benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide intermediate (A-6), which is subsequently reacted with a substituted secondary amine (Z1)n-A (A-7) in one or more suitable polar solvents (dioxane) in the presence of base (NaOtBu, KOtBu) and palladium catalyst (RuPhos Pd G3, RuPhos, Pd2dbas) at elevated temperature (60-100 °C) or with a substituted primary amine (Z1)n-A-L1(A-8, L1= Co-3alkyleneNH2) in one or more suitable polar solvents (DMSO) in the presence of base (P2Et) and catalyst (tBuBrettPhos Pd G3) at room temperature. The reaction gives the compound of Formula (I) (L1= C-N bond, or NH, or Ci-salkyleneNH bond) directly or indirectly, for example after removal of protecting groups, further elaboration of functional groups, salt formation, etc.

[0343] Scheme B

[0344] Scheme B shows a general method for preparing compounds of Formula (I). In accordance with this method, a substituted N-(2-halo-6-sulfamoylphenyl)acetamide intermediate (A-3, LG=Br) is reacted with sodium bisulfite and an R1-substituted aldehyde (B-1) in an appropriate polar solvent (DMF) at elevated temperature (e.g., 120 °C) to give a substituted 5- halo-3-alkyl-4H benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide intermediate (A-6), which is subsequently reacted as described in Schemes A, D, and E. The reaction gives the compound of Formula (l)(L1= C-N bond) directly or indirectly, for example after removal of protecting groups, further elaboration of functional groups, salt formation, etc. 70311W001

[0345] Scheme C

[0346] Scheme C shows a general method for preparing compounds of Formula (I). In accordance with the method, a substituted aniline (C-1) is reacted with sulfurisocyanatidic chloride in the presence of a polar solvent (nitromethane) at reduced temperature (e.g., -40 to 0°C) to give a urea intermediate (not shown) which is subsequently treated with aluminum trichloride at reduced temperature (e.g., -20 to 0°C) and then at elevated temperature (e.g., 75°C) to give a 3-hydroxy-4H-benzo[e][l,2,4]thiadiazine 1 ,1-dioxide intermediate (C-2), which may exist as a corresponding tautomer, a 2H-benzo[ e ][l ,2,4]thiadiazin-3( 4H)-one 1 ,1-dioxide derivative. Following ring closure, the 2H-benzo[e][l,2,4]thiadiazin-3(4H)-one 1 ,1-dioxide derivative (C-2) is reacted with acid (H2SO4) at elevated temperature (e.g., 90°C -110°C) to give a substituted 2- aminoaryl sulfonamide intermediate (C-3). The substituted 2-aminoaryl sulfonamide intermediate (C-3) is reacted with iodine monochloride in a suitable combination of solvents (DMF, acetic acid) at room temperature to give a substituted 2-amino-3-iodoarylsulfonamide intermediate, which is subsequently reacted with R1-substituted acid chloride (A-4) in in an appropriate solvent (dioxane) at elevated temperature (e.g., 60-90°C) to give a substituted 2-iodo-6- sulfamoylphenyl)alkylcarboxamide intermediate (C-5). The substituted 2-iodo-6- sulfamoylphenyl)alkylcarboxamide intermediate (C-5) is reacted with a non-nucleophilic base (e.g., Na2CC>3, NaOH) in a suitable solvent (water) at elevated temperature (90-120 °C) to give a 5-iodo-3-alkyl-4H benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide intermediate (C-6), which is subsequently reacted as described in Scheme E to give the compound of Formula (I). 70311WG01

[0347] Scheme D

[0348] Scheme D shows a general method for preparing compounds of Formula (I). In accordance with this method, a substituted 5-halo-3-alkyl-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide intermediate (A-6, LG=Br) is reacted with is reacted with a potassium alkyl trifluoroborate (D-1) in the presence of a nickel and iridium catalyst (e.g., (4,4'-Dtbbpy)NiCl2,

[0349] (lr[dF(CF3)ppy]2(dtbpy))PFe, etc.), an organic base (e.g., 2,6-lutidine) and one or more polar solvents (e.g., acetonitrile) under irradiation (450 nm). The reaction gives the compound of Formula 1 (L1= C-C bond) directly or indirectly, e.g., after removal of protecting groups, further elaboration of functional groups, salt formation, etc.

[0350] Scheme E

[0351] Scheme E shows a general method for preparing compounds of Formula (I). In accordance with the method, a substituted 5-halo-3-alkyl-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide intermediate (A-6, LG=I) is reacted with is reacted with an alkanol (E-1) in the presence of copper iodide, dimethylglycine, an inorganic base (e.g., CS2CO3), neat under elevated temperature (150 °C). The reaction gives the compound of Formula 1 (L1= O) directly or indirectly, e.g., after removal of protecting groups, further elaboration of functional groups, salt formation, etc. 70311W001

[0352] Scheme F

[0353] Scheme F shows a general method for preparing compounds of Formula 1. In accordance with the method, a substituted 5-halo-3-alkyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide intermediate (A-6, X=Br) is reacted with is reacted with an alkanol (F-1 , C1-3 refers to a C1- salkylene) in the presence of palladium catalyst (e.g., AdCyBrettPhos, [Pd(allyl)CI]2, etc.), an non- nucleophilic base (e.g., NaOtBu, etc) and one or more polar solvents (e.g., dioxane) under elevated temperature (40 °C). The reaction gives the compound of Formula 1 (L1= O-Ci-3alkylene) directly or indirectly, eg after removal of protecting groups, further elaboration of functional groups, salt formation, etc.

[0354] Abbreviations 70311W001 70311W001

[0355] Analytical LCMS Methods

[0356] High pH Method 1A lnstrument:Agilent 1260 HPLC MSD:6125B single quadrupole MSD

[0357] Column: Xbridge C18,2.1*50mm, 5pm

[0358] Column Temp: 40°C

[0359] Mobile Phase:A: H2O+10nM NH4HCO3

[0360] Mobile Phase:B: ACN

[0361] Flow Rate: 0.8 mL / min 70311WQ01

[0362] High pH Method 1B lnstrument:Agilent 1260 HPLC MSD:6125B single quadrupole MSD

[0363] Column: Xbridge C18,2.1*50mm, 5pm Column Temp: 40°C

[0364] Mobile Phase:A: H2O+10nM NH4HCO3

[0365] Mobile Phase:B: ACN

[0366] Flow Rate: 0.8 mL / min Analytical LCMS Methods 1-3

[0367] UV detection was an averaged signal from wavelength of 210nm to 350nm.

[0368] Injection volume: 0.5 uL

[0369] MS Conditions (Waters SQD or QDa)

[0370] QDa Settings: MS: Waters Acquity QDa mass detector 70311W001

[0371] Ionisation mode: Alternate-scan Positive and Negative Electrospray

[0372] Scan Range: 100 to 1250 AMU

[0373] Targeted Sampling Frequency: 8 Hz

[0374] SQD Settings:

[0375] MS: Waters Acquity SQD

[0376] Ionisation mode: Alternate-scan Positive and Negative Electrospray

[0377] Scan Range: 100 to 1250 AMU

[0378] Scan Time: 0.12 seconds

[0379] General Method 1 (High pH)

[0380] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (30mm x 2.1mm i.d. 1.7pm packing diameter) at 45 °C.

[0381] The solvents employed were:

[0382] A = 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with 25% ammonium hydroxide solution.

[0383] B = Acetonitrile

[0384] The gradient employed was:

[0385] General Method 2 (Formic Acid)

[0386] The UPLC analysis was conducted on an Acquity UPLC CSH C18 column (30mm x 2.1mm i.d. 1.7pm packing diameter) at 45 °C.

[0387] The solvents employed were:

[0388] A = 0.1% v / v solution of Formic Acid in Water. 70311W001

[0389] B = 0.1% v / v solution of Formic Acid in Acetonitrile.

[0390] The gradient employed was:

[0391] General Method 3 (TFA) The LIPLC analysis was conducted on an Acquity LIPLC CSH C18 column (30mm x

[0392] 2.1mm i.d. 1.7pm packing diameter) at 45 °C

[0393] The solvents employed were:

[0394] A = 0.1% v / v solution of TFA in Water.

[0395] B = 0.1% v / v solution of TFA in Acetonitrile. The gradient employed was:

[0396] Mass Directed Autopreparative HPLC (MDAP) Methods

[0397] Mass directed autopreparative HPLC was used for preparation of the compounds of this invention, and the conditions are given below. The UV detection was an averaged signal from wavelength of 210 nm to 350 nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization. 70311W001

[0398] High pH MDAP Method A

[0399] Method A was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d.

[0400] 5pm packing diameter) at ambient temperature. The solvents employed were:

[0401] A = 10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia B = acetonitrile

[0402] The gradient employed was:

[0403] High pH MDAP Method B

[0404] Method B was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0405] A = 10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia

[0406] B = acetonitrile

[0407] The gradient employed was: 70311W001

[0408] High pH MDAP Method C

[0409] Method C was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d.

[0410] 5pm packing diameter) at ambient temperature. The solvents employed were:

[0411] A = 10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia B = acetonitrile

[0412] The gradient employed was:

[0413] High pH MDAP Extended Method C

[0414] Method Ext_C was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0415] A = 10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia

[0416] B = acetonitrile

[0417] The gradient employed was: 70311W001

[0418] High pH MDAP Method D

[0419] Method D was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d.

[0420] 5pm packing diameter) at ambient temperature. The solvents employed were:

[0421] A = 10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia B = acetonitrile

[0422] The gradient employed was:

[0423] Formic Acid Prep LCMS Large Scale Method A2

[0424] The CSH~For_MethA_2 was conducted on a XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0425] A = 0.1% v / v solution of Formic Acid in Water.

[0426] B = 0.1% v / v solution of Formic Acid in Acetonitrile.

[0427] The gradient employed was: 70311W001

[0428] Formic Acid Prep LCMS Method B

[0429] The CSH~For_MethB was conducted on a XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were: A = 0.1 % v / v solution of Formic Acid in Water.

[0430] B = 0.1 % v / v solution of Formic Acid in Acetonitrile.

[0431] The gradient employed was:

[0432] MS Conditions MS: Waters Acquity QDa mass detector

[0433] Ionisation mode: Alternate-scan Positive and Negative Electrospray

[0434] Scan Range: 160 to 1250 amu

[0435] Targeted Sampling Frequency: 2 Hz

[0436] Low pH Method B Extended The HPLC analysis was conducted on an XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0437] A = 0.1 % v / v solution of Formic Acid in Water.

[0438] B = 0.1 % v / v solution of Formic Acid in Acetonitrile. 70311W001

[0439] The gradient employed was:

[0440] Low pH Method C

[0441] The HPLC analysis was conducted on an XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0442] A = 0.1% v / v solution of Formic Acid in Water.

[0443] B = 0.1% v / v solution of Formic Acid in Acetonitrile.

[0444] The gradient employed was: Low pH Method C Extended

[0445] The HPLC analysis was conducted on an XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0446] A = 0.1% v / v solution of Formic Acid in Water. 70311W001

[0447] B = 0.1% v / v solution of Formic Acid in Acetonitrile.

[0448] The gradient employed was:

[0449] Low pH Method D Extended The HPLC analysis was conducted on an XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were:

[0450] A = 0.1% v / v solution of Formic Acid in Water.

[0451] B = 0.1% v / v solution of Formic Acid in Acetonitrile.

[0452] The gradient employed was:

[0453] Low pH MDAP TFA Method Ext_B

[0454] Method Ext_B was conducted on an Xselect CSH C18 column (typically 150mm x 30mm i.d. 5pm packing diameter) at ambient temperature. The solvents employed were: 70311W001

[0455] A = 0.1 % v / v solution of TFA in Water

[0456] B = 0.1 % v / v solution of TFA in Acetonitrile

[0457] The gradient employed was:

[0458] Preparative SFC and Chiral Purification Methods

[0459] Performed on a Shimadzu Prep using Shimadzu PrepSolution / LabSolution software. Column Temperature: 30 °C:

[0460] Chiral Method XA: Isocratic A: 65% CO2 : B: 35% Methanol on column Chiralpak IG (250 x 20mm, 5pm) (50 mL / min).

[0461] Chiral Method XB: Isocratic A: 78% CO2 : B: 22% Methanol on column Chiralpak IH (250 x 20mm, 5pm)(50 mL / min).

[0462] Chiral Method XC: Isocratic A: 80% CO2 : B: 20% Isopropanol on column Chiralpak IG (250 x 20mm, 5pm)( 50 mL / min).

[0463] Chiral Method XD: Isocratic A: 75% CO2 : B: 25% Ethanol on column Chiralpak AD-H (250 x 20mm, 5pm)(50 mL / min).

[0464] Chiral Method XE: Isocratic A: 85% CO2 : B: 15% Methanol on column Chiralpak AD-H (250 x 20mm, 5pm)( 50 mL / min).

[0465] Chiral Method XF: Isocratic A: 80% CO2 : B: 20% Methanol w / 0.5% Isopropyl amine on column Chiralpak IC (250 x 20mm, 5pm)( 50 mL / min).

[0466] Chiral Method XG: Isocratic A: 70% CO2 : B: 30% Methanol w / 0.5% Isopropyl amine on column Chiralpak IH (250 x 30mm, 5pm)( 50 mL / min). 70311W001

[0467] Chiral Method XH: Using isocratic A: 75% CO2 : B: 25% Ethanol w / 0.5% Isopropyl amine on column Chiralpak IH (250 x 20mm, 5pm)( 50 mL / min).

[0468] Chiral Method XI: Using isocratic A: 80% CO2 : B: 20% Methanol on column Chiralpak AD-H (250 x 30mm, 5pm)(80 mL / min).

[0469] Chiral Method XJ: Using isocratic A: 70% Heptane w / 0.1% Formic acid : B: 30% Ethanol w / 0.1 % Formic acid on column Chiralpak AD-H (250 x 20mm, 5pm)( 20 mL / min).

[0470] Chiral Method XK: Using isocratic A: 75% CO2: B: 25% Methanol on column Chiralpak AS-H (250 x 20mm, 5pm)( 50 mL / min).

[0471] Chiral Method XL: Using isocratic A: 85% CO2 : B: 15% Ethanol on column Chiralpak AD- H (250 x 20mm, 5pm)( 50 mL / min).

[0472] Chiral Method XM: Using isocratic A: 60% Heptane w / 0.1 % Formic acid : B: 40% Ethanol w / 0.1% Formic acid on column Chiralpak IA (250 x 20mm, 5pm)(20 mL / min).

[0473] Chiral Method XN: Usiung isocratic A: 75% CO2: B: 25% Ethanol(containing 0.5% isopropylamine to minimize tailing)on Chiralpak IG, 5 microns(20 mm x 250 mm), (50 mL / min).

[0474] Chiral Method XO: Using isocratic A: 80% CO2 : B: 20% Ethanol on column Chiralpak AD- H (250 x 100 mm, 20 pm)( 50 mL / min).

[0475] Chiral Method XP: Using isocratic A: 85% Heptane w / 0.1% Formic acid : B: 15% Ethanol w / 0.1% Formic acid on column Chiralpak AD (250 x 30mm, 5pm) (45 mL / min).

[0476] Chiral Method XQ: Using isocratic A: 75% CO2: B: 25% Methanol on column Chiralpak IG (250 x 20mm, 5pm)( 50 mL / min).

[0477] Chiral Method XR: Using isocratic A: 50% CO2: B: 50% Ethanol w / 0.5% Isopropyl amine on column Chiralpak IH (250 x 20mm, 5pm) ( 45 mL / min).

[0478] Unless otherwise stated starting materials for the preparation of Intermediates and Examples are commercially available.

[0479] Intermediates

[0480] Intermediate 1

[0481] 5-bromo-3-cyclopropyl-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide 70311W001

[0482] A 100 mL round-bottomed flask was charged with 2-amino-3-bromobenzenesulfonamide (2.88 g, 11.47 mmol) in 1 ,4-Dioxane (50 mL) to give a yellow solution at room temperature. Under nitrogen, cyclopropanecarbonyl chloride (1.041 mL, 11.47 mmol) was added dropwise to the reaction mixture. The reaction mixture was heated to 80°C. After 2h, the reaction mixture was concentrated. Sodium hydroxide (11.47 mL, 57.3 mmol) and water (50 mL) was added to the reaction mixture. The reaction mixture was heated to 120 °C. After 16h, the reaction mixture was acidified to pH 6. The solids were filtered and washed with water (20 mL). The crude product was chromatographed on silica gel and eluted with EtOAc in heptanes (5% to 70%) to obtain 5-bromo- 3-cyclopropyl-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (1.2 g, 3.98 mmol, 34.7 % yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6, 298 K) b(ppm) = 11.11 (s, 1 H), 8.14 - 7.95 (m, 1 H), 7.83 (dd, J = 1.5, 7.8 Hz, 1 H), 7.48 - 7.26 (m, 1 H), 2.58 - 2.52 (m, 1 H), 1.20 - 1.10 (m, 2H), 1.10 -1.02 (m, 2H). LCMS: m / z =303.0 (M+H)+, rt 0.71 min, Method 3.

[0483] Intermediate 2

[0484] 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

[0485] Step 1

[0486] 5-bromo-7-fluoro-3-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0487] To a stirred solution of sulfurisocyanatidic chloride (162 g, 1143 mmol) in nitromethane (400 mL) was added a solution of 2-bromo-4-fluoroaniline (167 g, 879 mmol) in nitromethane (1600 mL) at -40 °C. The reaction mixture was warmed to 0 °C and stirred for 10 min. TLC (heptane / EA=5 / 1 , Rf-SM=0.5) showed the reaction was consumed completely. Aluminium chloride was then added (234 g, 1758 mmol) at 0-5 °C. The reaction mixture temperature was heated to 75 °C and stirred for 12h. After 12 h, LCMS showed the product. Four duplicate reactions were combined for work up. The reaction mixture was cooled to 15 °C and poured into ice cold water (2000 mL). To the mixture was added EA (2000 mL), and stirred at 15 °C for 10 min. The organic phase was separated and aqueous phase was extracted with EA (1000 mL x 2). The organic phases were collected washed with brine (1000 mL), dried with Na2SO4 (300 g) and concentrated at 45 °C for 0.5 h to give a dark solid liquid mixture (2.0 kg). The residue was 70311W001 triturated with MTBE (1000 mL) at 15 °C and stirred for 12 h. The suspension was filtered, the filter cake was washed with MTBE (500 mL). The filter cake was collected and dried in vacuo at 40 °C to give 5-bromo-7-fluoro-3-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (600 g, 1220 mmol, 90 % yield) as light pink solid. LCMS: Ms-H+ = 293, 295 , Rt 1.645 min, Method 1A.

[0488] Step 2

[0489] 2-amino-3-bromo-5-fluorobenzenesulfonamide

[0490] The mixture of 5-bromo-7-fluoro-3-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (300g, 813 mmol) in H2SO4 (3000 mL, 2.81x104mmol) was stirred at 110 °C oil bath for 14 h. After 14 h, LCMS showed the starting material was consumed completely and 74.4% product was detected. Duplicate reaction then combined for workup. The reaction was cooled down to 15 °C and poured into ice (7000 g) slowly at 10 °C-15 °C. Then adjusted pH to 8~9 with NaOH (5 kg) solid and earthy yellow solid was formed during adjust pH. Add EA (5000 mL) to the above mixture and the mixture was filtered and filtrate was clear (filtered cake is Na2SO4). The solution was extracted with EA (2000 mL x 2). Organic phase was collected and washed with brine (2000 mL), dried with Na2SO4 (200 g), and concentrated at 45 °C to give a brown solid. The crude product (250 g) was triturated with DCM (1 V, 250 mL) at 25 °C for 12 h and filtered. The filtrate was concentrated in vacuo at 40 °C to give the product 2-amino-3-bromo-5-fluorobenzenesulfonamide (170 g, 622 mmol, 76 % yield) as celadon solid. LCMS: Ms-H+ =267, Rt 2.21 min, Method 1A.

[0491] Step 3

[0492] N-(2-bromo-4-fluoro-6-sulfamoylphenyl)cyclopropanecarboxamide

[0493] 2-amino-3-bromo-5-fluorobenzenesulfonamide (35g, 130 mmol) was dissolved in 1 ,4- Dioxane (630 mL) to give a yellow solution at 15 °C under nitrogen. Cyclopropanecarbonyl chloride (17.00 g, 163 mmol)) was added dropwise to the reaction mixture. The reaction mixture was heated to 80 °C. After 12h, LCMS showed 36.2% product. Cyclopropanecarbonyl chloride (17.40 g, 166 mmol) was added dropwise to the reaction mixture at 80 °C. Then the reaction was stirred at 80 °C for 2 h. After 2 h, showed 68.6% product and 4.9% starting material. The reaction was concentrated at 55 °C directly and gave crude N-(2-bromo-4-fluoro-6- sulfamoylphenyl)cyclopropanecarboxamide (50 g, 93 mmol, 71.8 % yield) as yellow solid. The crude product was used next step without purification. LCMS (ES) m / z 336.8 [M+H]+, Rt=1.935 min, Method 1A.

[0494] Step 4

[0495] 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

[0496] N-(2-bromo-4-fluoro-6-sulfamoylphenyl)cyclopropanecarboxamide (50 g, 148 mmol) was added to sodium carbonate (157 g, 148 mmol) (5 M, 0.5 mL) at 20 °C. The reaction mixture was 70311W001 heated to 95-100 °C. After 12h, LCMS showed 79.8% product and 10.6% starting material. The reaction was cooled down to 15 °C and solid precipitated. The reaction mixture was adjusted pH to ~6 with HCI (6 M) at 10-15 °C. The mixture was filtered and filter cake was dried in vacuo at 45 °C to give crude product. The crude product was triturated with MTBE (3 V, 120 mL) at 25 °C for 12 h and filtered. The filtrate was concentrated and dried in vacuo at 40 °C to give the product 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (30 g, 94 mmol, 63.1 % yield) as light yellow solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 1.04 - 1.12 (m, 4H), 2.50 - 2.52 (m, 1 H), 7.73-7.75 (m, 1 H), 8.06-8.09 (m, 1 H), 11.24 (s, 1 H). LCMS: Ms+H+ = 318.8, 320.8 , Rt= 2.116 min, Method 1A.

[0497] Intermediate 3

[0498] 5-bromo-3-ethyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0499] To a solution of 2-amino-3-bromo-5-fluorobenzenesulfonamide (5.0 g, 1 Eq, 18.58 mmol) in DMF (45 mL) was added propionaldehyde (3.777 g, 4.69 mL, 3.5 Eq, 65.03 mmol), and Hydrogen sulfite sodium (2.90 g, 1.96 mL, 1.5 Eq, 27.87 mmol), and the reaction mixture was stirred at 120 °C for 3h. The reaction mixture was cooled with an ice-bath, quenched with water (150 mL), and the precipitate was collected by filtration and dried under vacuum to give 5-bromo- 3-ethyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (3.5 g, 60% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.29 - 1.42 (m, 3H), 2.78 - 2.90 (m, 2H), 7.64 - 7.77 (m, 1 H), 7.83 - 8.00 (m, 1 H). LC-MS (ES) m / z = 309.1 [M+H]+, rt 0.50 min, Method 1.

[0500] Intermediate 4

[0501] 3-cyclopropyl-7-fluoro-5-iodo-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0502] Step 1 70311W001

[0503] 7-fluoro-3-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0504] To a stirred solution of sulfurisocyanatidic chloride (83 g, 585 mmol) in nitromethane (400 mL) was added a solution of 4-fluoroaniline (50 g, 450 mmol) in nitromethane (100 mL) at -20°C. The reaction mixture was warmed to 0 °C and stirred for 10 min. TLC (heptane / EA=3 / 1 , Rf- SM=0.5) showed the starting material was consumed completely. Then was added aluminum chloride (120 g, 900 mmol) at 0~5 °C. The reaction mixture temperature was heated to 75 °C and stirred for 12h. After 12 h, LCMS showed the product. The reaction mixture was cooled to 15 °C and poured into ice cold water (500 mL). To the mixture was added EA (200 mL), and stirred at 15 °C for 10 min. The organic phase was separated and the aqueous phase was extracted with EA (100 mL x 2). The organic phases were collected, washed with brine (100 mL), dried with Na2SC>4 (100 g) and concentrated at 45 °C for 0.5 h to give a dark solid liquid mixture (100 g). The crude product (70 g) was triturated with MTBE (3 V, 210 mL) at 25 °C for 12 h and filtered. The filter cake was dried in vacuo at 40 °C to give 7-fluoro-3-hydroxy-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (50 g, 215 mmol, 47.8 % yield) as a gray solid. LC-MS (ES) m / z = 217 [M+HJ+, rt 1.227 min, Method 1 B.

[0505] Step 2

[0506] 2-amino-5-fluorobenzenesulfonamide (80 g, 421 mmol)

[0507] The mixture of 7-fluoro-3-hydroxy-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (290 g, 1140 mmol) in H2SO4 (2900 mL, 2.72x104mmol) was stirred at 95-100 °C for 8 h. After 8 h, LCMS showed the starting material was consumed completely. The reaction was cooled down to 15 °C and poured into ice (3000 g) and EA (2000 mL) slowly at 10 °C-15 °C. The pH was adjusted to 8~9 with NaOH (3500 g) solid . Added EA (4000 mL) to the above mixture and the mixture was filtered to afford a clear filtrate. The solution was extracted with EA (2000 mL x 2). Organic phases were collected and washed with brine (1000 mL), dried with Na2SO4 (500 g), and concentrated at 45 °C to give a black solid. The crude product (300 g) was triturated with DCM (2 V, 600 mL) at 25 °C for 12 h and filtered. The filtrate was concentrated in vacuo at 40 °C to give 2-amino-5- fluorobenzenesulfonamide as a gray solid (187 g, 974 mmol, 85 % yield). LC-MS (ES) m / z = 189 [M-H]+, rt 1.728 min, Method 1 B.

[0508] Step 3

[0509] 2-amino-5-fluoro-3-iodobenzenesulfonamide

[0510] To a solution of 2-amino-5-fluorobenzenesulfonamide (80 g, 421 mmol) in N,N- Dimethylformamide (DMF) (800 mL) was dropwise added a solution of iodine monochloride (63.2 mL, 1262 mmol) in Acetic Acid (400 mL) at 20-25 °C. The reaction solution was stirred for 2 h at 22 °C. After 12 h, LCMS showed 76.3% product, 3.2% starting remained. Water (2000 mL) and EA (2000 mL) was added. The mixture was adjusted pH to 6-7 with a solution of NaOH (5 M) and 70311W001 extracted with EtOAc (3X 1000 mL). The combined organic layers was washed with aqueous Na2S2C>3 (1000 mL), sat. LiCI (1000 mL) and brine (1000 mL), dried over Na2SO4, filtered and then concentrated at 45 °C to give a crude product. The crude product (150 g) was triturated with DCM (2 V, 300 mL) at 25 °C for 0.5 h and filtered. The filtrate was concentrated in vacuo at 40 °C to give the product 2-amino-5-fluoro-3-iodobenzenesulfonamide (96 g, 300 mmol, 71.3 % yield) as a light purple solid. LC-MS (ES) m / z = 315 [M-H]+, rt 2.335 min, Method 1A.

[0511] Step 4

[0512] N-(4-fluoro-2-iodo-6-sulfamoylphenyl)cyclopropanecarboxamide

[0513] 2-amino-5-fluoro-3-iodobenzenesulfonamide (96g, 304 mmol) was dissolved in 1 ,4- Dioxane (1728mL) to give a yellow solution at 15 °C under nitrogen. Cyclopropanecarbonyl chloride (47.6 g, 456 mmol)) was added dropwise to the reaction mixture. The reaction mixture was heated to 75 °C. After 12 h, LCMS showed the 87.1 % product was detected. The reaction was cooled to 40 °C and concentrated at 45 °C to give a brown solid (116 g, 75% yield). LCMS (ES) m / z = 384.8 [M-HJ+, Rt 1.999 min, Method 1A.

[0514] Step 5

[0515] 3-cyclopropyl-7-fluoro-5-iodo-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0516] N-(4-fluoro-2-iodo-6-sulfamoylphenyl)cyclopropanecarboxamide (116g, 302 mmol) was added to sodium carbonate, 10% wt aqueous solution (1728 mL, 1798 mmol) at 20 °C. The reaction mixture was heated to 65 °C. After 2 h, LCMS showed 83.1 % product. The reaction was cooled to 20 °C. The reaction was extracted with MTBE (1500 mL) and aqueous phase was adjusted to pH 5~6 with 6 M HCI at 20 °C. The mixture was filtered and filter cake was washed with MTBE (50 mL). The filter cake was dissolved in DCM (500 mL), dried with Na2SO4 (20 g) and dried in vacuo to give product. The organic phase was adjusted to pH 5~6 with 6 M HCI at 20 °C and filtered and filter cake was washed with MTBE (200 mL). Solid of the two batches was combined and dried in vacuo at 40 °C to afford the desired product 3-cyclopropyl-7-fluoro-5-iodo- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as an off-white solid (75 g, 67% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.05 - 1.13 (m, 4H), 2.47 - 2.50 (m, 1 H), 7.71-7.74 (m, 1 H), 8.18-8.21 (m, 1 H), 10.73 (s, 1 H). LCMS (ES) m / z = 366.8 [M-H]+, Rt 2.254 min, Method 1A.

[0517] Intermediate 5

[0518] 1-ethyl-5-(trifluoromethyl)piperazin-2-one 70311W001

[0519] To a solution of 5-(trifluoromethyl)piperazin-2-one, 2Hydrochloride (300.00 mg, 1 Eq, 1.2446 mmol) in DMF (8 mL) was added sodium hydride (124.5 mg, 60% Wt, 2.5 Eq, 3.1115 mmol) at 0 °C, and the mixture was stirred for 30 min. lodoethane (232.95 mg, 120.7 pL, 1.2 Eq, 1.4935 mmol) was added, and the solution was stirred for 18h. The reaction mixture was quenched with saturated NH4CI aqueous solution, extracted with EtOAc (3x). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ISCO, 12 mg prepacked silica gel column, 0 to 100% EtOAc / heptane) to give 1-ethyl-5- (trifluoromethyl)piperazin-2-one as a pale brown solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.12 - 1.19 (m, 3 H) 3.36 - 3.62 (m, 6 H) 3.73 - 3.89 (m, 1 H). LC-MS (ES) m / z = 197.0 [M+H]+, rt 0.34 min, Method 1 .

[0520] Intermediate 6 rac-2-((3R,5R)-5-(trifluoromethyl)pyrrolidin-3-yl)propan-2-ol

[0521] Step 1 rac-methyl (3R,5R)-1-benzyl-5-(trifluoromethyl)pyrrolidine-3-carboxylate

[0522] Benzyl bromide (1.0982 g, 763.7 pL, 1.5 Eq, 6.4207 mmol) was added to a solution of methyl cis-5-(trifluoromethyl)pyrrolidine-3-carboxylate hydrochloride (1.0 g, 1 Eq, 4.2805 mmol) and Et3N (1.2994 g, 1.79 mL, 3 Eq, 12.841 mmol) in DCM (15.0 mL). The mixture was stirred for 4 h. LCMS was then taken, and no desired products were observed (ELSD and MS). The reaction was stirred overnight, and LCMS was then taken and observed as before. The reaction was partly concentrated then re-dissolved in MeCN (15 mL) and potassium carbonate (1.1831 g, 2 Eq, 8.5609 mmol) was added and heated at 40 °C for a total of 8 h. The reaction was then concentrated, diluted with DCM, and then loaded onto a Redisep pre-column and purified on a 80g Redisep Gold column (0-30% EtOAc / heptane) to afford rac-methyl (3R,5R)-1-benzyl-5- (trifluoromethyl)pyrrolidine-3-carboxylate as a clear oil (725 mg, 58% yield).1H NMR (400 MHz, DMSO-d6) 5 7.38 - 7.23 (m, 5H), 3.98 (d, J = 14.2 Hz, 1 H), 3.66 (d, J = 13.7 Hz, 1 H), 3.64 - 3.55 (m, 4H), 3.18 - 3.06 (m, 2H), 2.73 - 2.67 (m, 1 H), 2.44 (dt, J = 13.5, 9.2 Hz, 1 H), 2.20 - 2.12 (m, 1 H). LCMS (ES) = 288.1 [M+H]+, rt 1.11 min, Method 3.

[0523] Step 2 rac-2-((3R,5R)-1-benzyl-5-(trifluoromethyl)pyrrolidin-3-yl)propan-2-ol 70311W001

[0524] To rac-methyl (3R,5R)-1-benzyl-5-(trifluoromethyl)pyrrolidine-3-carboxylate (700.00 mg, 1 Eq, 2.4366 mmol) in THF (12.0 mL) was cooled in an ice bath then added by dropwise was added methylmagnesium bromide (1.1622 g, 3.2489 mL, 3.0 molar, 4. Eq, 9.7466 mmol). The reaction was then stirred in the ice bath for 0.5 h, removed from the ice bath, and stirred for 2 h. LCMS observed only desired product. The reaction was then quenched with sat. NH4CI solution (4mL), diluted with water (20mL) and then extracted with EtOAc (3X 20mL). The organic extracts were then combined and washed with brine, dried over MgSCL, then filtered and concentrated to afford the desired product (725 mg, quantitative yield). Used without further purification.1H NMR (400 MHz, DMSO-d6) 5 7.36 - 7.29 (m, 4H), 7.27 - 7.21 (m, 1 H), 4.25 (s, 1 H), 3.93 (d, J = 14.0 Hz, 1 H), 3.64 (d, J = 14.0 Hz, 1 H), 3.60- 3.51 (m, 1 H), 2.83 (t, J = 10.0 Hz, 1 H), 2.47 (s, 1 H), 2.24 - 2.12 (m, 1 H), 2.06 (dt, J = 12.5, 7.5 Hz, 1 H), 1.82 - 1.72 (m, 1 H), 1.03 (d, J = 12.0 Hz, 6H). ). LCMS (ES) = 288.1 [M+H]+, rt 0.63 min, Method 3.

[0525] Step 3 rac-2-((3R,5R)-5-(trifluoromethyl)pyrrolidin-3-yl)propan-2-ol

[0526] To rac-2-((3R,5R)-1-benzyl-5-(trifluoromethyl)pyrrolidin-3-yl)propan-2-ol (100.00 mg, 1 Eq, 348.03 pmol) in EtOH (5.0 mL) was added Pd / C (37.038 mg, 10% Wt, 0.1 Eq, 34.803 pmol). To the mixture was then attached a balloon of H2 gas, then degassed under vacuum and recharged with H2 three times. The mixture was then stirred vigorously for 2h. LCMS observed about 10% starting material remaining. The reaction was then stirred for an additional 1h and observed no SM. The reaction was then filtered, and the filtrate was then concentrated to afford the desired product (65 mg, 93% yield). Used without further purification.1H NMR (400 MHz, DMSO-d6) 5 4.24 (s, 1 H), 3.79 - 3.66 (m, 1 H), 2.91 - 2.81 (m, 1 H), 2.58 - 2.52 (m, 1 H), 2.03 - 1.87 (m, 2H), 1.71 - 1.56 (m, 1 H), 1.10 - 0.92 (m, 7H). LCMS (ES) = 198.2 [M+H]+, rt 0.26 min, Method 3.

[0527] Intermediate 7

[0528] 4-methyl-2-(trifluoromethyl)piperidin-4-ol

[0529] HCI

[0530] Step 1 tert-butyl 4-hydroxy-4-methyl-2-(trifluoromethyl)piperidine-1 -carboxylate

[0531] A 100 mL RB flask was charged with tert-butyl 4-oxo-2-(trifluoromethyl)piperidine-1- carboxylate (1.8740 g, 1 Eq, 7.0122 mmol) and THF (20.0 mL, 65 °C). A rubber septum with a 70311W001 nitrogen inlet needle was attached and the stirred homogeneous solution was stirred at room temperature. A solution of methylmagnesium bromide (919.74 mg, 2.5711 mL, 3.0 molar, 1.1 Eq, 7.7134 mmol) in diethyl ether was added dropwise via syringe. A slight warming was observed during addition. After addition was complete, the reaction was stirred for 3 h. The resulting homogeneous mixture was quenched via addition of saturated ammonium chloride (10 mL) and diluted with EtOAc (25 mL). The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 X 20 mL). The combined EtOAc layers were washed with water, dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give a pale yellow liquid, 1.71 grams. NMR indicated about 2:1 mixture of ketone:alcohol. TLC (1 :1 EtOAc: heptane, KMnO4 staining) indicated the presence of starting ketone. MDAP Purification High pH Method C afforded the desired product as a waxy white crystalline solid (482.6 mgs, 24% yield).1H NMR (400 MHz, DMSO-d6) 5 4.78 - 4.65 (m, 1 H), 4.38 (s, 1 H), 3.86 (br d, J = 10.8 Hz, 1 H), 3.17 (br s, 1 H), 1.91 - 1.82 (m, 1 H), 1.71 (dd, J = 14.7, 8.3 Hz, 1 H), 1.58 - 1.48 (m, 1 H), 1.47 - 1.34 (m, 10H), 1.12 (s, 3H). LCMS (ES) = 228 [M- 56+H]+, rt 0.90 min, Method 3.

[0532] Step 2

[0533] 4-methyl-2-(trifluoromethyl)piperidin-4-ol

[0534] A 100 mL RB flask was charged with tert-butyl 4-hydroxy-4-methyl-2- (trifluoromethyl)piperidine-l -carboxylate (457.9 mg, 1 Eq, 1.616 mmol). 1 ,4-dioxane was added (2 mL) and the suspension was warmed slightly to fully dissolve substrate. The solution was cooled to 5 °C and HOI (589.3 mg, 4.041 mL, 4.0 molar, 10 Eq, 16.16 mmol) was added via syringe. The homogeneous solution was stirred for 30 minutes at room temperature after which there was no remaining starting material. The dioxane was removed in vacuo and the resulting solid was pumped under high vacuum to give a white solid (370.7 mgs). NMR in MeOH-d4 indicated ca. 7:1 desired productstarting material. The mixture was suspended in 4 mL of 4M HCI in 1 ,4-dioxane and stirred for 3 h at room temperature. The reaction was concentrated in vacuo and pumped under high vacuum to give 4-methyl-2-(trifluoromethyl)piperidin-4-ol, Hydrochloride as a white solid (353.1 mgs, 99% yield).1H NMR (400 MHz, METHANOL-d4) 5 4.40 - 4.26 (m, 1 H), 3.59 - 3.49 (m, 1 H), 3.23 (td, J = 13.4, 3.8 Hz, 1 H), 2.17 - 2.08 (m, 1 H), 2.01 - 1.79 (m, 3H), 1.42 (s, 3H). LCMS (ES) = 184.4 [M+HJ+, rt 0.12 min, Method 3.

[0535] A 100 mL RB flask was charged with 4-methyl-2-(trifluoromethyl)piperidin-4-ol, Hydrochloride (344.80 mg, 1 Eq, 1.5699 mmol). The solid was dissolved in 3 mL of water and saturated aqueous NaHCCh was added dropwise until the pH of the solution was 8. Bubbling was observed upon addition. The slightly basic aqueous solution was concentrated in vacuo and redissolved in 3 mL of warm water. The aqueous solution was extracted with 3 x 15 mL of 10% isopropanokchloroform. The combined organics were washed with 1 mL of saturated NaCI 70311W001 solution, dried over sodium sulfate, filtered, concentrated in vacuo and pumped under high vacuum to give 4-methyl-2-(trifluoromethyl)piperidin-4-ol as a white crystalline solid (230.2 mgs, 72% yield).1H NMR (400 MHz, METHANOL-d4) 5 3.19 - 3.11 (m, 1 H), 2.98 - 2.89 (m, 1 H), 2.64 - 2.53 (m, 1 H), 1.70 (dt, J = 12.4, 2.3 Hz, 1 H), 1.56 - 1.47 (m, 2H), 1.45 - 1.36 (m, 1 H), 1.17 (s, 3H). LCMS (ES) = 184.0 [M+HJ+, rt 0.50 min, Method 1.

[0536] Intermediate 8 and 9 tert-butyl (2S,5S)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 1) tert-butyl (2S,5R)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 2)

[0537] HCO2H tBuOH oc oc

[0538] Isomer 1 Isomer 2

[0539] Step 1 methyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3,3,3-trifluoropropanoate

[0540] To a solution of methyl 2-amino-3,3,3-trifluoropropanoate, Hydrochloride (1500.00 mg, 1 Eq, 7.7499 mmol) in DMF (40.0 mL) were added (tert-butoxycarbonyl)-L-alanine (1.4664 g, 1 Eq, 7.7499 mmol), HATU (4.4203 g, 1.5 Eq, 11.625 mmol), and DIEA (3.0050 g, 4.05 mL, 3 Eq, 23.250 mmol) at 0 °C, and the reaction mixture was stirred at rt for 18h. The reaction mixture was quenched with saturated NH4CI aqueous solution (50 mL) and extracted with EtOAc (3x). The extract was dried (Na3SO4) and concentrated. The residue was purified using column chromatography (ISCO, 40g prepacked silica gel column, 0 to 80% EtOAc / heptane) to give methyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3,3,3-trifluoropropanoate as an off white solid (2.21 g, 83% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.11 - 1.23 (m, 3 H) 1.29 - 1.45 (m, 9 H) 3.29 - 3.35 (m, 1 H) 3.69 - 3.81 (m, 3 H) 4.01 - 4.19 (m, 1 H) 5.30 - 5.51 (m, 1 H). LC-MS (ES) m / z = 329.0 [M+H]+, rt 0.85 min, Method 1.

[0541] Step 2

[0542] (3S)-3-methyl-6-(trifluoromethyl)piperazine-2, 5-dione

[0543] A solution of methyl 2-((S)-2-((tert-butoxycarbonyl)amino)propanamido)-3,3,3- trifluoropropanoate (800 mg, 1 Eq, 2.4369 mmol) in formic acid (9.760 g, 8.0 mL, 87.01 Eq, 212.0 70311W001 mmol) was stirred at rt for 18h. The reaction mixture was concentrated and dried under vacuum. The residue was then dissolved in toluene (5.0 mL) and 2-Butanol (6.0 mL), and the reaction mixture was stirred at reflux for 24h. The residue was dried under vacuum. The solid was treated with diethyl ether and collected by filtration and dried to give (3S)-3-methyl-6- (trifluoromethyl)piperazine-2, 5-dione as a white solid (330 mg, 66% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.23 - 1.35 (m, 3 H) 3.87 - 4.00 (m, 1 H) 4.67 - 4.83 (m, 1 H) 8.69 - 8.79 (m, 1 H) 8.85 - 8.98 (m, 1 H). LC-MS (ES) m / z = 169.1 [M+HJ+, rt 0.13 min, Method 1.

[0544] Step 3

[0545] (2S)-2-methyl-5-(trifluoromethyl)piperazine, 2 Hydrochloride

[0546] To a solution of (3S)-3-methyl-6-(trifluoromethyl)piperazine-2, 5-dione (380.00 mg, 1 Eq, 1.9375 mmol) in THF (7.0 mL) was added borane tetra hydrofuran complex (999.0 mg, 11.625 mL, 1 .0 molar, 6 Eq, 11.625 mmol), and the solution was stirred at rt for 1 h, and 3h at reflux. The mixture was cooled with ice-bath, and treated with 4.3 mL of 1 N HCI aqueous solution over 5 min and concentrated. The residue was dissolved in MeOH (5 mL) and treated with 0.8 mL of 3N HCI in TBME. The mixture was heated at 60 °C for 1 h, and cooled to rt and concentrated. The residue was washed with diethyl ether and dried under vacuum to give (2S)-2-methyl-5- (trifluoromethyl)piperazine, 2 Hydrochloride as a white solid (430 mg, 87% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.47 - 1.54 (m, 3 H) 3.47 - 3.63 (m, 2 H) 3.75 - 4.08 (m, 2 H) 4.43 - 4.83 (m, 1 H). LC-MS (ES) m / z = 169.1 [M+HJ+, rt 0.44, 0.47 min, Method 1.

[0547] Step 4 tert-butyl (2S,5S)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 1) tert-butyl (2S,5R)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 2)

[0548] To a solution of (2S)-2-methyl-5-(trifluoromethyl)piperazine, 2 Hydrochloride (950.00 mg, 1 Eq, 3.9406 mmol) in water (14.0 mL) and THF (7.0 mL) was added potassium carbonate (1 .6338 g, 3 Eq, 11.822 mmol) and Boc-anhydride (1.2041 g, 1.27 mL, 1.4 Eq, 5.5168 mmol), and the solution was stirred for 24h. The reaction mixture was concentrated and the residue was treated with DCM:MeOH (1 :1) mixture (20 mL), stirred for 5 min, and concentrated. The residue was purified using column chromatography (ISCO, 24g prepacked silica gel column, 0 to 60% EtOAc / heptane) to give tert-butyl (2S,5S)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 1) (165 mg, 15% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.22 - 1.28 (m, 3 H) 1.49 - 1.53 (m, 9 H) 2.80 - 3.05 (m, 3 H) 3.27 - 3.33 (m, 1 H) 3.97 - 4.10 (m, 1 H) 4.14 - 4.28 (m, 1 H). LC-MS (ES) m / z = 169.1 [M-Boc+H]+, rt 0.98 min, Method 1. tert-butyl (2S,5R)-2-methyl-5-(trifluoromethyl)piperazine-1 -carboxylate (Isomer 2) as a colorless oil (81 mg, 7% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.20 - 1.26 (m, 3 H) 70311W001

[0549] 1.42 - 1.48 (m, 9 H) 2.57 - 2.68 (m, 1 H) 3.06 - 3.19 (m, 1 H) 3.33 - 3.44 (m, 2 H) 4.04 - 4.19 (m, 2 H). LC-MS (ES) m / z = 169.2 [M-Boc+H]+, rt 0.96 min, Method 1.

[0550] Intermediate 10

[0551] (5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholine

[0552] KOtBu LiAIH4iPrOH / DCM THF

[0553] Step 2 Step 3

[0554] Step 1

[0555] 2-chloro-N-((S)-4,4,4-trifluoro-1-hydroxybutan-2-yl)propanamide

[0556] An aqueous solution of potassium carbonate (5.7941 g, 3 Eq, 41.926 mmol) in water (12.0 mL) was added to a solution of (S)-2-amino-4,4,4-trifluorobutan-1-ol (2.0 g, 1 Eq, 13.975 mmol) in THF (20.0 mL) at -10 °C. 2-Chloropropanoyl chloride (1.9517 g, 1.492 mL, 1.1 Eq, 15.373 mmol) was then added dropwise to the stirring solution of above. The mixture was stirred at -10 °C for 1 h. 28 mL of water was added, and most of THF was removed by evaporation. Aqueous was extracted with DCM (3X). The combined extracts were washed with brine, dried over Na2SO4, filtered, concentrated, and dried in vacuo to afford 2-chloro-N-((S)-4,4,4-trifluoro-1-hydroxybutan- 2-yl)propanamide (2.6600 g, 11.386 mmol, 81.473 %) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 6.95 (br s, 1 H) 4.45 (q, J=6.85 Hz, 1 H) 4.21 - 4.36 (m, 1 H) 3.76 - 3.87 (m, 2 H) 2.46 - 2.62 (m, 2 H) 1.76 (dd, J=6.85, 1.47 Hz, 3 H). LC-MS (ES) m / z = 234.0 [M+H]+, rt 0.50 min, Method 1 .

[0557] Step 2

[0558] (5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholin-3-one

[0559] A solution of potassium tert-butoxide (5.1105 g, 4 Eq, 45.544 mmol) in 2-propanol (65.0 mL) was added dropwise to a solution of 2-chloro-N-((S)-4,4,4-trifluoro-1-hydroxybutan-2- yl)propanamide (2.6600 g, 1 Eq, 11.386 mmol) in DCM (65.0 mL) at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h at RT. It was then neutralized by addition of 2M HCI. Solvent was removed under reduced pressure to give a white solid. The solid was taken up in EtOAc (100 mL) and the solution was washed with H2O (2X) and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and dried in vacuo to afford (5S)-2-methyl-5-(2,2,2- trifluoroethyl)morpholin-3-one (1.6900 g, 8.5717 mmol, 75.283 %) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 6.23 (br s, 1 H) 4.25 (q, J=7.00 Hz, 1 H) 3.85 - 3.95 (m, 2 H) 3.80 70311W001

[0560] (br s, 1 H) 2.47 - 2.63 (m, 2 H) 1 .50 (d, J=7.00 Hz, 3 H). LC-MS (ES) m / z = 198.0 [M+H]+, rt 0.46 min, Method 1.

[0561] Step 3

[0562] (5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholine

[0563] A solution of (5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholin-3-one (1.6900 g, 1 Eq, 8.5717 mmol) in THF (20.0 mL) was added dropwise to a solution of LAH (975.9 mg, 3 Eq, 25.715 mmol) in THF (60.0 mL) at 0 °C. The reaction mixture was allowed to warm up to RT and stirred overnight (18 h). The reaction mixture was cooled to 0 °C and the reaction was carefully quenched by successive addition of H2O (2.2 mL), 2M aq NaOH (4.4 mL), and H2O (6.6 mL). The resulting slurry was stirred at RT for 1 h then filtered through celite. The filter cake was washed with EtOAc (3x100 mL). The filtrate was dried over Na2SO4, filtered, concentrated, dried in vacuo to afford (5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholine (0.70 g, 3.822 mmol, 44.58 %) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 3.79 - 3.85 (m, 1 H) 3.71 - 3.76 (m, 1 H) 3.61 - 3.71 (m, 1 H) 3.21 (td, J=5.26, 2.69 Hz, 1 H) 2.72 (s, 1 H) 2.66 - 2.77 (m, 1 H) 2.22 - 2.49 (m, 2 H) 1.19 (d, J=5.87 Hz, 3 H). LC-MS (ES) m / z = 184.1 [M+HJ+, rt 0.51 min, Method 1.

[0564] Intermediate 11

[0565] N-(4-methyl-2-(trifluoromethyl)piperidin-4-yl)acetamide

[0566] Step 1 benzyl 4-hydroxy-4-methyl-2-(trifluoromethyl)piperidine-1 -carboxylate

[0567] To a RB flask charged with Lanthanum(lll) chloride bis(lithium chloride) complex solution in THF (8.2982 mL, 0.6 molar, 1 .5 Eq, 4.9789 mmol) under nitrogen was added methylmagnesium bromide in diethyl ether (593.69 mg, 1.6596 mL, 3.0 molar, 1.5 Eq, 4.9789 mmol) dropwise at 0 °C, and the reaction mixture was stirred at rt for 3 h. A solution of benzyl 4-oxo-2- (trifluoromethyl)piperidine-l-carboxylate (1000 mg, 1 Eq, 3.3193 mmol) in THF (3.0 mL) was added into the mixture at 0 °C. The reaction was stirred for 18 h, then quenched with saturated NH4CI aqueous solution. The mixture was extracted with ethyl acetate, the extract was dried over anhydrous Na2SO4, and concentrated. The residue was purified using column chromatography (ISCO, 24g prepacked silica gel, 0 to 70% EtOAc / heptane) to give benzyl 4-hydroxy-4-methyl-2- (trifluoromethyl)piperidine-l -carboxylate as a colorless oil (750 mg, 68% yield).1H NMR (400 70311W001

[0568] MHz, METHAN0L-d4) 6 ppm 1.23 (s, 3 H) 1.49 - 1.72 (m, 2 H) 1.75 - 1.91 (m, 1 H) 1.97 - 2.15 (m, 1 H) 3.35 - 3.52 (m, 1 H) 3.97 - 4.16 (m, 1 H) 4.76 - 4.87 (m, 1 H) 5.08 - 5.29 (m, 2 H) 7.25 - 7.50 (m, 5 H). LC-MS (ES) m / z = 318.2 [M+HJ+, rt 0.97 min, Method 1 .

[0569] Step 2 benzyl 4-acetamido-4-methyl-2-(trifluoromethyl)piperidine-1 -carboxylate

[0570] To a solution of benzyl 4-hydroxy-4-methyl-2-(trifluoromethyl)piperidine-1 -carboxylate (300.00 mg, 1 Eq, 945.45 pmol) in acetonitrile (8 mL) was added sulfuric acid (278.2 mg, 151.2 pL, 3 Eq, 2.8363 mmol) at 0 °C, and the mixture was then stirred at rt for 4h. The mixture was cooled to 0 °C, basified with dropwise addition of saturated NaHCCh aqueous solution, and extracted with EtOAc (3x). The extract was dried (Na2SC>4) and concentrated. The residue was purified using column chromatography (ISCO, 40 g prepacked silica gel column, 0 to 80% EtOAc / heptane) to give benzyl 4-acetamido-4-methyl-2-(trifluoromethyl)piperidine-1 -carboxylate as a colorless oil (170 mg, 48% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.33 - 1.43 (m, 3 H) 1.51 - 1.64 (m, 1 H) 1.70 - 1.85 (m, 4 H) 2.11 - 2.26 (m, 1 H) 2.75 - 2.87 (m, 1 H) 3.10 - 3.26 (m, 1 H) 3.99 - 4.13 (m, 1 H) 4.55 - 4.75 (m, 1 H) 5.09 - 5.25 (m, 2 H) 7.28 - 7.40 (m, 5 H). LC- MS (ES) m / z = 359.2 [M+HJ+, rt 1.0 min, Method 1.

[0571] Step 3

[0572] N-(4-methyl-2-(trifluoromethyl)piperidin-4-yl)acetamide

[0573] To a RB flask charged with benzyl 4-acetamido-4-methyl-2-(trifluoromethyl)piperidine-1- carboxylate (170.00 mg, 1 Eq, 474.38 pmol) and 10% palladium on carbon (50.484 mg, 1 Eq, 474.38 pmol) was added methanol (3.0 mL) under N2. The mixture was degassed by bubbling N2 and then H2 and stirred for 18h under a H2 atmosphere (balloon). The mixture was filtered through celite and concentrated. The residue was purified using column chromatography (ISCO, 0 to 100% 3:1 EtOAc: EtOH / DCM) to give N-(4-methyl-2-(trifluoromethyl)piperidin-4-yl)acetamideas a white solid (105 mg, 97% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.23 - 1.34 (m, 1 H) 1.34 - 1 .47 (m, 4 H) 1 .93 - 2.01 (m, 3 H) 2.09 - 2.22 (m, 1 H) 2.60 - 2.72 (m, 1 H) 2.77 - 3.03 (m, 2 H) 3.25 - 3.42 (m, 1 H). LC-MS (ES) m / z = 225.2 [M+HJ+, rt 0.43 min, Method 1. 70311W001

[0574] Example 1

[0575] 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide, 2:1 mixture of diastereomers

[0576] Step 1

[0577] 1 -benzyl 2-methyl (2S,4R)-4-(tosyloxy)pyrrolidine-1 ,2-dicarboxylate

[0578] To a solution of 1 -benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate (24.0 g, 1 Eq, 85.932 mmol) in dichloromethane (200.00 mL) at 23 °C was added triethylamine (11.304 g, 15.6 mL, 1.3 Eq, 111.71 mmol), Ts-CI (19.659 g, 1.2 Eq, 103.12 mmol) followed by DMAP (1.0498 g, 0.1 Eq, 8.5932 mmol). The resulting mixture was allowed to stir for 12h. Upon completion, sat. aq. NH4CI (100mL) was added to the reaction and the resulting mixture was allowed to stir for 5 min. The layers were separated and the aq layer was extracted with DCM (2x50mL). The organic extracts were combined, dried over MgSCL, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column (0-100% EtOAc / Hep, 300g column) to give the desired product 1 -benzyl 2-methyl (2S,4R)-4-(tosyloxy)pyrrolidine-1 ,2- dicarboxylate (33.500 g, 77.282 mmol, 89.933%) as a light brown viscous oil.1H NMR (400 MHz, METHANOL-d4) 5 7.81 (t, J = 8.0 Hz, 2H), 7.45 (dd, J = 13.8, 8.3 Hz, 2H), 7.41 - 7.27 (m, 5H), 5.22 - 4.96 (m, 3H), 4.43 (td, J = 8.3, 5.0 Hz, 1 H), 3.76 - 3.53 (m, 5H), 2.55 - 2.42 (m, 4H), 2.25 - 2.12 (m, 1 H) (Contains rotamers). LCMS (ES) = 434.1 [M+H]+, rt 1.14 min, Method 2.

[0579] Step 2a

[0580] Benzyl (2S,4R)-2-(hydroxymethyl)-4-(tosyloxy)pyrrolidine-1 -carboxylate

[0581] To a solution of 1-benzyl 2-methyl (2S,4R)-4-(tosyloxy)pyrrolidine-1 ,2-dicarboxylate (5.500 g, 1 Eq, 12.688 mmol) in tetrahydrofuran (150.0 mL) at 0 °C was added 2M lithium borohydride in THF (608.0 mg, 13.957 mL, 2.0 molar, 2.2 Eq, 27.914 mmol). The resulting mixture 70311W001 was allowed to warm to 23 °C and stirred for 4h. Upon completion, the reaction was cooled to 0 °C. Ice was added followed by water (50mL). The pH was adjusted to ~4 using 1 N HCI (~ 28mL 1 N HCI) (Caution: addition of HCI to the reaction can have a large exotherm if not added slowly at low temp.). EtOAc (50mL) was added and the resulting mixture was stirred for 5 min. The layers were separated and the aq. layer was extracted with EtOAc (2x20mL). The EtOAc extracts were combined, dried over MgSO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column (0-100% EtOAc / Hep, 120g column) to give the desired product benzyl (2S,4R)-2-(hydroxymethyl)-4-(tosyloxy)pyrrolidine-1-carboxylate (4.80 g, 11.838 mmol, 93.302 %) as a viscous colorless oil.1H NMR (400 MHz, METHANOL-d4) 5 7.85 - 7.74 (m, 2H), 7.47 - 7.30 (m, 7H), 5.19 - 5.06 (m, 3H), 4.05 - 3.98 (m, 1 H), 3.84 (dd, J = 11.5, 4.0 Hz, 1 H), 3.77 - 3.66 (m, 1 H), 3.55 - 3.43 (m, 2H), 2.49 - 2.41 (m, 3H), 2.25 - 2.16 (m, 2H). LCMS (ES) = 406.2 [M+H]+, rt 1.03 min, Method 2.

[0582] Step 2b

[0583] Benzyl (2S,4R)-2-formyl-4-(tosyloxy)pyrrolidine-1 -carboxylate

[0584] To a solution of oxalyl chloride (2.2537 g, 1.554 mL, 1.5 Eq, 17.757 mmol) in dichloromethane (200.0 mL) at -78 °C was added DMSO (2.867 g, 2.604 mL, 3.1 Eq, 36.698 mmol). The mixture was allowed to stir for 15 min before adding a DCM (50mL) solution of benzyl (2S,4R)-2-(hydroxymethyl)-4-(tosyloxy)pyrrolidine-1-carboxylate (4.80 g, 1 Eq, 11.838 mmol). The mixture was stirred at -78 °C for 15 min. Triethylamine (5.3905 g, 7.42 mL, 4.5 Eq, 53.272 mmol) was added and the mixture was allowed to stir for 5 min before being transferred to an ice bath. The reaction was stirred for 1 h. Sat. aq. NH4CI (20mL) was added and the mixture was allowed to stir for 15 min. The layers were separated and the aq. layer was extracted with DCM (2x30mL). The extracts were combined and dried over MgSCL, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column (0-100% EtOAc / Hep, 80g column, 33 mins) to give the desired product as the aldehyde hydrate.1H NMR (400 MHz, METHANOL-d4) 5 7.85 - 7.74 (m, 2H), 7.50 - 7.30 (m, 7H), 5.30 - 5.01 (m, 4H), 4.09 - 3.95 (m, 1 H), 3.80 - 3.57 (m, 1 H), 3.53 - 3.39 (m, 1 H), 2.51 - 2.41 (m, 3H), 2.40 - 2.17 (m, 1 H), 2.14 - 1.94 (m, 1 H). LCMS (ES) = 404.2 [M+H]+, rt 1.07 min, Method 2.

[0585] Step 3

[0586] Benzyl (2S,4R)-2-formyl-4-(tosyloxy)pyrrolidine-1 -carboxylate

[0587] To a solution of benzyl (2S,4R)-2-formyl-4-(tosyloxy)pyrrolidine-1 -carboxylate (4.10 g, 1 Eq, 10.162 mmol) in tetrahydrofuran (50.0 mL) at 0 °C was added t-butylsulfinamide, racemic (1.8475 g, 1.5 Eq, 15.244 mmol) followed by titanium ethoxide (4.6363 g, 4.230 mL, 2 Eq, 20.325 mmol). After 15 min, the reaction was removed from the ice bath and allowed to stir for 24h. The reaction mixture was then cooled to 0 °C and slowly quenched with brine (10mL). The mixture 70311W001 was filtered through a plug of elite and the filtrate was extracted with diethyl ether (3x20mL). The extracts were combined and dried over MgSCU, filtered and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (0-50% EtOAc / Hep, 120g column) to give the desired product benzyl (2S,4R)-2-formyl-4-(tosyloxy)pyrrolidine-1 -carboxylate (4.10 g, 1 Eq, 10.162 mmol) as a white foamy solid.1H NMR (400 MHz, METHANOL-d4) 5 7.99

[0588] - 7.88 (m, 1 H), 7.86 - 7.76 (m, 2H), 7.51 - 7.29 (m, 7H), 5.18 - 5.04 (m, 3H), 4.85 - 4.70 (m, 1 H), 3.83 - 3.56 (m, 2H), 2.47 (d, J = 10.0 Hz, 3H), 2.43 - 2.35 (m, 1 H), 2.28 - 2.13 (m, 1 H), 1.45

[0589] - 1.05 (m, 9H) contains 1 :1 mixture of diastereomers + rotamers. LCMS (ES) = 507.2 [M+H]+, rt 1.24 min, Method 2.

[0590] Step 4

[0591] Benzyl (1S,4S)-5-(tert-butylsulfinyl)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate

[0592] To a solution of benzyl (2S,4R)-2-((E)-((tert-butylsulfinyl)imino)methyl)-4- (tosyloxy)pyrrolidine-l -carboxylate (5.0 g, 90% Wt, 1 Eq, 8.8822 mmol) and Tetrabutylammoniumdifluorotriphenylsilicate (TBAT) (5.7543 g, 1.2 Eq, 10.659 mmol) in tetrahydrofuran (50.0 mL) at -50 °C was added a THF (10mL) solution of trimethyl(trifluoromethyl)silane (1.6420 g, 1.67 mL, 1.3 Eq, 11.547 mmol). The reaction was allowed to stir for 1 h at -50 °C before being quenched with sat. aq. NH4CI (0.5mL). The resulting mixture was diluted with Et20 (20mL) and stirred an additional 5 min. The layers were separated and the aq. layer was extracted with Et20 (2x50mL). The extracts were combined, dried over MgSCL, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column (0-60% EtOAc / Hep, 80g column) to give the desired product benzyl (1S,4S)-5- (tert-butylsulfinyl)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.0 g, 6.8 mmol, 77 %, 92% purity) as a light brown oil and a mixture of diastereomers.1H NMR (400 MHz, METHANOL-d4) 5 7.44 - 7.25 (m, 5H), 5.23 - 5.04 (m, 2H), 4.82 - 4.64 (m, 1 H), 4.60 - 4.46 (m, 1 H), 4.41 - 4.05 (m, 2H), 3.63 - 3.33 (m, 1 H), 2.25 - 1.99 (m, 1 H), 1.96 - 1.77 (m, 1 H), 1.33 - 1.12 (m, 9H) (contains diastereomers). LCMS (ES) = 406.2 [M+H]+, rt 1.07,1.11 min, Method 2.

[0593] Step 5 benzyl (1S,4S)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, Hydrochloride

[0594] To a solution of benzyl (1S,4S)-5-(tert-butylsulfinyl)-6-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 92% Wt, 1 Eq, 2.2747 mmol) in methanol (50.0 mL) at 23 °C was added 4N hydrogen chloride in dioxane (107.8 mg, 739.28 pL, 4.0 molar, 1.3 Eq, 2.9571 mmol) dropwise. The reaction was allowed to stir for 12h at 23 °C. Upon completion, the reaction was concentrated under vacuum and triturated with diethyl ether to give the desired product benzyl (1S,4S)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 70311W001

[0595] Hydrochloride (650.00 mg, 1.9303 mmol, 84.859 %) as a white solid and a mixture of diastereomers.1H NMR (400 MHz, METHANOL-d4) 5 7.48 - 7.30 (m, 5H), 5.26 - 5.13 (m, 2H), 5.09 - 4.92 (m, 1 H), 4.76 - 4.51 (m, 2H), 3.81 - 3.48 (m, 2H), 2.40 - 2.26 (m, 1 H), 2.20 - 2.10 (m, 1 H) (2:1 mixture of diastereomers). LCMS (ES)= 301.1 [M+H]+, rt 0.64, 0.81 min, Method 2.

[0596] Step 6

[0597] Benzyl (1 S,4S)-5-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-6-

[0598] (trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0599] Argon was bubbled through a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (739.26 mg, 1.3 Eq, 2.3163 mmol), benzyl (1S,4S)-6- (trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, Hydrochloride (600.00 mg, 1 Eq, 1.7818 mmol) (Mixture of diastereomers) and sodium t-butoxide (684.9 mg, 4 Eq, 7.1272 mmol) in a 20mL microwave vial for 5 mins. RuPhos G3 (393.10 mg, 0.26378 Eq, 0.470 mmol) was added. The vial was capped and the resulting mixture was heated in a heating block on a conventional hotplate at 70 °C for 12h. The content of the microwave vial was transferred to an erlenmyer flask. Water (1 mL) was added to the reaction mixture followed by EtOAc (20mL). The resulting mixture was stirred for 5 min. MgSO4was added until there was a free-flowing solid. The solid was filtered and the filtrate was concentrated under vacuum. The crude mixture was purified by silica gel chromatography (30-100% EtOAc / Hep, 80g column) to give the desired product as a white solid and (2:1) mixture of diastereomers.1H NMR (400 MHz, METHANOL-d4) 5 7.70 - 7.18 (m, 7H), 5.33 - 5.13 (m, 2H), 5.01 - 4.76 (m, 1 H), 4.62 - 4.17 (m, 1 H), 4.00 - 3.86 (m, 1 H), 3.65 - 3.38 (m, 1 H), 3.32 - 3.18 (m, 1 H), 2.73 (br d, J = 10.5 Hz, 1 H), 2.44 - 2.24 (m, 1 H), 2.16 - 2.02 (m, 2H), 1.28 - 1.09 (m, 4H) (contains 2:1 mixture of diastereomers). LCMS (ES) = 539.1 [M+HJ+, rt 1.11 , 1.16 min, Method 2.

[0600] Step 7

[0601] 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0602] To a solution of benzyl (1S,4S)-5-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (645.00 mg, 1 Eq, 1.1977 mmol) in tetrahydrofuran (15.0 mL) under an atmosphere of argon was added 10% palladium on carbon (127.46 g, 0.1% Wt, 1 Eq, 1.1977 mmol). The reaction was backflushed with hydrogen and allowed to stir under an atmosphere of hydrogen for 2h. Upon completion, the reaction was filtered through a plug of celite and the filtrate was concentrated under vacuum to give the desired product 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)- 2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (484.00 mg, 1.1 mmol, 95 %, 95% purity) as an off-white solid and a 2:1 mixture of diastereomers.1H NMR (400 70311W001

[0603] MHz, METHANOL-d4) 6 7.68 - 7.56 (m, 2H), 7.45 - 7.36 (m, 2H), 4.55 - 4.46 (m, 1 H), 4.18 - 4.13 (m, 1 H), 4.08 (s, 1 H), 4.01 (s, 1 H), 3.90 (s, 1 H), 3.81 (br s, 1 H), 3.49 (dd, J = 10.3, 1.3 Hz, 1 H), 3.10 (dd, J = 10.3, 2.8 Hz, 1 H), 2.97 (dd, J = 11.0, 1.5 Hz, 1 H), 2.74 (dd, J = 11.0, 2.0 Hz, 1 H), 2.66 (br d, J = 10.0 Hz, 1 H), 2.41 - 2.34 (m, 1 H), 2.19 (br d, J = 10.5 Hz, 1 H), 2.09 (tt, J = 7.9, 4.6 Hz, 1 H), 1.92 - 1.83 (m, 2H), 1.30 - 1.23 (m, 4H), 1.21 - 1.12 (m, 4H) contains a 2:1 mixture of diastereomers. LCMS (ES) = 405.1 [M+H]+, rt 0.44, 0.48 min, Method 2.

[0604] Example 2 and 3

[0605] Example 2: 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Isomer 1)

[0606] Example 3: 3-cyclopropyl-7-fluoro-5-((1S,3R,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (Isomer 2)

[0607] 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, 2:1 mixture of diastereomers (484.00 mg) was separated by SFC chiral chromatography (isocratic A: 80% CO2 : B: 20% Methanol on column Chiralpak IG (250 x 20mm, 5pm)( 50). LCMS (ES) = 405.1 [M+H]+to afford the two desired stereoisomers named in order of elution.

[0608] Isomer 1 : 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (266.1 mg) as an amorphous solid. Recrystallization: ~240mg was dissolved in 4mL IPA. Heptane (4-6mL) was added until the mildly cloudy solution persisted. The mixture was heated until the hot solution became clear. The mixture was allowed to cool to room temperature. Within the first 10 min, crystals were observed forming along the glass. After 30 min, the mixture was heated to dissolve any potential amorphous compound that may have crashed out, and the resulting mixture (containing crystals) was allowed to cool to room temperature. After 5h, the fine needles were collected after filtration and air drying to afford the product (200 mg) as a solid in a solvate with i- 70311W001

[0609] PrOH (1:1 ratio).1H NMR (400 MHz, METHANOL-cU) 67.63 (dd, J= 10.3, 2.4 Hz, 1H), 7.41 (dd, J= 7.1, 2.7 Hz, 1H), 4.14 (q, J = 7.5 Hz, 1H), 4.01 (s, 1H), 3.90 (s, 1H), 2.97 (dd, J= 11.0, 1.2 Hz, 1H), 2.74 (dd, J= 11.2, 2.0 Hz, 1H), 2.65 (brd, J= 10.3 Hz, 1H), 2.37 (tt, J= 7.9, 4.6 Hz, 1H), 1.87 (brd, J= 9.8 Hz, 1H), 1.31 - 1.21 (m, 2H), 1.20-1.11 (m, 2H). LCMS (ES) = 405.1 [M+H]+, rt 0.43 min, Method 2.

[0610] Isomer 2: 3-cyclopropyl-7-fluoro-5-((1S,3R,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (134.8 mg) as a crystalline solid.1H NMR (400 MHz, METHANOL-d4) 57.60 (dd, J= 10.3, 2.4 Hz, 1H), 7.40 (dd, J= 7.1, 2.7 Hz, 1H), 4.51 (qd, J= 7.3, 2.4 Hz, 1H), 4.09 (s, 1H), 3.80 (br s, 1H), 3.49 (dd, J = 10.3, 1.0 Hz, 1H), 3.10 (dd, J= 10.0, 2.7 Hz, 1H), 2.19 (brd, J= 10.3 Hz, 1H), 2.09 (tt, J= 7.8,

[0611] 4.5 Hz, 1H), 1.86 (brd, J= 10.3 Hz, 1H), 1.33-1.11 (m, 4H). LCMS (ES) = 405.1 [M+HJ+, rt0.35 min, Method 2.

[0612] Stereochemical assignments were made using experimental VCD and IR spectra.

[0613] Examples 4-5 were synthesized in an analogous manner to Examples 1-3. 70311W001

[0614] Example 6

[0615] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(2-hydroxyethyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide formate

[0616] To a solution of 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (100.0 mg, 1 Eq, 247.29 pmol) in methanol (3.0 mL) at 23 °C was added 1 ,4-dioxane-2,5-diol (29.700 mg, 1 Eq, 247.29 pmol) followed by sodium cyanoborohydride (31.08 mg, 2 Eq, 494.58 pmol). The reaction was allowed to stir for 2h. Upon completion, the reaction was concentrated under vacuum, taken up in 2mL DMSO and purified by MDAP [Formic Acid Method B, 15-55% (0.1% v / v solution of Formic Acid in Acetonitrile) / (0.1% v / v solution of Formic Acid in Water), XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter)] to give the desired product 3-cyclopropyl- 7-fluoro-5-((1S,3S,4S)-5-(2-hydroxyethyl)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, formate (53.700 mg, 83 pmol, 34%, 91 % Purity) as a 70311W001 white solid.1H NMR (400 MHz, METHANOL-d4) 5 7.70 (dd, J = 10.3, 2.8 Hz, 1 H), 7.39 (dd, J = 6.8, 2.8 Hz, 1 H), 4.32 (q, J = 7.8 Hz, 1 H), 3.94 (s, 1 H), 3.80 (s, 1 H), 3.70 - 3.63 (m, 2H), 3.03 - 2.94 (m, 1 H), 2.93 - 2.86 (m, 1 H), 2.75 (dt, J = 12.8, 5.1 Hz, 1 H), 2.59 - 2.48 (m, 2H), 2.39 - 2.31 (m, 1 H), 2.05 - 1.96 (m, 1 H), 1.31 - 1.21 (m, 2H), 1.20 - 1.09 (m, 2H). LCMS (ES) = 449.1 [M+H]+, rt 0.45 min, Method 2.

[0617] Example 7

[0618] 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-methyl-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-

[0619] 2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide formate

[0620] To a solution of 3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (90.0 mg, 1 Eq, 222.56 pmol) in Methanol (3.0 mL) at 23 °C was added formaldehyde (13.37 mg, 2 Eq, 445.13 pmol) followed by sodium cyanoborohydride (27.97 mg, 2 Eq, 445.13 pmol). The reaction was allowed to stir for 2h. Upon completion, the reaction was concentrated under vacuum, taken up in 2mL DMSO and purified by MDAP [Formic Acid Prep Method B, 15-55% (0.1 % v / v solution of Formic Acid in Acetonitrile) / (0.1% v / v solution of Formic Acid in Water), XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter)] to give the desired product 3-cyclopropyl-7-fluoro- 5-((1S,3S,4S)-5-methyl-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide formate (45.300 mg, 81 pmol, 36 %, 99% purity) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 [8.55 (s, 3H) formic acid], 7.62 (dd, J = 10.5, 2.5 Hz, 1 H), 7.40 (dd, J = 6.8, 2.8 Hz, 1 H), 4.25 (q, J = 7.5 Hz, 1 H), 3.98 (s, 1 H), 3.70 (s, 1 H), 2.91 (d, J = 11 .0 Hz, 1 H), 2.59 - 2.57 (m, 3H), 2.54 (br d, J = 11 .0 Hz, 1 H), 2.47 (dd, J = 11 .0, 2.5 Hz, 1 H), 2.42 - 2.31 (m, 1 H), 2.07 (d, J = 10.5 Hz, 1 H), 1.31 - 1.21 (m, 2H), 1.21 - 1.12 (m, 2H). LCMS (ES) = 419.1 [M+H]+, rt 0.43 min, Method 2.

[0621] Examples 8-10 were synthesized in an analogous manner (For example, NaCNBHs or Na(OAc)3BH) to Example 7. 70311W001 70311W001

[0622] Example 11

[0623] 3-cyclopropyl-7-fluoro-5-((1S,2S,5R)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide, formate

[0624] Step 1

[0625] Benzyl (1 S,2S,5R)-3-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-2-

[0626] (trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0627] Argon was bubbled through a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide (344.99 mg, 1.3 Eq, 1.0810 mmol), benzyl (1S,2S,5R)-2- 70311W001

[0628] (trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, Hydrochloride (280.00 mg, 1 Eq, 831.50 pmol) (single isomer) and sodium t-butoxide (319.6 mg, 4 Eq, 3.3260 mmol) in a 20mL microwave vial for 5 min. RuPhos G3 (139.09 mg, 0.20 Eq, 166.30 pmol) was added. The vial was capped and the resulting mixture was heated in a heating block on a conventional hotplate at 70 °C for 48h. the content of the microwave vial was transferred to an erlenmyer flask. Water (1 mL) was added to the reaction mixture followed by EtOAc (20mL). The resulting mixture was stirred for 5 min. MgSC>4 was added until there was a free-flowing solid. The solid was filtered and the filtrate was concentrated under vacuum. The crude mixture was purified by silica gel chromatography (30-100% EtOAc / Hep, 80g column, 33mins) to give the desired product benzyl (1S,2S,5R)-3-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (131.00 mg, 243.26 pmol, 29.255 %).1H NMR (400 MHz, METHANOL-d4) 5 7.64 - 7.15 (m, 5H), 7.02 - 6.87 (m, 2H), 5.45 - 5.35 (m, J = 12.5 Hz, 1 H), 5.35 - 5.13 (m, 1 H), 5.10 - 5.00 (m, 1 H), 4.60 - 4.35 (m, 2H), 3.97 - 3.85 (m, J = 10.5 Hz, 1 H), 3.75 - 3.51 (m, 1 H), 2.81 - 2.50 (m, 1 H), 2.34 - 2.10 (m, 1 H), 1.85 (br d, J = 9.5 Hz, 1 H), 1.40 - 1.10 (m, 4H). contains rotamers. LCMS (ES) = 539.1 [M+HJ+, rt 1.17 min, Method 2.

[0629] Step 2

[0630] 3-cyclopropyl-7-fluoro-5-((1S,2S,5R)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, formate

[0631] To a solution of benzyl (1S,2S,5R)-3-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (130.00 mg, 1 Eq, 241.40 pmol) in tetrahydrofuran (15.0 mL) under an atmosphere of argon was added 10% palladium on carbon (25.690 g, 0.1 % Wt, 1 Eq, 241.40 pmol). The reaction was backflushed with hydrogen and allowed to stir under an atmosphere of hydrogen for 2h. Upon completion, the reaction was filtered through a plug of celite, and the filtrate was concentrated under vacuum. The crude product was purified by MDAP (MDAP [Method A2, 5-35% (0.1% v / v solution of Formic Acid in Acetonitrile) / (0.1% v / v solution of Formic Acid in Water), XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter)]) to give the desired product 3- cyclopropyl-7-fluoro-5-((1S,2S,5R)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, Formic acid salt (40.0 mg, 94 pmol, 39 %, 95% Purity) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 8.18 - 7.81 (m, 1 H), 7.57 (d, J = 5.0 Hz, 1 H), 4.81 - 4.10 (m, 3H), 3.90 (br d, J = 11.0 Hz, 1 H), 3.57 - 3.40 (m, 1 H), 3.15 - 2.71 (m, 2H), 2.40 - 2.01 (m, 1 H), 1.36 - 1.21 (m, 2H), 1.19 - 1.04 (m, 2H). LCMS (ES) = 405.2 [M+HJ+, rt 0.44 min, Method 2.

[0632] Examples 12-14 were synthesized in an analogous manner to Example 11 70311W001 70311W001

[0633] 70311W001

[0634] Example 15 rac-3-cyclopropyl-7-fluoro-5-((1S,5R,7R)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)-

[0635] 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, Hydrochloride

[0636] Step 1

[0637] Cyclopenta-1 ,3-diene

[0638] A single-neck 100 mL RB flask was charged with 3a,4,7,7a-tetrahydro-1 H-4,7- methanoindene (34.5 g, 35.0 mL, 1 Eq, 261 mmol) and a stir bar. A short-path distillation apparatus with thermometer was attached and the flask was heated to 190 °C in a sand bath. A few milliliters of a clear liquid began to distill at 43 °C and the fraction was discarded. At a head temperature of 43-45 °C, a larger fraction of clear liquid was collected in a 50 mL RB receiving flask immersed in an ice-water bath. After the head temperature began to exceed 45 °C, the heat was turned off and the 50 mL RB flask was removed, capped with a rubber septum, and placed in a freezer for 1 h. The literature reports that the product cyclopentadiene monomer begins to revert back to the dimer above 25 °C. Product obtained was a colorless liquid, 2.52 g, and was used in the next step immediately without handling or data acquisition.

[0639] Step 2

[0640] Exo-2-benzyl-3-(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene

[0641] Reference: Tetrahedron Lett. 2014, 55, 6339-6342.

[0642] A 250 mL RB flask with stir bar was charged with N-benzyl-2,2,2-trifluoroethan-1-imine (4.7560 g, 1 Eq, 25.410 mmol) and DCM (40 mL). The flask was capped with a rubber septum 70311W001 containing a nitrogen needle inlet. BFaOEt2 (3.6064 g, 3.220 mL, 1 Eq, 25.410 mmol) was added via syringe and the resulting homogeneous yellow solution was stirred for 10 min at rt. A solution of freshly distilled cyclopentadiene (2.519 g, 1.5 Eq, 38.12 mmol) in DCM (20 mL) was added via syringe and the solution was stirred for 15 h at rt. LC / MS indicated 2 peaks with M+H 254. The reaction was quenched by addition of 30 mL of saturated aqueous NaHCCh and the mixture was stirred for 10 min. The mixture was transferred to a separatory funnel and 50 mL of saturated NaCI was added in order to disperse the emulsion. The layers were separated and the aqueous layer was extracted twice with 50 mL DCM. The combined DCM layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give an orange liquid which was purified via silica gel chromatography (Isco Combiflash, 0-30% DCM:heptane over 35 minutes, 330 g gold column, 150 mL / min flow rate) to afford the product Exo-2-benzyl-3-(trifluoromethyl)-2- azabicyclo[2.2.1]hept-5-ene as a colorless liquid (3.31 gm, 51 %). NMR indicated desired exoisomer1H NMR (400 MHz, CHLOROFORM-d) 5 7.41 - 7.29 (m, 5H), 6.54 (td, J = 3.7, 1.5 Hz, 1 H), 6.30 (dd, J = 5.4, 2.0 Hz, 1 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.71 (s, 1 H), 3.23 (d, J = 12.7 Hz, 1 H), 3.11 (d, J = 1.5 Hz, 1 H), 2.24 (q, J = 7.8 Hz, 1 H), 1.91 (d, J = 8.3 Hz, 1 H), 1.36 (d, J = 8.3 Hz, 1 H). LCMS (ES) = 254.0 [M+HJ+, rt 1.35 min, Method 1.

[0643] 19F NMR was consistent with description in the reference for exo-isomer: peak at -72.5 PPm

[0644] Mixed fractions containing the endo-isomer were combined (2.36 g) and purified via silica gel chromatography (Isco Combiflash, 0-20% DCM:heptane over 35 minutes then held at 20% DCM for 20 minutes, 220 g gold column, 150 mL / min, loaded as a solution in 12 mL of 5:1 heptane:DCM) to afford Endo-2-benzyl-3-(trifluoromethyl)-2-azabicyclo[2.2.1]hept-5-ene as a colorless oil (1.094 gm, 17%).

[0645] NMR indicated desired endo-isomer:1H NMR (400 MHz, CHLOROFORM-d) 5 7.45 - 7.20 (m, 5H), 6.41 (dd, J = 5.5, 3.0 Hz, 1 H), 6.23 - 6.13 (m, 1 H), 4.17 (d, J = 13.5 Hz, 1 H), 3.66 (s, 1 H), 3.62 (br d, J = 6.0 Hz, 1 H), 3.37 - 3.31 (m, 1 H), 3.22 (qd, J = 7.8, 3.0 Hz, 1 H), 1.86 - 1 .79 (m, 1 H), 1 .62 (d, J = 8.5 Hz, 1 H). LCMS (ES) = 254.0 [M+HJ+, rt = 1 .27 min, Method 1 .

[0646] 19F NMR was consistent with description in the reference for endo- isomer: peak at -70.5 PPm

[0647] Step 3

[0648] Rac-(3S)-2-benzyl-3-(trifluoromethyl)-2-azabicyclo[2.2.1]heptane-5,6-diol

[0649] A 250 mL RB flask was charged with exo-2-benzyl-3-(trifluoromethyl)-2- azabicyclo[2.2.1]hept-5-ene (1.3160 g, 1 Eq, 5.1960 mmol), Acetone (15.0 mL, 56 °C), Water (2.0 mL, 100 °C), and 4-methylmorpholine 4-oxide (620.89 mg, 1.02 Eq, 5.30 mmol). The resulting cloudy solution was stirred at room temperature for 5 min. Osmium(VIII) oxide (158.52 mg, 2.5% 70311W001

[0650] Wt, 0.003 Eq, 15.588 pmol) in tert-butanol was added and the mixture instantly became an orange homogeneous solution. The reaction was stirred for 2.5 h. Additional osmium(VIII) oxide (158.52 mg, 2.5% Wt, 0.003 Eq, 15.588 pmol) was added and the reaction was stirred for 15 h. Additional osmium(VIII) oxide (158.52 mg, 2.5% Wt, 0.003 Eq, 15.588 pmol) was added and the reaction was stirred for 30 min. The reaction was quenched with 30 mL of 5% sodium sulfite and the biphasic solution was stirred for 15 min. The mixture was concentrated in vacuo in order to remove acetone and the resulting aqueous solution was diluted with EtOAc (50 mL) and transferred to a separatory funnel. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined aqueous layers were washed with saturated NaCI, dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give an orange syrup. The syrup was purified via silica gel chromatography (Isco Combiflash, 0-40% EtOAc:heptane over 36 minutes, 120 gram gold column, 85 mL / min flow rate, loaded as a solution in 6 mL DCM) to give the desired product Rac-(3S)-2-benzyl-3-(trifluoromethyl)-2-azabicyclo[2.2.1]heptane-5,6- diol as a white solid (1.225 gm, 82% yield).1H NMR (400 MHz, CHLOROFORM-d) 5 7.45 - 7.29 (m, 5H), 4.31 (br d, J = 5.9 Hz, 1 H), 4.00 (d, J = 13.7 Hz, 1 H), 3.91 (br d, J = 5.4 Hz, 1 H), 3.72 (br d, J = 13.7 Hz, 1 H), 3.00 (s, 1 H), 2.95 - 2.84 (m, 1 H), 2.64 - 2.50 (m, 2H), 2.44 - 2.30 (m, 1 H), 1.87 - 1.79 (m, 1 H), 1.75 - 1.65 (m, 1 H). LCMS (ES) = 288.1 [M+HJ+, rt 0.92 min, Method 1.

[0651] Step 4

[0652] Rac-(7S)-6-benzyl-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane

[0653] Reference: J. Am. Chem. Soc. 2019, 141 (30), 12159-12166.

[0654] A 100 mL RB flask was charged with (3S)-2-benzyl-3-(trifluoromethyl)-2- azabicyclo[2.2.1]heptane-5,6-diol (1.2110 g, 1 Eq, 4.2154 mmol) and MeOH (20 mL) and the solution was stirred at room temperature. Ammoniumtetraboratetetrahydrate (1.3323 g, 1.2 Eq, 5.0585 mmol) was added as a solid followed by addition of solid sodium metaperiodate (1.0820 g, 1.2 Eq, 5.0585 mmol) and MeOH (10 mL). The resulting white suspension was stirred for 17 h. The reaction was filtered and the methanolic filtrate was transferred to a 100 mL RB flask. Solid sodium cyanoborohydride (794.7 mg, 3.0 Eq, 12.646 mmol) was added in 2 portions (2 eq / 530 mg were added and an additional 1 eq / 265 mg was added after 20 minutes). The clear reaction was stirred for 6.5 h. After 6.5 h, acetic acid (759.4 mg, 723.9 pL, 3.0 Eq, 12.646 mmol) was added as a solution in MeOH (2 mL) and the mixture was stirred for 25 min. The reaction was neutralized by addition of saturated aqueous NaHCOs and the MeOH was removed in vacuo. The resulting aqueous layer was extracted with EtOAc (2 x 50 mL) and the EtOAc extracts were washed with saturated aqueous NaCI, dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give a pale yellow oil, 1 .214 g. The oil was purified via reversephase chromatography (MDAP High pH Method D, 50-99% MeCN:high pH aqueous, 4 x 3 mL injections). The desired fractions were combined and concentrated in vacuo until the MeCN had 70311W001 been removed and mostly water remained. The oily aqueous solution was extracted with 50 mL of EtOAc. The layers were separated and the EtOAc layer was dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give the desired product Rac-(7S)-6- benzyl-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane as a colorless oil (231.4 mgs., 20% yield).1H NMR (400 MHz, CHLOROFORM-d) 5 7.47 - 7.18 (m, 5H), 4.23 - 4.15 (m, 1 H), 4.07 - 3.98 (m, 1 H), 3.49 (q, J = 8.0 Hz, 1 H), 3.21 - 3.11 (m, 1 H), 2.99 - 2.87 (m, 3H), 2.56 (d, J = 12.0 Hz, 1 H), 2.41 (br s, 1 H), 2.16 (dt, J = 10.9, 5.3 Hz, 1 H), 1.53 (d, J = 11.0 Hz, 1 H), 1.45 (br s, 1 H). LCMS (ES) = 271.6[M+H]+, rt 1.13 min, Method 1.

[0655] Step 5

[0656] Rac-2-(trimethylsilyl)ethyl (7S)-6-benzyl-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3- carboxylate

[0657] A 100 mL RB flask was charged with (7S)-6-benzyl-7-(trifluoromethyl)-3,6- diazabicyclo[3.2.1]octane (228.90 mg, 1 Eq, 846.84 pmol) and MeCN (4 mL). DIEA (120.40 mg, 162 pL, 1.1 Eq, 931.52 pmol) was added as a solution in 1 mL MeCN followed by addition of solid 4-nitrophenyl (2-(trimethylsilyl)ethyl) carbonate (263.96 mg, 1.1 Eq, 931.52 pmol). The resulting homogeneous yellow solution was stirred for 17 h at room temperature. The MeCN was removed in vacuo and the residue was dissolved in EtOAc (40 mL). The EtOAc was washed sequentially with 1 N NaOH, water, 1 N HCI, water, and saturated NaCI. The EtOAc layer was dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give a pale yellow oil. The oil was purified via silica gel chromatography (Isco Combiflash, 0-50% EtOAc:heptane over 15 minutes, desired product eluted at 22% EtOAc, 24 gram gold column, loaded as a solution in 3 mL of 1 :1 DCM:heptane, flow rate = 35 mL / min) to give the desired product Rac-2- (trimethylsilyl)ethyl (7S)-6-benzyl-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate as a colorless syrup (196.6 mgs, 54% yield).1H NMR (400 MHz, DMSO-d6) 5 7.34 - 7.18 (m, 5H), 4.23 - 4.09 (m, 2H), 4.08 - 3.90 (m, 2H), 3.88 - 3.77 (m, 1 H), 3.61 (br d, J = 7.5 Hz, 1 H), 3.24 - 3.13 (m, 1 H), 3.08 - 2.92 (m, 1 H), 2.85 (br s, 1 H), 2.72 - 2.56 (m, 1 H), 2.42 (br d, J = 2.0 Hz, 1 H), 1.97 - 1 .83 (m, 1 H), 1 .56 (d, J = 11 .5 Hz, 1 H), 0.98 (br d, J = 8.0 Hz, 2H), 0.00 (s, 9H). LCMS (ES) = 415.2[M+H]+, rt 1.56 min, Method 2.

[0658] Step 6

[0659] Rac-2-(trimethylsilyl)ethyl (7S)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate

[0660] A 100 mL RB flask was charged with 2-(trimethylsilyl)ethyl (7S)-6-benzyl-7- (trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate (195.00 mg, 1 Eq, 470.40 pmol) and methanol (10.0 mL). Palladium dihydroxide (165.15 mg, 20% Wt, 0.5 Eq, 235.20 pmol) was added and the flask was evacuated and placed under a balloon of hydrogen with stirring at room temperature for 2.5 h. The hydrogen was evacuated and the mixture was filtered through celite 70311W001 while rinsing with methanol. The filtrate was concentrated in vacuo and pumped under high vacuum to give the desired product Rac-2-(trimethylsilyl)ethyl (7S)-7-(trifluoromethyl)-3,6- diazabicyclo[3.2.1]octane-3-carboxylate as a pale yellow syrup (156.6 mgs, 97% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 4.01 - 4.18 (m, 2 H) 3.74 - 3.88 (m, 1 H) 3.64 - 3.71 (m, 2 H) 3.28 - 3.52 (m, 2 H) 2.78 - 3.08 (m, 2 H) 2.34 - 2.47 (m, 1 H) 1.74 - 1.97 (m, 1 H) 1.47 - 1.68 (m, 1 H) 0.93 (t, J=8.07 Hz, 2 H) -0.06 - 0.06 (m, 9 H). LCMS (ES) = 325.1 [M+HJ+, rt 1.48 min, Method 2.

[0661] Step 7

[0662] Rac-2-(trimethylsilyl)ethyl (7S)-6-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate

[0663] A 20 mL microwave vial with stir bar was charged with 5-bromo-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (141.00 mg, 1 Eq, 441.80 pmol), 2-(trimethylsilyl)ethyl (7S)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate (143.33 mg, 1 Eq, 441.80 pmol), tris(dibezylideneacetone)dipalladium (40.457 mg, 0.1 Eq, 44.180 pmol), 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (41.233 mg, 0.2 Eq, 88.360 pmol), sodium 2- methylpropan-2-olate (106.1 mg, 118 pL, 2.5 Eq, 1.1045 mmol), and 1 ,4-Dioxane (5.0 mL, 101 °C). Nitrogen was bubbled into the solution for 10 min and the mixture was heated at 95 °C for 15 h. The reaction was cooled and neutralized by addition of 1 N aqueous HCI. EtOAc (20 mL) and water (10 mL) were added and the biphasic mixture was stirred for 5 min. The mixture transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organics were washed with saturated NaCI, dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give an orange syrup. The syrup was purified via silica gel chromatography (Isco Combiflash, 24 gram gold column, flow rate = 35 mL / min, 5-50% EtOAc:heptane over 25 minutes then hold at 50% EtOAc for 10 minutes, product eluted at 48% EtOAc, loaded as a solution in 5 mL DOM) to give the desired product Rac-2-(trimethylsilyl)ethyl (7S)-6-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carboxylate as an off-white solid (76.0 mgs, 30% yield).1H NMR (400 MHz, DMSO-d6) 5 10.72 (br s, 1 H), 7.71 - 7.50 (m, 1 H), 7.45 - 7.27 (m, 1 H), 4.65 (br d, J = 6.4 Hz, 1 H), 4.18 - 4.03 (m, 2H), 3.92 (br s, 1 H), 3.28 (br s, 1 H), 3.22 - 3.05 (m, 1 H), 2.82 - 2.74 (m, 1 H), 2.67 (br dd, J = 3.7, 1.7 Hz, 1 H), 1.82 (d, J = 11.2 Hz, 1 H), 1.32 - 1.21 (m, 2H), 1.17 - 0.98 (m, 5H), 0.89 - 0.83 (m, 1 H), 0.83 - 0.72 (m, 1 H), 0.16 - -0.22 (m, 9H). LCMS (ES) = 563.2 [M+HJ+, rt 1.27 min, Method 2.

[0664] Step 8

[0665] Rac-(7S)-6-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-7- (trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carbaldehyde 70311W001

[0666] A 50 mL RB flask was charged with 2-(trimethylsilyl)ethyl (7S)-6-(3-cyclopropyl-7-fluoro- 1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane- 3-carboxylate (72.800 mg, 1 Eq, 129.39 pmol) and THF (2.0 mL, 65 °C). 1M Tetrabutylammonium fluoride (135.32 mg, 517.54 pL, 1.0 molar, 4 Eq, 517.54 pmol) in THF was added and the pale orange solution was stirred at room temperature for 14 h. Additional tetrabutylammonium fluoride (135.32 mg, 517.54 pL, 1.0 molar, 4 Eq, 517.54 pmol) was added and the reaction was stirred for 3 h. The reaction was diluted with 20 mL EtOAc and transferred to a separatory funnel. The organics were washed with water and saturated aqueous NaCI, dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give an orange syrup. The syrup was purified via silica gel chromatography (Isco Combiflash, 4 gram gold column, loaded as a solution in DCM, 0-20% MeOH:DCM over 15 minutes, 18 mL / min flow rate) to give a pale yellow semisolid. The semi-solid was purified via reverse-phase chromatography (MDAP High pH Method C, 30-85% MeCN:pH 10 aqueous, loaded as a solution in 0.9 mL DMSO) to give an off-white solid. The solid was dissolved in 5 mL EtOAc and washed with 3 x 3 mL of K3PO4 solution (450 mgs dissolved into 10 mL of water). The EtOAc layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an off-white solid. The solid was purified via reverse-phase chromatography (MDAP Formic Acid Method B, 15-55% MeCN: aqueous formic acid) to give Rac- (7S)-6-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-7-(trifluoromethyl)- 3,6-diazabicyclo[3.2.1]octane-3-carbaldehyde as a white solid (20.0 mgs). LC / MS indicated a mixture of 59% desired product and 41 % N-formylated product. NMR in MeOH-d4 indicated a mixture. The product was used without further purification. LCMS (ES) = 447.1 [M+H]+, rt 0.77 min, Method 2.

[0667] Step 9 rac-3-cyclopropyl-7-fluoro-5-((1S,5R,7R)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, hydrochloride

[0668] A 4 mL reaction vial was charged with (7S)-6-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octane-3-carbaldehyde (18.3 mg, 1 Eq, 0.0410 mmol) and methanol (1 .0 mL, 65 °C). The solution was stirred and warmed slightly in order to fully dissolve. A 1 M HCI / MeOH solution was made by dissolving 2 mL of concentrated HCI up to 24 mL with MeOH. The methanolic HCI (1.64 mg, 45.1 pL, 1.0 molar, 1.1 Eq, 45.1 pmol) solution was added via syringe and the resulting slight suspension was heated at 58 °C for 15 h and then at reflux for 5 h. The reaction was concentrated in vacuo and the residue was redissolved in 2 mL of MeOH and concentrated in vacuo to give a white solid. The solid was dissolved in MeOH (1 mL) and methanolic HCI (1.64 mg, 45.1 pL, 1.0 molar, 1.1 Eq, 45.1 pmol) was added. This was done to ensure all of the amine was converted to the HCI salt. The homogeneous mixture was concentrated in vacuo. The resulting solid was dissolved in 1 mL of MeCN and the solution was concentrated. The resulting solid was dissolved in 1 mL of MeOH 70311W001 and the solution was concentrated in vacuo and pumped under high vacuum to afford rac-3- cyclopropyl-7-fluoro-5-((1S,5R,7R)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan-6-yl)-4H- benzo[e][1,2,4]thiadiazine 1 ,1-dioxide, hydrochloride as a white solid (16.1 mg, 83%).1H NMR (400 MHz, DMSO-d6) 5 10.73 - 10.57 (m, 1 H), 9.78 (br s, 1 H), 8.37 (dd, J = 10.8, 2.8 Hz, 1 H), 8.09 - 7.89 (m, 1 H), 7.45 (dd, J = 6.8, 2.8 Hz, 1 H), 4.87 (br d, J = 7.5 Hz, 1 H), 4.09 (br d, J = 4.5

[0669] Hz, 1H), 3.53 (br d, J = 12.0 Hz, 1H), 3.32 - 3.25 (m, 1 H), 3.01 - 2.93 (m, 2H), 2.84 (br d, J = 5.0 Hz, 1H), 2.69 - 2.61 (m, 1H), 2.48 - 2.43 (m, 1H), 2.00 (br d, J = 11.5 Hz, 1H), 1.17 - 1.04 (m, 3H), 1.05 - 0.98 (m, 1H). LCMS (ES) = 419.2 [M+H]+, rt 0.50 min, Method 2.

[0670] Example 16 was synthesized in an analogous manner to Example 15. 70311W001

[0671] Example 17

[0672] 3-cyclopropyl-7-fluoro-5-((1 R,3S,4S)-3-(trifluoromethyl)-2-azabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0673] Argon was bubbled through a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (250.00 mg, 1 Eq, 783.33 pmol), (1 R,3S,4S)-3- (trifluoromethyl)-2-azabicyclo[2.2.1]heptane, hydrochloride (236.90 mg, 1.5 Eq, 1.1750 mmol) and sodium t-butoxide (225.8 mg, 3 Eq, 2.3500 mmol) in 1 ,4-dioxane in a microwave vial for 5 min. RuPhos G3 (65.516 mg, 0.1 Eq, 78.333 pmol) was added. The vial was capped and the resulting mixture was heated on a conventional hotplate at 80 °C for 12 h. The reaction had progressed to 35% product after 12 hs with 39% starting material remaining. 0.1 eq Ruphos and 3eq NaOtBu was added and the mixture was heated at 80 °C for an additional 6h. The reaction progressed to 51% conversion to the desired product. 0.5mL H2O was added and the resulting mixture was stirred for 5 min. EtOAc (5mL) was added followed by MgSC The solid was filtered out and the filtrate was concentrated under vacuum. The residue was purified by MDAP [High pH Method C, 30-85% (10 mM Ammonium Bicarbonate in H2O adjusted to pH 10 with Ammonia) / Acetonitrile, XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter)] to give the desired product 3-cyclopropyl-7-fluoro-5-((1 R,3S,4S)-3-(trifluoromethyl)-2- azabicyclo[2.2.1]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (30.0 mg, 74.368 pmol, 9.4938 %) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 7.54 (dd, J = 10.3, 2.4 Hz, 1 H), 7.34 (dd, J = 7.1 , 2.7 Hz, 1 H), 3.95 (q, J = 7.8 Hz, 1 H), 3.82 (br s, 1 H), 2.80 - 2.74 (m, 1 H), 2.49 (br d, J = 10.3 Hz, 1 H), 2.37 - 2.26 (m, 1 H), 1.91 - 1.82 (m, 1 H), 1.79 - 1.71 (m, 1 H), 1.65 - 1.55 (m, 2H), 1.53 - 1.43 (m, 1 H), 1.28 - 1.18 (m, 2H), 1.17 - 1.06 (m, 2H). LCMS (ES) = 404.2 [M+H]+, rt 1.07 min, Method 1.

[0674] Example 18

[0675] (R)-3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide 70311W001

[0676] Argon was bubbled through a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (250.00 mg, 1 Eq, 783.33 pmol), (R)-3- (trifluoromethyl)morpholine, hydrochloride (225.11 mg, 1.5 Eq, 1.1750 mmol) and potassium tert- butoxide (263.69 mg, 3 Eq, 2.3500 mmol) in 1 ,4-dioxane in a microwave vial for 5 min. RuPhos G3 (65.516 mg, 0.1 Eq, 78.333 pmol) was added. The vial was capped and the resulting mixture was heated at 70 °C for 12 h. 2eq of the base and 0.2 mol% catalyst was added and the reaction was sealed and heated at 100 °C for 18h. 0.5mL H2O was added and the resulting mixture was stirred for 5 min. EtOAc (5mL) was added followed by MgSC The solid was filtered out and the filtrate was concentrated under vacuum. The residue was purified by reverse phase chromatography (MDAP [Low pH Method C, 30-85% (0.1% v / v solution of Formic Acid in Acetonitrile) / (0.1 % v / v solution of Formic Acid in Water), XSELECT CSH C18 column (150mm x 30mm i.d. 5pm packing diameter))The UV detection was an averaged signal from wavelength of 210nm to 350nm] to give the desired product (R)-3-cyclopropyl-7-fluoro-5-(3- (trifluoromethyl)morpholino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (79.0 mg, 200.83 pmol, 25.638 %) as a light brown solid.1H NMR (400 MHz, DMSO-d6) 5 10.77 (s, 1 H), 7.94 - 7.67 (m, 1 H), 7.55 - 7.42 (m, 1 H), 4.32 - 4.12 (m, 2H), 4.01 - 3.82 (m, 3H), 3.58 - 3.35 (m, 1 H), 2.97 - 2.85 (m, 1 H), 2.45 - 2.34 (m, 1 H), 1.19 - 1.07 (m, 3H), 1.05 - 0.96 (m, 1 H). LCMS (ES) = 394.1 [M+H]+, rt 0.78 min, Method 1.

[0677] Example 19, 20, 21, and 22

[0678] Example 19: tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3- (trifluoromethyl)piperazine-l -carboxylate

[0679] Example 20: rac-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0680] Example 21 : (S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 1)

[0681] Example 22: (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 2)

[0682] 70311W001

[0683] Step 1

[0684] Example 19: tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3- (trifluoromethyl)piperazine-l -carboxylate

[0685] To a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (450.00 mg, 1 Eq, 1.4100 mmol) in 1 ,4-Dioxane (9.0 mL) were added tert-butyl 3- (trifluoromethyl)piperazine-l -carboxylate (501 .89 mg, 1 .4 Eq, 1 .9740 mmol), sodium tert-butoxide (338.8 mg, 2.5 Eq, 3.5250 mmol), tris(dibezylideneacetone)dipalladium (129.12 mg, 0.1 Eq, 141.00 pmol) and dicyclohexyl(2',6'-diisopropoxy-[1 ,1'-biphenyl]-2-yl)phosphane (131.59 mg, 0.2 Eq, 282.00 pmol), and the reaction mixture was degassed by bubbling N2 and then stirred at 90 °C for 40h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and filtered through a short pad of Celite. The filtrate was concentrated and the residue was purified using column chromatography (ISCO, 40 g prepacked silica gel column, 0 to 60% EtOAc / DCM) to give tertbutyl 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-3-

[0686] (trifluoromethyl)piperazine-l-carboxylate as a white solid (325 mg, 45% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 0.98 - 1.21 (m, 4 H) 1.44 (s, 9 H) 2.29 - 2.46 (m, 1 H) 2.90 - 3.06 (m, 1 H) 3.37 - 3.64 (m, 2 H) 3.66- 4.42 (m, 4 H) 7.41 - 7.54 (m, 1 H) 7.58 - 7.94 (m, 1 H) 10.63 - 10.79 (m, 1 H). LC-MS (ES) m / z = 493.2 [M+HJ+, rt 0.93 min, Method 1.

[0687] Step 2

[0688] Example 20: Rac-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0689] To a solution of tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 , 2, 4]thiadiazin-5-yl)-3-(trifluoromethyl)piperazine-1 -carboxylate (320.00 mg, 1 Eq, 649.76 pmol) in DCM (4.0 mL) was added TFA (740.86 mg, 500.6 pL, 10 Eq, 6.4976 mmol), and the reaction mixture was stirred for 5h. The mixture was concentrated and the residue was purified using MDAP under basic conditions (High pH Method B) to give 3-cyclopropyl-7-fluoro-5-(2- 70311W001

[0690] (trifluoromethyl)piperazin-l -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as a white solid (153 mg, 59% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.10 - 1.19 (m, 2 H) 1.24 - 1.31 (m, 2 H) 2.15 - 2.34 (m, 1 H) 2.89 - 3.00 (m, 1 H) 3.03 - 3.21 (m, 4 H) 3.36 - 3.42 (m, 1 H) 3.82 - 3.98 (m, 1 H) 7.41 - 7.54 (m, 1 H) 7.63 - 7.87 (m, 1 H). LC-MS (ES) m / z =393.1 [M+HJ+, rt 0.59 min, Method 1 .

[0691] Step 3

[0692] Example 21 : (S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0693] Example 22: (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0694] 3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (94 mg) was resolved using preparative SFC [Chiralpak IG, 5 microns (21 mm x 250 mm), 220 nm UV, 50 mL / min, 30 deg C, 80:20 CO2:MeOH] to afford (S)-3-cyclopropyl-7-fluoro-5- (2-(trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (29 mg).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.08 - 1.37 (m, 4 H) 2.17 - 2.39 (m, 1 H) 2.83 - 3.21 (m, 5 H) 3.33 - 3.46 (m, 1 H) 3.77 - 3.98 (m, 1 H), 7.38 - 7.56 (m, 1 H) 7.59 - 7.84 (m, 1 H). LC-MS (ES) m / z = 393.1 [M+H]+, rt 0.60 min, Method 1 , and

[0695] (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (29 mg).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.08 - 1.21 (m, 2 H) 1.22 - 1.33 (m, 2 H) 2.19 - 2.41 (m, 1 H) 2.86 - 3.24 (m, 5 H) 3.35 - 3.45 (m, 1 H), 3.81 - 3.96 (m, 1 H) 7.43 - 7.53 (m, 1 H) 7.60 - 7.80 (m, 1 H). LC-MS (ES) m / z = 393.1 [M+HJ+, rt 0.61 min, Method 1.

[0696] Example 23

[0697] 3-cyclopropyl-7-fluoro-5-(4-(2-hydroxyethyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0698] To a solution of 3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (34.0 mg, 1 Eq, 86.653 pmol) in acetonitrile (1.0000 mL) in a 10-ml microwave tube was added 2-bromoethan-1-ol (11.911 mg, 6.756 pL, 1.1 Eq, 95.318 pmol), potassium carbonate (11.975 mg, 1 Eq, 86.653 pmol), sodium iodide (12.988 mg, 1 Eq, 70311W001

[0699] 86.653 pmol), and the vial was sealed and the reaction mixture was stirred at 45 °C for 10h. The reaction mixture was diluted with MeOH (10 mL) and filtered. The filtrate was concentrated and the residue was purified using MDAP to give 3-cyclopropyl-7-fluoro-5-(4-(2-hydroxyethyl)-2- (trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as a white solid (29 mg, 76% yield). 1 H NMR (400 MHz, METHANOL-d4) 5 ppm 1.06 - 1.29 (m, 4 H) 2.25 (br s, 1 H) 2.56

[0700] - 2.79 (m, 4 H) 2.87 - 3.14 (m, 3 H) 3.17 - 3.29 (m, 1 H) 3.73 (t, J=5.87 Hz, 2 H) 4.00 (br s, 1 H) 7.46 (br s, 1 H) 7.59 - 7.86 (m, 1 H). LC-MS (ES) m / z = 437.2 [M+HJ+, rt 0.64 min, Method 1.

[0701] Examples 24 and 25

[0702] Example 24: 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-(4- methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one

[0703] Example 25: 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thiadiazi n-5-y l)-5-

[0704] (trifluoromethyl)piperazin-2-one

[0705] Step 1 1 -(4-methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one

[0706] To a solution of 5-(trifluoromethyl)piperazin-2-one, hydrochloride (330.00 mg, 1 Eq, 1.6131 mmol) in DMF (8 mL) was added sodium hydride (148.4 mg, 60% Wt, 2.3 Eq, 3.7100 mmol) at O °C, and the mixture was stirred for 30 min. 1-chloromethyl-4-methoxy-benzene (303.15 mg, 262.7 pL, 1.2 Eq, 1.9357 mmol) was added, and the solution was stirred for 18 h. The reaction mixture was quenched with saturated NH4CI aqueous solution, extracted with EtOAc (3x). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (ISCO, 12 mg prepacked silica gel column, 0 to 100% EtOAc / heptane) to give 1-(4-methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one as a pale brown solid (290 mg, 61 %).1H NMR (400 MHz, METHANOL-d4) 5 ppm 3.34 (dt, J=3.13, 1.69 Hz, 1 H) 3.37 - 3.52 (m, 2 H) 3.52 - 3.59 (m, 2 H) 3.72 - 3.84 (m, 4 H) 4.52 - 4.69 (m, 2 H) 6.90 - 6.97 (m, 2 H) 7.20 - 7.32 (m, 2 H).

[0707] LC-MS (ES) m / z =289.1 [M+HJ+, rt 0.73 min, Method 2. 70311W001

[0708] Step 2

[0709] Example 24: 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-(4- methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one

[0710] To a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (230.00 mg, 1 Eq, 720.66 pmol) in 1 ,4-Dioxane (5.0 mL) were added 1-(4-methoxybenzyl)-5- (trifluoromethyl)piperazin-2-one (270.07 mg, 1.3 Eq, 936.86 pmol), sodium tert-butoxide (173.1 mg, 2.5 Eq, 1.8017 mmol), Tris(dibezylideneacetone)dipalladium (65.993 mg, 0.1 Eq, 72.066 pmol) and dicyclohexyl(2',6'-diisopropoxy-[1 ,1'-biphenyl]-2-yl)phosphane (67.260 mg, 0.2 Eq, 144.13 pmol), and the reaction mixture was degassed by bubbling N2 and then stirred at 95 °C for24h. The reaction mixture was cooled to rt, treated with saturated NH4CI aq. solution, extracted with EtOAc (3x). The extract was dried (Na2SC>4), filtered and concentrated. The residue was purified using column chromatography (ISCO, 40g prepacked silica gel column, 0 to 18% EtOAc / DCM) to give 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1- (4-methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one as an off-white solid (193 mg, 49%).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.12 - 1.20 (m, 2 H) 1.23 - 1.32 (m, 2 H) 2.10 - 2.22 (m, 1 H) 3.60 - 3.76 (m, 2 H) 3.83 (s, 3 H) 3.95 - 4.06 (m, 1 H) 4.16 - 4.38 (m, 2 H) 4.58 - 4.84 (m, 2 H) 6.92 - 7.02 (m, 2 H) 7.29 - 7.39 (m, 2 H) 7.41 - 7.56 (m, 2 H). LC-MS (ES) m / z = 527.2 [M+HJ+, rt 0.84 min, Method 1.

[0711] Step 3

[0712] Example 25: 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thiadiazi n-5-y l)-5-

[0713] (trifluoromethyl)piperazin-2-one

[0714] A solution of 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-(4- methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one (40.0 mg, 1 Eq, 75.972 pmol) in TFA (3 g, 2 mL, 3e+2 Eq, 0.03 mol) sealed in a 10-mL microwave tube was heated with stirred at 110 °C for 72h. The mixture was concentrated and the residue was purified using MDAP under basic conditions to give 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-5- (trifluoromethyl)piperazin-2-one as a white solid (16 mg, 51%).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.02 - 1.22 (m, 4 H) 2.34 - 2.42 (m, 1 H) 3.44 - 3.57 (m, 2 H) 4.02 - 4.24 (m, 2 H) 4.46 - 4.56 (m, 1 H) 7.58 (dd, J=7.00, 2.50 Hz, 1 H) 7.86 (dd, J=10.01 , 2.50 Hz, 1 H) 8.28 (br s, 1 H) 10.99 (s, 1 H). LC-MS (ES) m / z = 407.2 [M+HJ+, rt 0.55 min, Method 1.

[0715] Examples 26-30 and 32-87 were synthesized in an analogous manner to Examples 17-25. 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001

[0716] Example 88 rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0717] Step 1

[0718] Rac-2-((2S,4R)-2-(trifluoromethyl)piperidin-4-yl)isoindoline-1 , 3-dione

[0719] To a stirring solution of rac-(2S,4R)-2-(trifluoromethyl)piperidin-4-amine, 2Hydrochloride (700.00 mg, 1 Eq, 2.9036 mmol, commercially available) in Water (10.0 mL) were added potassium carbonate (1.3242 g, 3.3 Eq, 9.5819 mmol) and ethyl 1 ,3-dioxoisoindoline-2- carboxylate (700.12 mg, 1.1 Eq, 3.1940 mmol, commercially available), and the solution was stirred for 2h. The precipitate was collected by filtration, washed with water, and dried under vacuum, to give Rac-2-((2S,4R)-2-(trifluoromethyl)piperidin-4-yl)isoindoline-1 , 3-dione as a white solid (460 mg, 52% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.55 - 1.71 (m, 1 H) 1.81 - 1.92 (m, 1 H) 2.21 - 2.37 (m, 2 H) 2.59 - 2.74 (m, 1 H) 3.07 - 3.17 (m, 1 H) 3.24 - 3.36 (m, 1 H) 4.22 (tt, J=12.45, 4.07 Hz, 1 H) 7.63 - 7.78 (m, 4 H). LC-MS (ES) m / z = 299.1 [M+HJ+, rt 0.87 min, Method 1 .

[0720] Step 2

[0721] Rac-2-((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-yl)isoindoline-1 , 3-dione

[0722] To a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (230.00 mg, 1 Eq, 720.66 pmol) in 1 ,4-Dioxane (5.0 mL) was added rac-2-((2S)-2- (trifluoromethyl)piperidin-4-yl)isoindoline-1 , 3-dione (279.44 mg, 1.3 Eq, 936.86 pmol), sodium 2- methylpropan-2-olate (173.1 mg, 2.5 Eq, 1.8017 mmol), tris(dibezylideneacetone)dipalladium (65.993 mg, 0.1 Eq, 72.066 pmol) and dicyclohexyl(2',6'-diisopropoxy-[1 ,1'-biphenyl]-2- yl)phosphane (67.260 mg, 0.2 Eq, 144.13 pmol), and the reaction mixture was degassed by bubbling N2 and then stirred at 95 °C for 24h. The reaction mixture was cooled to rt, treated with saturated NH4CI aq. solution, extracted with EtOAc (3x). The extract was dried (Na2SO4), filtered and concentrated. The residue was purified using column chromatography (ISCO, 24g prepacked silica gel column, 0 to 80% EtOAc / DCM) to give rac-2-((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1- 70311W001 dioxido-4H-benzo[e][1 , 2, 4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-yl)isoindoline-1 , 3-dione as an off-white solid (92 mg, 21% yield). LC-MS (ES) m / z = 537.1 [M+H]+, rt 1.15 min, Method 1.

[0723] Step 3 rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

[0724] To a solution of 2-((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2 ,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-yl)isoindoline- 1 ,3-dione (60.0 mg, 1 Eq, 111.84 pmol) in EtOH (2.0 mL) were added hydrazinehydrate (112.0 mg, 108.9 pL, 20 Eq, 2.2367 mmol), and the reaction mixture stirred at 100 °C for 4h. The reaction mixture was concentrated and the residue was purified using MDAP (High pH Method B) under basic conditions to give rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (29 mg, 63% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.14 - 1.22 (m, 2 H) 1.26 - 1.34 (m, 2 H) 1.67 - 1.86 (m, 2 H) 1.92 - 2.03 (m, 1 H) 2.23 - 2.41 (m, 2 H) 2.97 - 3.15 (m, 3 H) 3.91 - 4.09 (m, 1 H) 7.45 - 7.55 (m, 1 H) 7.76 - 7.90 (m, 1 H). LC-MS (ES) m / z = 407.1 [M+HJ+, rt 0.78 min, Method 1.

[0725] Example 89 was synthesized in an analogous manner to Example 88. 70311W001

[0726] Example 90 and 91

[0727] Example 90: 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0728] Example 91 : 5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0729] A Chiral method was developed to resolve 133 mg of rac-5-((2R,4S)-4-amino-2- (trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide. Using isocratic A: 80% CO2 : B: 20% Methanol on column Chiralpak AS-H (250 x 20mm, 5pm)( 50 mL / min), two desired stereoisomers were successfully isolated and named in order of elution.

[0730] 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (52 mg, 38% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.14 - 1.22 (m, 2 H) 1.26 - 1.34 (m, 2 H) 1.67 - 1.86 (m, 2 H) 1.92 - 2.03 (m, 1 H) 2.23 - 2.41 (m, 2 H) 2.97 - 3.15 (m, 3 H) 3.91 - 4.09 (m, 1 H) 7.45 - 7.55 (m, 1 H) 7.76 - 7.90 (m, 1 H). LC- MS (ES) m / z = 407.2 [M+H]+, rt 0.77 min, Method 1. Absolute stereochemistry was assigned based on VCD studies.

[0731] 5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (50 mg, 37% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.12 - 1.22 (m, 2 H) 1.24 - 1.32 (m, 2 H) 1.65 - 1.86 (m, 2 H) 1.91 - 2.02 (m, 1 H) 2.22 - 2.38 (m, 2 H) 2.95 - 3.11 (m, 3 H) 3.89 - 4.04 (m, 1 H) 7.46 - 7.54 (m, 1 H) 7.74 - 7.85 (m, 1 H). LC- MS (ES) m / z = 407.2 [M+H]+, rt 0.76 min, Method 1. Absolute stereochemistry was assigned based on VCD studies.

[0732] Example 92

[0733] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide 70311W001

[0734] To a solution of 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (13.0 mg, 1 Eq, 31.988 pmol) in MeOH (0.30 mL) was added acetic acid (3.842 mg, 3.662 pL, 2 Eq, 63.976 pmol) and acetone (2.415 mg, 3.05 pL, 1.3 Eq, 41.585 pmol), and the reaction mixture was stirred for 15 min. Sodium cyanoborohydride (6.030 mg, 3 Eq, 95.965 pmol) was added and the mixture was stirred at rt for 2h. The reaction mixture was concentrated and the residue was purified using MDAP under basic conditions (High pH Method C) to give 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(isopropylamino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as a white solid (9 mg, 62% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.13 - 1.21 (m, 8 H) 1.24 - 1.33 (m, 2 H) 1.61 - 1.82 (m, 2 H) 1.98 - 2.09 (m, 1 H) 2.26 - 2.39 (m, 2 H) 2.95 - 3.18 (m, 4 H) 3.93 - 4.06 (m,

[0735] 1 H) 7.47 - 7.55 (m, 1 H) 7.75 - 7.87 (m, 1 H). LC-MS (ES) m / z = 449.2 [M+HJ+, rt 0.97 min, Method 1 .

[0736] Examples 93-97 were synthesized in an analogous manner to Example 92.

[0737] 70311W001 70311W001 70311W001

[0738] Example 98

[0739] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((propan-2-yl-d7)amino)-2-(trifluoromethyl)piperidin-1-yl)-

[0740] 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0741] To a solution of 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (57.0 mg, 1 Eq, 140.26 pmol) in deuterated MeOH (CD3OD) (1.20 mL) was added acetone-d6 (11.69 mg, 13.9 pL, 1.3 Eq, 182.33 pmol) and acetic acid-d4 (17.98 mg, 15.9 pL, 2 Eq, 280.51 pmol), and the reaction mixture was stirred at rt for 20 min. Sodium cyanoborodeuteride (27.71 mg, 3 Eq, 420.77 pmol) was added, and the mixture was stirred for 1.5h. The mixture was purified using MDAP under HPH conditions (High pH Method C) to give 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((propan-2-yl-d7)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (42 mg, 65% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.09 - 1.22 (m, 2 H) 1.22 - 1.33 (m, 2 H) 1.62 - 1.84 (m, 2 H) 1.97 - 2.10 (m, 1 H) 2.22 - 2.38 (m, 2 H) 2.88 - 3.17 (m, 3 H) 3.88 - 4.08 (m, 70311W001

[0742] 1 H) 7.43 - 7.57 (m, 1 H) 7.71 - 7.88 (m, 1 H). LC-MS (ES) m / z = 456.2 [M+H]+, rt 0.96 min, Method 1 .

[0743] Example 99

[0744] 3-cyclopropyl-5-((2S,4R)-4-(ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0745] A 50 mL RB flask was charged with 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)- 3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (230.00 mg, 1 Eq, 565.94 pmol) and MeOH (5 mL) and the solution was stirred at room temperature. A solution of acetic acid (67.97 mg, 65.04 pL, 2.0 Eq, 1.1319 mmol) in MeOH (1 mL) was added followed by addition of a solution of acetaldehyde (25.18 mg, 1.01 Eq, 571.60 pmol) in MeOH (1 mL). The solution was stirred for 5 minutes. Solid sodium cyanoborohydride (106.7 mg, 98.8 pL, 3 Eq, 1.6978 mmol) was added followed by addition of MeOH (1 mL). The homogeneous reaction was stirred for 15 h at room temperature. LC / MS indicated starting amine only. Additional acetaldehyde (25.18 mg, 1.01 Eq, 571.60 pmol) was added from a different bottle as a solution in MeOH (1 mL) and the reaction was stirred for 3 h. LC / MS indicated 2% desired mass. Additional acetaldehyde (24.93 mg, 31.1 pL, 1 Eq, 565.94 pmol) from a different bottle was added as a solution in MeOH (1 mL). LC / MS after 5 h indicated no change. Additional acetaldehyde (24.93 mg, 31.1 pL, 1 Eq, 565.94 pmol) from a 3rd bottle was added as a solution in MeOH (1 mL). LC / MS after 2 h indicated about 2:1 mixture of desired product:bis ethyl. The volume was reduced to 6 mL and the reaction was purified via reverse-phase chromatography (MDAP, basic Method D, 50-99% MeCN:pH 10 aqueous, 2 x 3 mL injections). The desired fractions were combined, concentrated in vacuo, and pumped under high vacuum to give a white solid. XRPD indicated crystalline material. The product was dried in a vacuum oven at 50 °C for 16 h and cooled to give 3-cyclopropyl-5-((2S,4R)-4- (ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as a white crystalline solid (65.3 mgs, 27% yield).1H NMR (400 MHz, METHANOL-d4) 5 7.83 - 7.74 (m, 1 H), 7.55 - 7.44 (m, 1 H), 4.02 - 3.90 (m, 1 H), 3.13 - 2.85 (m, 3H), 2.81 - 2.72 (m, 2H), 2.39 - 2.26 (m, 2H), 2.10 - 1.98 (m, 1 H), 1.82 - 1.64 (m, 2H), 1.29 - 1.24 (m, 2H), 1.23 - 1.18 (m, 3H), 1.16 (dd, J = 7.8, 4.4 Hz, 2H). LC-MS (ES) m / z = 435.2 [M+H]+, rt 0.46 min, Method 2.

[0746] Examples 100-101 was synthesized in an analogous manner to Example 99. 70311W001 70311W001

[0747] Example 102

[0748] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-

[0749] 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0750] To a solution of 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (135.0 mg, 1 Eq, 332.19 pmol) in MeOH (2.50 mL) was added acetone (25.08 mg, 31.7 pL, 1.3 Eq, 431.84 pmol) and acetic acid (39.90 mg, 38.03 pL, 2 Eq, 664.37 pmol), and the reaction mixture was stirred for 15 min. Sodium cyanoborohydride (62.62 mg, 3 Eq, 996.56 pmol) was added and the mixture was stirred at rt for 2h. Formaldehyde (188.7 mg, 173 pL, 37% Wt, 7 Eq, 2.3253 mmol) and NaBH3CN (167 mg, 2.66 mmol) were added, and the reaction mixture was stirred for additional 2h. The reaction mixture was purified using MDAP under basic conditions (High pH Method C) to give 3-cyclopropyl-7- fluoro-5-((2S,4R)-4-(isopropyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (101 mg, 64% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.10 - 1.19 (m, 8 H) 1.21 - 1.33 (m, 2 H) 1.81 - 2.02 (m, 3 H) 2.20 - 2.29 (m, 1 H) 2.30 - 2.38 (m, 4 H) 2.87 - 3.04 (m, 2 H) 3.04 - 3.20 (m, 2 H) 3.90 - 4.05 (m, 1 H) 7.44 - 7.54 (m, 1 H) 7.70 - 7.86 (m, 1 H). LC-MS (ES) m / z = 463.2 [M+HJ+, rt 1.06 min, Method 1.

[0751] Example 103

[0752] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0753] To a solution of 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (90.0 mg, 1 Eq, 221.46 pmol) in acetonitrile (2.0 mL) was added potassium carbonate (7.6513 mg, 3.24 pL, 0.25 Eq, 55.364 pmol), potassium iodide (42.276 mg, 19.26 pL, 1.15 Eq, 254.68 pmol), and 1 ,4-dibromobutane (50.208 mg, 27.7 pL, 1.05 Eq, 232.53 pmol) and the reaction mixture was stirred at reflux for 4h. The reaction 70311W001 mixture was cooled to rt and filtered. The filtrate was concentrated and the residue was purified using MDAP under basic conditions (High pH Method C) to give 3-cyclopropyl-7-fluoro-5- ((2S,4R)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide as a off-white solid (37 mg, 36%).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.10 - 1.22 (m, 2 H) 1.23 - 1.32 (m, 2 H) 1.76 - 1.96 (m, 6 H) 2.02 - 2.15 (m, 1 H) 2.32 - 2.43 (m, 2 H) 2.43 -

[0754] 2.56 (m, 1 H) 2.70 - 2.81 (m, 4 H) 2.91 - 3.02 (m, 1 H) 3.03 - 3.11 (m, 1 H) 3.86 - 4.01 (m, 1 H) 7.45 - 7.54 (m, 1 H) 7.73 - 7.85 (m, 1 H). LC-MS (ES) m / z = 461.1 [M+H]+, rt 1.01 min, Method 1.

[0755] Example 104 was synthesized in an analogous manner to Example 103. 70311W001

[0756] Example 105

[0757] 5-((2S,4R)-4-((2-aminoethyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0758] Step 1

[0759] 2-(2-(((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-yl)amino)ethyl)isoindoline-1 , 3-dione

[0760] A 50 mL RB flask was charged with 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-

[0761] 3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (235.70 mg, 1 Eq, 579.97 pmol) and MeOH (6 mL) and the solution was stirred at room temperature. A solution of acetic acid (69.65 mg, 66.65 pL, 2.0 Eq, 1.1599 mmol) in MeOH (1 mL) was added followed by addition of a solution of 2-(1 ,3-dioxoisoindolin-2-yl)acetaldehyde (142.63 mg, 1.3 Eq, 753.96 pmol)in MeOH (1 mL). The solution was stirred for 5 min. Solid sodium cyanoborohydride (109.3 mg, 101 pL, 3.0 Eq, 1.7399 mmol) was added followed by addition of MeOH (1 mL). The homogeneous reaction was stirred for 15h at room temperature. LC / MS indicated 48% desired mass. The MeOH was removed in vacuo and the residue was dissolved in a mixture of 12 mL EtOAc and 10 mL saturated aqueous NaHCOs. The layers were separated and the EtOAc layer was washed with saturated NaCI solution. The EtOAc layer was dried over sodium sulfate, filtered, concentrated in vacuo, and pumped under high vacuum to give a white foam, 358.0 mgs which was purified via silica gel chromatography (Isco Combiflash, 24 gram gold column, 0-10% MeOH:DCM over 15.4 minutes, product eluted at 8% MeOH, 35 mL / min flow rate, loaded as a solution in 5 mL DOM containing a few drops of MeOH), The desired fractions were combined, concentrated in vacuo, and pumped under high vacuum to give 2-(2-(((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 , 2, 4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-yl)amino)ethyl)isoindoline-1 , 3-dione as a white solid (219.0 mgs, 63% yield).1H NMR (400 MHz, METHANOL-d4) 5 7.92 - 7.88 (m, 2H), 7.85 - 7.82 (m, 2H), 7.79 (dd, J = 9.5, 2.5 Hz, 1 H), 7.48 (dd, J = 7.0, 2.5 Hz, 1 H), 3.89 (t, J = 6.3 Hz, 3H), 3.09 - 2.91 (m, 5H), 2.37 - 2.27 (m, 2H), 2.08 - 1.97 (m, 1 H), 1.78 - 1.62 (m, 2H), 1.31 - 1.22 (m, 2H), 1.15 (dd, J = 8.0, 4.0 Hz, 2H). LC-MS (ES) m / z = 580.0 [M+HJ+, rt 1.07 min, Method 1 . 70311W001 step 2

[0762] 5-((2S,4R)-4-((2-aminoethyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0763] A 100 mL RB flask was charged with 2-(2-(((2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido- 4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-yl)amino)ethyl)isoindoline-1 ,3- dione (217.20 mg, 1 Eq, 374.76 pmol) and EtOH (10mL). A solution of hydrazinehydrate (148.2 mg, 144.2 pL, 7.9 Eq, 2.9606 mmol) in EtOH (2 mL) was added and the suspension was heated at reflux for 15h. Observed a colorless solution. LC / MS indicated 99% desired mass. The solution was allowed to cool to room temperature over 2 h. Observed a white suspension. The suspension was filtered while washing with EtOH and the resulting filtrate was concentrated in vacuo and pumped under high vacuum to give a white solid, 176.3 mgs which was purified via silica gel chromatography (Isco Combiflash, 0-25% of 10% NH4OH / MeOH mix: DOM over 15 minutes, 12 gram gold column, 30 mL / min flow rate, product eluted at 21% NH4OH / MeOH mix, loaded as a solution in DOM containing a few drops of MeOH). The desired fractions were combined, concentrated in vacuo, and pumped under high vacuum to afford 5-((2S,4R)-4-((2- aminoethyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as a white solid (136.0 mgs, 81 % yield).1H NMR (400 MHz, METHANOL-d4) 5 7.79 - 7.68 (m, 1 H), 7.47 (dd, J = 7.3, 2.8 Hz, 1 H), 4.03 (br d, J = 2.5 Hz, 1 H), 3.16 - 2.98 (m, 2H), 2.93 - 2.76 (m, 5H), 2.40 - 2.22 (m, 2H), 2.10 - 1.99 (m, 1 H), 1.82 - 1.59 (m, 2H), 1.31 - 1.21 (m, 2H), 1.13 (dq, J = 7.7, 3.8 Hz, 2H). LC-MS (ES) m / z = 450.0 [M+HJ+, rt 0.73 min, Method 1.

[0764] Example 106

[0765] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0766] 1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol (909.67 mg, 562.9 pL, 10 Eq, 5.4134 mmol) was mixed with 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (220.00 mg, 1 Eq, 541.34 pmol), and methyl trifluoromethanesulfonate (133.25 mg, 89.4 pL, 1.5 Eq, 812.01 pmol) was added. The mixture was stirred for 1 h. LCMS indicated that it was a mixture of 18 % of SM, 63 % of desired mono- Me product and 14 % of undesired di-Me product. The reaction was quenched by 0.45 mL of 2N 70311W001

[0767] HCI. The residue was dissolved in DMSO and purified by MDAP (High pH Extended Method C) XSelect CSH Prep C18 5um OBD column, 30-85%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 27 min run time) to afford 3- cyclopropyl-7-fluoro-5-((2S,4R)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (145 mg, 64% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 8.24 - 8.33 (m, 1 H) 7.63 (br s, 1 H) 7.38 (br d, J=5.00 Hz, 1 H) 4.54 (br dd, J=2.50, 1.00 Hz, 1 H) 2.99 - 3.18 (m, 3 H) 2.87 (br s, 1 H) 2.47 (s, 3 H) 2.12 - 2.29 (m, 2 H) 1.94 (br d, J=11.51 Hz, 1 H) 1.72 (br dd, J=11.51 , 3.50 Hz, 1 H) 1.62 (q, J=11.84 Hz, 1 H) 0.91 - 1.06 (m, 4 H). LCMS (ES, m / z): 421.0 (M+H)+, rt 0.84 min, Method 1.

[0768] Example 107

[0769] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methyl-d3)amino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0770] To a solution of 5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (150.0 mg, 1 Eq, 369.09 pmol) in 1 , 1 ,1 , 3,3,3- Hexafluoropropan-2-ol (5.8301 g, 3.637 mL, 94 Eq, 34.695 mmol) was added methyl-d3 trifluoromethanesulfonate (92.525 mg, 62.64 pL, 1.5 Eq, 553.64 pmol), and the reaction mixture was stirred for 18h. The mixture was purified using MDAP under HPH conditions (High pH Method B) to give 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methyl-d3)amino)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (45 mg, 29% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.10 - 1.22 (m, 2 H) 1.23 - 1.34 (m, 2 H) 1.60 - 1.81 (m, 2 H) 1.98 - 2.08 (m, 1 H) 2.26 - 2.40 (m, 2 H) 2.70 - 2.84 (m, 1 H) 2.94 - 3.14 (m, 2 H) 3.88 - 4.07 (m, 1 H) 7.42 - 7.55 (m, 1 H) 7.73 - 7.88 (m, 1 H). LC-MS (ES) m / z = 424.0 [M+HJ+, rt 0.82 min, Method 1. 70311W001

[0771] Example 108

[0772] 3-cyclopropyl-5-((2S,4R)-4-(ethyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0773] Acetaldehyde (49.77 mg, 63.4 pL, 5 Eq, 1.1298 mmol) was added to a solution of 3- cyclopropyl-7-fluoro-5-((2S,4R)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (95.0 mg, 1 Eq, 225.96 pmol) in DCM (4.0 mL) at 0 °C under N2. The mixture was stirred for 30 minutes. A solution of sodium triacetoxyhydroborate (143.67 mg, 3 Eq, 677.88 pmol) in DCM (4.0 mL) was added. The mixture was allowed warm up to RT and stirred for 2 h, LCMS indicated that most of starting material remained, and only a tiny amount of desired was observed. An additional portion of acetaldehyde (49.77 mg, 63.4 pL, 5 Eq, 1.1298 mmol) was added, and the mixture was stirred for 2 h at RT, after which the reaction was complete. The mixture was concentrated, and the residue dissolved in DMSO and purified by MDAP (High pH Method C) (XSelect CSH Prep C185um OBD column, 30-85%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 17 min run time) to afford 3-cyclopropyl-5-((2S,4R)-4-(ethyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)- 7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (74 mg, 73% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.70 (br s, 1 H) 7.92 (br d, J=9.01 Hz, 1 H) 7.47 (br d, J=5.00 Hz, 1 H) 4.06 (br s, 1 H) 2.93 (br d, J=11 .51 Hz, 1 H) 2.62 - 2.84 (m, 2 H) 2.44 - 2.57 (m, 3 H) 2.20 (br s, 3 H) 1 .84 - 2.00 (m, 2 H) 1 .59 - 1 .80 (m, 2 H) 0.91 - 1 .12 (m, 7 H). LCMS (ES, m / z): 449.0 (M+H)+, rt 1.0 min, Method 1.

[0774] Example 109 and 110

[0775] Example 109: (R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one

[0776] Example 110: (S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-

[0777] (trifluoromethyl)piperidin-4-one 70311W001

[0778] Step 1

[0779] 3-cyclopropyl-7-fluoro-5-(7-(trifluoromethyl)-1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0780] A 100 mL flask with stir bar was charged with 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (2.50 g, 1 Eq, 7.8333 mmol), 7-(trifluoromethyl)-1,4-dioxa- 8-azaspiro[4.5]decane (1.6542 g, 1 Eq, 7.8333 mmol), Pd2(dba)3(1.0760 g, 0.15 Eq, 1.1750 mmol), 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1'-biphenyl (1.0966 g, 0.3 Eq, 2.3500 mmol) (RuPhos), NaOtBu (2.258 g, 3 Eq, 23.500 mmol), and 1 ,4-Dioxane (50.0 mL). Argon was bubbled into the solution for 10 minutes and the mixture was heated at 90 °C (preheated bath) for 2.5h. LC / MS indicated ~ 56 % of desired product. The reaction mixture was cooled down to RT, filtered through a small pad of celite and washed with EtOAc. The filtrate was concentrated, the residue was purified by normal phase chromatography (Combiflash, 120 g Gold column, 85 mL / min, 0-75% EtOAc in Heptane) to give an orange oil which was further purified by normal phase chromatography (Combiflash, 80 g Gold column, 60mL / min, 0-20% EtOAc in DCM) to afford the product 3-cyclopropyl-7-fluoro-5-(7-(trifluoromethyl)-1 ,4-dioxa-8-azaspiro[4.5]decan-8- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (1.73 g, 3.8494 mmol, 49.142 %) as a light orange foam.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.79 (s, 1 H) 7.95 - 8.11 (m, 1 H) 7.53 (br d, J=4.75 Hz, 1 H) 4.11 - 4.23 (m, 1 H) 3.94 - 4.03 (m, 4 H) 2.90 - 3.08 (m, 2 H) 2.51 - 2.58 (m, 1 H) 2.23 - 2.39 (m, 1 H) 2.00 - 2.18 (m, 2 H) 1.60 - 1.76 (m, 1 H) 1.09 - 1.15 (m, 2 H) 0.99 - 1.08 (m, 2 H). LCMS (ES, m / z): 450.0 (M+H)+, rt 0.92 min, Method 1.

[0781] Step 2

[0782] 1 -(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-2- (trifluoromethyl)piperidin-4-one 70311W001

[0783] Hydrogen chloride (1.458 g, 40.0 mL, 1.0 molar, 10.043 Eq, 40.0 mmol) was added to an solution of 3-cyclopropyl-7-fluoro-5-(7-(trifluoromethyl)-1 ,4-dioxa-8-azaspiro[4.5]decan-8-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (1.7900 g, 1 Eq, 3.9829 mmol) in THF (40.0 mL). The mixture was heated to 80 °C for 24h to completion by LCMS. The reaction was cooled down to RT, and slowly quenched with aq. NaHCCh. The aqueous phase was extracted with EtOAc (3x50 mL). The extracts were washed with brine and then dried over Na2SO4, concentrated, and purified by normal phase chromatography (Combiflash, 80 g Gold column, 60mL / min, 0-30% EtOAc in DCM) to afford the product 1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-2-(trifluoromethyl)piperidin-4-one (1.3100 g, 3.23 mmol, 81.1 %) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.73 (s, 1 H) 7.66 - 8.09 (m, 1 H) 7.51 (br d, J=4.50 Hz, 1 H) 4.68 (td, J=7.63, 3.25 Hz, 1 H) 3.40 - 3.75 (m, 3 H) 2.53 - 2.90 (m, 3 H) 2.30 - 2.45 (m, 1 H) 1.08 - 1.18 (m, 3 H) 0.98 - 1.08 (m, 1 H). LCMS (ES, m / z): 406.0 (M+H)+, rt 0.66 min, Method 1.

[0784] Step 3

[0785] (R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one

[0786] (S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one

[0787] A Chiral method was developed to resolve 1.2 grams of 1-(3-cyclopropyl-7-fluoro-1 ,1- dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-one using isocratic A: 70% CO2 : B: 30% Isopropanol on column Chiralpak IB-N (250 x 20mm, 5pm)( 80 mL / min). The two desired stereoisomers were successfully isolated.

[0788] (R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one as a white solid (568.9 mg, 48% yield). The experimental VCD and IR spectra were compared with the calculated spectra of the modeled structure. The comparisons suggest that the absolute configuration is (R)-.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.73 (s, 1 H) 7.87 (s, 1 H) 7.52 (br d, J=5.00 Hz, 1 H) 4.67 (ddq, J=11.76, 7.82, 3.98, 3.98, 3.98 Hz, 1 H) 3.40 - 3.53 (m, 2 H) 2.54 - 2.81 (m, 2 H) 2.39 (br s, 1 H) 1.11 - 1.17 (m, 4 H) 1.01 - 1.10 (m, 2 H). LCMS (ES, m / z): 406.0 (M+H)+, rt 0.69 min, Method 1. The experimental VCD and IR spectra were compared with the calculated spectra of the modeled structure. The comparisons suggest that the absolute configuration is (R).

[0789] (S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one as a white solid (569.9 mg, 47% yield). The experimental VCD and IR spectra were compared with the calculated spectra of the modeled structure. The comparisons suggest that the absolute configuration is (S)-.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.73 (s, 1 H) 7.87 (s, 1 H) 7.52 (br d, J=5.50 Hz, 1 H) 4.63 - 4.73 (m, 1 H) 3.39 - 3.52 (m, 2 H) 70311W001

[0790] 2.54 - 2.85 (m, 2 H) 2.39 (br s, 1 H) 1.09 - 1.17 (m, 4 H) 1.00 - 1.08 (m, 2 H). LCMS (ES, m / z): 406.0 (M+H)+, rt 0.69 min, Method 1. The experimental VCD and IR spectra were compared with the calculated spectra of the modeled structure. The comparisons suggest that the absolute configuration is (S).

[0791] Example 111 and 112

[0792] Example 111 : 3-cyclopropyl-7-fluoro-5-((2S,4S)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0793] Example 112: 3-cyclopropyl-7-fluoro-5-[(2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl]-4H- 1A6,2,4-benzothiadiazine-1 ,1-dione

[0794] Sodium triacetoxyborohydride (392.12 mg, 3 Eq, 1.8502 mmol) was added to a solution of (S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-

[0795] (trifluoromethyl)piperidin-4-one (250.00 mg, 1 Eq, 616.72 pmol) in DCM (5.0 mL). The mixture was stirred for 30 h at RT. Starting material was consumed, and two diastereomers were observed by LCMS. The mixture was concentrated, dissolved in minimum amount of MeOH, and purified by reverse phase chromatography (EZ-Prep HPH, XBidge Prep C18 Gold column, 42.5 mL / min, 0-20 % acetonitrile (with 0.1 % NH4OH, v / v) / water(with 0.1 % NH4OH, v / v) to give two isomers:

[0796] 3-cyclopropyl-7-fluoro-5-((2S,4S)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (22.5 mg, 9.9% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.59 (br s, 1 H) 7.32 (br s, 1 H) 4.10 (br s, 1 H) 3.91 - 4.05 (m, 1 H) 3.13 (ddd, J=12.26, 8.76, 4.00 Hz, 1 H) 2.83 (br s, 1 H) 2.13 (br s, 1 H) 1.94 - 2.09 (m, 3 H) 1.70 (br s, 1 H) 1.14 (m, 2 H) 0.97 - 1.08 (m, 2 H). LCMS (ES, m / z): 408.1 (M+H)+, rt 0.68 min, Method 1. Based on the structural elucidation of 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-hydroxy-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide, the stereochemistry was assigned as (2S,4S).

[0797] And

[0798] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (190 mg, 77% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.66 (dd, J=9.51 , 2.50 Hz, 1 H) 7.37 (dd, J=7.25, 2.75 Hz, 1 H) 3.73 - 3.90 (m, 2 H) 2.90 - 2.99 (m, 1 H) 2.80 - 2.89 (m, 1 H) 2.13 - 2.25 (m, 2 H) 1.79 - 1.92 (m, 2 H) 70311W001

[0799] 1.72 (q, J=12.01 Hz, 1 H) 1.10 - 1.19 (m, 2 H) 1.00 - 1.08 (m, 2 H). LCMS (ES, m / z): 408.1 (M+H)+, 0.78 min, Method 1. ROESY NMR showed H17(ax.)-H21(ax.) and H19(ax.)-H21(ax.) correlations. NMR data were consistent with 3-cyclopropyl-7-fluoro-5-[(2S,4R)-4-hydroxy-2- (trifluoromethyl)piperidin-1-yl]-4H-benzo[e][1 .2.4]thiadiazine-1 , 1 -dioxide.

[0800] Example 113

[0801] 5-((2S,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0802] Step 1

[0803] (2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-yl 4-methylbenzenesulfonate

[0804] TsCI (67.39 mg, 1.2 Eq, 353.48 pmol) was added to a solution of 3-cyclopropyl-7-fluoro- 5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (120.00 mg, 1 Eq, 294.57 pmol) and DMAP (3.5987 mg, 0.1 Eq, 29.457 pmol) in pyridine (782 mg, 0.80 mL, 33.6 Eq, 9.89 mmol) at 0 °C. The mixture was allowed to warm up to RT and stirred for 2 h. LCMS indicated that a fair amount of starting material remained (23%) and only ~11 % of desired product was observed. An additional portion of TsCI (67.387 mg, 1.2 Eq, 353.48 pmol) was added and the mixture was stirred for 24 h and after stirring for an additional 40h, starting material was consumed. The reaction was concentrated, the residue was dissolved in DCM (15 mL) and water (20 mL) was added. The biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (3X15 mL). The combined organic layers were dried over Na2SC>4, filtered and then concentrated. The residue was purified by normal phase chromatography (Combiflash, 24 g Gold column, 35 ml / min, 0-10% EtOAc in DCM) to afford the product (2S,4R)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-yl 4-methylbenzenesulfonate (140.00 mg, 249.30 pmol, 84.6 %) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.77 (s, 1 H) 7.88 (d, J=8.51 Hz, 3 H) 7.54 (d, J=8.01 Hz, 3 H) 4.67 - 4.82 (m, 1 H) 4.18 - 4.30 (m, 1 H) 2.97 (br s, 1 H) 2.83 - 2.94 (m, 1 H) 2.45 - 2.49 (m, 1 H) 2.45 (s, 3 H) 2.12 - 2.28 (m, 2 H) 1 .97 - 2.09 (m, 1 H) 1.79 - 1.92 (m, 1 H) 1.09 - 1.17 (m, 2 H) 1.00 - 1.08 (m, 2 H). LCMS (ES, m / z): 562.3 (M+H)+, rt 1.11 min, Method 1.

[0805] Step 2 70311W001

[0806] 5-((2S,4S)-4-azido-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0807] Sodium azide (15.5 mg, 2 Eq, 238.6 pmol) was added to a solution of (2S,4R)-1-(3- cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4- yl 4-methylbenzenesulfonate (67.0 mg, 1 Eq, 119.31 pmol) in DMSO (0.75 mL). The mixture was stirred for 2 h at RT, ~87 % of starting material remained and ~3 % of product was observed. The mixture was heated to 45 °C and stirred for 12 h, ~7 % of starting material was remained, ~33 % of desired product was observed. The mixture was purified by MDAP (High pH Ext Method C) (XSelect CSH Prep C18 5um OBD column, 30-85%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 27 min run time) to afford product 5-((2S,4S)-4-azido-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (12.6 mg, 29.1 pmol, 24.4 % yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 8.97 (br s, 1 H) 7.38 - 7.52 (m, 1 H) 7.21 - 7.30 (m, 1 H) 4.07 (br s, 1 H) 3.64 - 3.79 (m, 1 H) 3.03 - 3.14 (m, 1 H) 2.87 - 2.99 (m, 1 H) 2.05 - 2.19 (m, 1 H) 1 .82 - 2.05 (m, 3 H) 1.50 - 1 .58 (m, 1 H) 1.21 - 1 .37 (m, 2 H) 1.04 (br dd, J=7.63, 3.63 Hz, 2 H). LCMS (ES, m / z): 433.1 (M+H)+, rt 0.94 min, Method 1.

[0808] Step 3

[0809] 5-((2S,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0810] Trimethylphosphane (4.43 mg, 58.28 pL, 1 molar, 2 Eq, 58.28 pmol) was added to a solution of 5-((2S,4S)-4-azido-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (12.6 mg, 1 Eq, 29.14 pmol) in THF (0.25 mL) and H2O (2.6 mg, 2.6 pL, 5 Eq, 145.7 pmol). The mixture was stirred for 3 h, LCMS indicated that ~12 % of starting material remained, ~35 % of desired product was observed. An additional portion of trimethylphosphane (4.43 mg, 58.28 pL, 1 molar, 2 Eq, 58.28 pmol) was added and the mixture was stirred for 16 h, LCMS indicated that starting material was consumed, ~84 % of desired product was observed. The mixture was combined with another batch for workup. The combined mixture was coated on silical gel by solid loading and purified by normal phase chromatography (Combiflash, 12 g Gold column, 30 ml / min, 0-10 % MeOH (with 0.05 % NH4OH, v / v) in DCM) to give a white solid (23.5 mg) which was further purified by MDAP (High pH Method B) (XSelect CSH Prep C18 5um OBD column, 15-55%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 17 min run time) to afford product 5-((2S,4S)- 4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide as a white solid (14.5 mg, 60.3% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.09 (br d, J=5.50 Hz, 1 H) 6.99 (br s, 1 H) 4.98 (br s, 1 H) 3.45 (br t, J=10.76 Hz, 1 H) 3.29 - 3.39 (m, 1 H) 3.12 - 3.20 (m, 1 H) 2.14 - 2.23 (m, 1 H) 1.95 - 2.09 (m, 2 H) 1.81 (br s, 1 H) 1.70 (qd, 70311W001

[0811] J=11.26, 4.75 Hz, 1 H) 1.07 (dt, J=9.26, 4.38 Hz, 1 H) 0.94 (dt, J=8.76, 4.13 Hz, 1 H) 0.83 (br dd, J=7.75, 3.75 Hz, 2 H). LCMS (ES, m / z): 407.1 (M+H)+, rt 0.63 min, Method 1.

[0812] Example 114 and 115

[0813] Example 114: 5-((2S,4S)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1

[0814] Example 115: 5-((2S,4R)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0815] 2-Methylpropan-2-amine (103.7 mg, 149 pL, 2.3 Eq, 1.4185 mmol) and titanium(IV) isopropoxide (525.85 mg, 561 pL, 3 Eq, 1.8502 mmol) were added to a suspension of (S)-1-(3- cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4- one (250.0 mg, 1 Eq, 616.72 pmol) in THF (2.0 mL), and the mixture was stirred for 16 h under N2. MeOH (4.0 mL) was added, the mixture was cooled to 0 °C, and NaBH4 (35.00 mg, 1.5 Eq, 925.08 pmol) was added. The reaction was allowed to warm up to RT and stirred for 30 min. LCMS indicated that starting material was consumed, ~78 % of desired product, ~12 % of possible isomer were observed. The mixture was coated on silical gel / cel ite (1 :1 , w / w) by solid loading and purified by normal phase chromatography (Combiflash, 40 g golden column, 40 mL / min, 0-10 % MeOH (with 0.05 % NH4OH, v / v) in DCM) to give a light-yellow solid which was further purified by MDAP (High pH Extended Method C) (XSelect CSH Prep C18 5um OBD column, 30-85%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 27 min run time) to afford:

[0816] 5-((2S,4S)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (14.5 mg, 5% yield) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.23 (br s, 1 H) 7.12 - 7.29 (m, 1 H) 7.01 (br s, 1 H) 5.24 (br s, 1 H) 3.64 (br s, 1 H) 3.40 (br s, 1 H) 3.19 - 3.29 (m, 1 H) 2.27 (br s, 2 H) 2.12 (br s, 1 H) 1.90 (br s, 2 H) 1.33 (br s, 9 H) 1.16 - 1.22 (m, 1 H) 0.82 - 1.10 (m, 3 H). LCMS (ES, m / z): 463.0 (M+H)+, rt 0.88 min, Method 1.

[0817] And

[0818] 5-((2S,4R)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-

[0819] 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (182 mg, 64% yield) as a white solid.1H NMR (400 70311W001

[0820] MHz, METHAN0L-d4) 6 ppm 7.76 (br dd, J=9.51 , 2.25 Hz, 1 H) 7.46 (dd, J=7.00, 2.75 Hz, 1 H) 3.98 (br s, 1 H) 2.94 - 3.08 (m, 3 H) 2.25 - 2.35 (m, 1 H) 2.19 (br dd, J=12.38, 2.63 Hz, 1 H) 1.80 - 1.97 (m, 2 H) 1.70 - 1.79 (m, 1 H) 1.22 - 1.27 (m, 2 H) 1.20 (s, 9 H) 1.11 - 1.16 (m, 2 H). LCMS (ES, m / z): 463.0 (M+H)+, rt 1.03 min, Method 1.

[0821] ROESY showed H17-H18 (eq.) correlation but not H18 (ax.) correlation indicating H17 was axial. H19 and H21 was overlapped at 3.03 ppm. The peak had correlation with H18(eq.) but not H18(ax.), indicating H19 was axial. NMR data were consistent with 5-[(2S,4R)-4-(tert- butylamino)-2-(trifluoromethyl)piperidin-1-yl]-3-cyclopropyl-7-fluoro-4H-1A6,2,4-benzothiadiazine- 1 , 1-dione.

[0822] Example 116

[0823] 3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((R)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide

[0824] (R)-1 ,1 ,1-trifluoropropan-2-amine (115.49 mg, 100.6 pL, 2.3 Eq, 1.0213 mmol) and titanium(IV) isopropoxide (378.61 mg, 404 pL, 3 Eq, 1.3321 mmol) was added to a suspension of (S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-one (180.0 mg, 1 Eq, 444.04 pmol) in THF (2.0 mL). The mixture was stirred for 16h under N2. MeOH (3.0 mL) was added to the mixture and the mixture was cooled to 0 °C. NaBH4 (25.20 mg, 1.5 Eq, 666.06 pmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. LCMS indicated that >50 % of imine(intermediate) remained, ~19 % of desired product was observed. The mixture was cooled to 0 °C, and an additional portion of NaBH4 (25.20 mg, 1.5 Eq, 666.06 pmol) was added. The reaction was allowed to warm up to RT and stirred for 1h. LCMS indicated >20 %)of imine(intermediate) remained, ~58 % of desired product. The mixture was cooled to 0 °C, another portion of NaBH4 (25.20 mg, 1.5 Eq, 666.06 pmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. LCMS indicated >10 % of imine(intermediate) remained, ~72 % of desired product. The mixture was stirred overnight, after which LCMS indicated that imine(intermediate) was consumed: ~84 % of desired product and ~10 % of possible isomer were observed. The mixture was coated on silical gel / celite (1 :1 , w / w) by solid loading and purified by normal phase chromatography (Combiflash, 24 g golden column, 35 mL / min, 0-5 % MeOH (with 0.05 % NH4OH, v / v) in DCM) to give a white solid 70311W001 which is a mixture of diastereoisomers. 145 mg of was submitted for chiral separation. A Chiral method was developed using isocratic A: 85% CO2 : B: 15% Ethanol on column Chiralpak AD-H (250 x 20mm, 5pm)( 50 mL / min). The major desired stereoisomer was successfully isolated (111.8 mg) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.66 (dd, J=9.51 , 2.50 Hz, 1 H) 7.37 (dd, J=7.00, 3.00 Hz, 1 H) 3.80 (ddd, J=11.63, 5.63, 3.25 Hz, 1 H) 3.33 (dt, J=14.38, 7.07 Hz, 1 H) 2.78 - 2.97 (m, 3 H) 2.16 - 2.25 (m, 2 H) 1.83 - 1.91 (m, 1 H) 1.53 - 1.68 (m, 2 H) 1.20 (d, J=6.50 Hz, 3 H) 1.10 - 1.18 (m, 2 H) 1.00 - 1.08 (m, 2 H). LCMS (ES, m / z): 503.3 (M+H)+, rt 1.14 min, Method 1.

[0825] 3.5 mg was submitted for relative stereochemistry(amino group) configuration NMR analysis. ROESY showed H16-H18 correlation. NMR data were consistent with 3-cyclopropyl-7- fluoro-5-[(2S,4R)-2-(trifluoromethyl)-4-{[(2R)-1 ,1 ,1-trifluoropropan-2-yl]amino}piperidin-1-yl]-4H- 1A6,2,4-benzothiadiazine-1 ,1-dione. Based on the NMR elucidation, the relationship between the amino group and 2-CF3 on piperidine ring is Cis-, the stereochemistry of two CF3 is known, therefore, the absolute stereochemistry of amino group at the 4-position of piperidine is R. Examples 117-118 were synthesized in an analogous manner to Example 116. 70311W001

[0826] Example 119

[0827] (R)-3-cyclopropyl-7-fluoro-5-(4-(methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0828] To a solution of (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide, Hydrochloride (132.9 mg, 1 Eq, 0.3100 mmol) in DMF (0.50 mL) and DCM (1.50 mL) was added triethylamine (125.5 mg, 173 pL, 4 Eq, 1.240 mmol) , and methanesulfonyl chloride (42.61 mg, 28.8 pL, 1.2 Eq, 372.0 pmol) at 0 °C, and the reaction mixture was stirred at rt for 1h. The reaction mixture was concentrated. The residue was purified using MDAP under basic conditions (High pH Method B) to give (R)-3-cyclopropyl-7-fluoro-5-(4- (methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1-dioxide (83.0 mg, 55.8%) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.67 - 7.95 (m, 1 H), 7.42 - 7.61 (m, 1 H), 4.11 - 4.24 (m, 1 H), 3.36 - 4.11 (m, 4 H), 3.12 - 3.27 (m, 2 H), 2.93 - 3.05 70311W001

[0829] (m, 3 H), 2.18-2.39 (m, 1 H), 1.23- 1.36 (m, 2 H), 1.10-1.21 (m, 2 H). LC-MS (ES) m / z = 471.0

[0830] [M+H]+, rt0.67 min, Method 1.

[0831] Examples 120-127 were synthesized in an analogous manner to Example 119. 70311W001 70311W001 70311W001 70311W001

[0832] Example 128

[0833] (R)-1-(4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3-

[0834] (trifluoromethyl)piperazin-1-yl)ethan-1-one

[0835] To a stirring solution of (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (80.0 mg, 1 Eq, 203.89 pmol) in DMF (15 mL) was added acetic acid (18.37 mg, 1.5 Eq, 305.83 pmol), HATU (155.05 mg, 2 Eq, 407.78 pmol) , and DIEA (79.058 mg, 107 pL, 3 Eq, 611.67 pmol), and the solution was stirred for 4h. The reaction mixture was purified using MDAP under basic conditions (High pH Method B) to give (R)-1-(4-(3- cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3-(trifluoromethyl)piperazin-1- yl)ethan-1-one (59.0 mg, 133 umol, 65.3%) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.58 - 7.87 (m, 1 H), 7.40 - 7.56 (m, 1 H), 3.99 - 4.40 (m, 2 H), 3.40 - 3.98 (m, 3 H), 2.98 - 3.23 (m, 1 H), 2.15 - 2.35 (m, 4 H), 1.24 - 1.37 (m, 2 H), 1.10 - 1.22 (m, 2 H). LC-MS (ES) m / z = 435.1 [M+H]+, rt 0.61 min, Method 1.

[0836] Examples 129-135 were synthesized in an analogous manner to Example 128. 70311W001 70311W001 70311W001 70311W001

[0837] Example 136

[0838] (R)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide To a solution of (R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (100.00 mg, 1 Eq, 254.86 pmol) in MeOH (1.50 mL) was added oxetan-3-one (27.55 mg, 22.4 pL, 1.5 Eq, 382.29 pmol) and acetic acid (30.61 mg, 29.18 pL, 2 Eq, 509.72 pmol), and sodium cyanoborohydride (48.05 mg, 3 Eq, 764.58 pmol), and the reaction mixture was stirred for 18h. The reaction mixture was purified using MDAP under basic conditions (High pH Method B) to give (R)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2- (trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (51.0 mg, 111 umol, 43.7%) as a white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm: 7.65 - 7.94 (m, 1 H), 7.38 - 7.57 (m, 1 H), 4.74 - 4.81 (m, 2 H), 4.61 - 4.72 (m, 2 H), 3.98 - 4.14 (m, 1 H), 3.63 - 3.80 (m, 1 H), 2.93 - 3.21 (m, 3 H), 2.70 - 2.86 (m, 1 H), 2.41 - 2.65 (m, 2 H), 2.18 - 2.37 (m, 1 H), 1.26 (br s, 2 H), 1.16 (br d, J=6.36 Hz, 2 H). LC-MS (ES) m / z = 449.1 [M+H]+, rt 0.69 min, Method 1.

[0839] Examples 137-142 were synthesized in an analogous manner to Example 136. 70311W001 70311W001 70311W001

[0840] Example 143, 144, and 145

[0841] Example 143: rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-

[0842] (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide Example 144: 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-

[0843] (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1)

[0844] Example 145: 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-

[0845] (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2)

[0846] Step 1 rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide 70311W001

[0847] 1 ,1 ,1 ,3,3,3-hexafluoropropan-2-ol (3.9969 g, 2.473 mL, 50 Eq, 23.785 mmol) was mixed with rac-5-((2R,4S)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (200.00 mg, 1 Eq, 475.70 pmol), and methyl trifluoromethanesulfonate (140.51 mg, 94.3 pL, 1.8 Eq, 856.27 pmol) was added. The mixture was stirred for 1 .5 h, and LCMS indicated that it was a mixture of 29 % SM, 64 % of desired mono- Me product and 5 % of undesired di-Me product. LCMS after 16 h indicated 69 % desired, 5 % bis, 24 % starting material. The reaction was quenched by 0.40 mL of 2N HCI and concentrated. The residue was dissolved in minimum amount of MeOH, and purified by MDAP (High pH Extended Method C) (XSelect CSH Prep C18 5um OBD column, 30-85%, acetonitrile / water with 10 mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 27 min run time) to afford rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (128.3 mg, 60 yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.72 - 7.81 (m, 1 H) 7.46 (dd, J=7.00, 2.75 Hz, 1 H) 3.89 (br s, 1 H) 3.00 - 3.09 (m, 1 H) 2.89 - 3.00 (m, 1 H) 2.61 (d, J=6.50 Hz, 2 H) 2.45 (s, 3 H) 2.26 (tt, J=8.07, 4.32 Hz, 1 H) 2.17 (br dd, J=12.63, 2.38 Hz, 1 H) 1.80 - 1.96 (m, 2 H) 1.52 - 1.70 (m, 2 H) 1.23 (br d, J=4.50 Hz, 2 H) 1.12 (br dd, J=7.50, 3.50 Hz, 2 H). LCMS (ES, m / z): 435.0 (M+H)+, rt 0.88 min, Method 1.

[0848] Step 2

[0849] Example 144: 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-

[0850] (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 1)

[0851] Example 145: 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-

[0852] (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 2)

[0853] 145 mg of rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide was chirally separated using isocratic A: 80% CO2 : B: 20% Methanol w / 0.5% Isopropyl amine on column ChiralpakAD- H (250 x 20mm, 5pm)( 50 mL / min). The two desired stereoisomers were successfully isolated and named in order of elution, Isomer 1 as a white solid (61 .4 mg, 36% yield) and Isomer 2 as a white solid (61.1 mg, 35% yield):

[0854] 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 1).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.66 (dd, J=9.51 , 2.00 Hz, 1 H) 7.36 (dd, J=7.00, 3.00 Hz, 1 H) 3.80 (br s, 1 H) 2.91 - 2.98 (m, 1 H) 2.80 - 2.89 (m, 1 H) 2.49 (d, J=6.50 Hz, 2 H) 2.33 (s, 3 H) 2.12 - 2.20 (m, 1 H) 2.04 - 2.11 (m, 1 H) 1.70 - 1.84 (m, 2 H) 1.42 - 1.59 (m, 2 H) 1.09 - 1.17 (m, 2 H) 1.02 (dd, J=7.75, 4.25 Hz, 2 H). LCMS (ES, m / z): 435.1 (M+H)+, rt 0.86 min, Method 1. 70311W001

[0855] 3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 2).1H NMR (400 MHz, METHANOL-d4) 5 ppm 7.65 (br d, J=9.51 Hz, 1 H) 7.36 (dd, J=7.00, 2.50 Hz, 1 H) 3.80 (br s, 1 H) 2.91 - 2.98 (m, 1 H) 2.80 - 2.89 (m, 1 H) 2.49 (d, J=7.00 Hz, 2 H) 2.33 (s, 3 H) 2.16 (tt, J=8.13, 4.13 Hz, 1 H) 2.07 (br dd, J=12.76, 2.25 Hz, 1 H) 1.70 - 1.81 (m, 2 H) 1.42 - 1.59 (m, 2 H) 1.09 - 1.18 (m, 2 H) 1.02 (dd, J=7.75, 4.25 Hz, 2 H). LCMS (ES, m / z): 435.2 (M+H)+, rt 0.86 min, Method 1.

[0856] Example 146, 147, 148

[0857] Example 146: Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0858] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide

[0859] Example 147: rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0860] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 1)

[0861] Example 148: rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0862] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (Isomer 2),

[0863] Isomer 1 Isomer 2

[0864] Step 1

[0865] Example 146: Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0866] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide

[0867] BH3.THF (12.24 mg, 142.39 pL, 1.0 molar, 2 Eq, 142.39 pmol) was added to a solution of Cis-rac-(2R,3S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)pyrrolidine-3-carboxylic acid (30.0 mg, 1 Eq, 71.196 pmol) in THF (0.50 mL) at 0 °C under N2. The mixture was stirred for 5 h. The reaction was concentrated. The residue was dissolved in MeOH, filtered by a syringe filter, and purified by MDAP (High pH Method B) to afford the product Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0868] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (18.500 mg, 45.4 pmol, 63.8 %) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 10.82 (s, 1 H) 7.68 - 7.76 (m, 1 H) 7.39 - 7.46 (m, 1 H) 5.23 (br t, J=5.00 Hz, 1 H) 4.20 - 4.31 (m, 1 H) 3.64 (br t, J=4.50 Hz, 3 H) 2.91 - 3.03 (m, 1 H) 2.38 - 2.47 (m, 1 H) 2.17 - 2.30 (m, 1 H) 1.85 - 1.96 (m, 1 H) 0.98 - 1.18 (m, 4 H). LC-MS (ES)= 408.1 [M+1]+, rt 0.72 min, Method 1.

[0869] Step 2 70311W001

[0870] Example 147: rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0871] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1)

[0872] Example 148: rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0873] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2)

[0874] The racemic mixture (42 mg) Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3- (hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide was separated by SFC chiral chromatography using isocratic A: 65% CO2 : B: 35% Methanol on column Chiralpak IH. The two desired stereoisomers were successfully isolated and named in order of elution:

[0875] Isomer 1 : rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0876] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, 38 mg.1H NMR (400 MHz, DMSO-d6) 5 10.82 (s, 1 H), 7.72 (dd, J = 10.3, 2.8 Hz, 1 H), 7.43 (dd, J = 7.3, 2.8 Hz, 1 H), 5.24 (t, J = 5.3 Hz, 1 H), 4.31 - 4.19 (m, 1H), 3.64 (br t, J = 5.5 Hz, 3H), 2.97 (br d, J = 7.5 Hz, 1H), 2.43 (s, 1H), 2.29 - 2.17 (m, 1H), 2.08 (s, 1H), 1.96 - 1.85 (m, 1 H), 1.17 - 1.01 (m, 4H). LC- MS (ES)= 408.2 [M+1 ]+, rt 0.87 min, Method 3.

[0877] And

[0878] Isomer 2: rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-

[0879] (trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide, 39 mg.1H NMR (400 MHz, DMSO-d6) 5 10.82 (s, 1H), 7.78 - 7.67 (m, 1 H), 7.46 - 7.38 (m, 1H), 5.27 - 5.19 (m, 1H), 4.30 - 4.19 (m, 1 H), 3.70 - 3.57 (m, 3H), 3.02 - 2.90 (m, 1H), 2.47 - 2.37 (m, 1H), 2.29 - 2.16 (m, 1 H), 2.08 (s, 1 H), 1.97 - 1.85 (m, 1 H), 1.16 - 0.98 (m, 4H). LC-MS (ES)= 408.1 [M+1]+, rt 0.87 min, Method 3.

[0880] Examples 149-152 were synthesized in an analogous manner to Examples 146-148.

[0881] 70311W001 70311W001 70311W001

[0882] Example 153 rac-5-((2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide

[0883] Step 1

[0884] Rac-2-((3S,6S)-6-(trifluoromethyl)piperidin-3-yl)isoindoline-1 , 3-dione

[0885] To a stirring solution of (3S,6S)-6-(trifluoromethyl)piperidin-3-amine, 2Hydrochloride (1000.00 mg, 1 Eq, 4.1480 mmol) in Water (15.0 mL) were added potassium carbonate (1.8917 g, 3.3 Eq, 13.688 mmol) and ethyl 1 ,3-dioxoisoindoline-2-carboxylate (1.1820 g, 1.3 Eq, 5.3924 mmol), and the solution was stirred for 18h. The precipitate was collected by filtration, washed with water, and dried under vacuum, to give 2-((3S,6S)-6-(trifluoromethyl)piperidin-3- yl)isoindoline-1 , 3-dione as a white solid (475 mg, 38% yield).1H NMR (400 MHz, METHANOL- d4) 5 ppm 1.82 - 1 .97 (m, 2 H) 1.97 - 2.08 (m, 1 H) 2.43 - 2.56 (m, 1 H) 2.90 - 3.01 (m, 1 H) 3.37 - 3.49 (m, 1 H) 3.51 - 3.63 (m, 1 H) 4.27 - 4.40 (m, 1 H) 7.79 - 7.90 (m, 4 H). LC-MS (ES) m / z = 299.1 [M+HJ+, rt 0.92 min, Method 1.

[0886] Step 2

[0887] Rac-2-((3S,6S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-6- (trifluoromethyl)piperidin-3-yl)isoindoline-1 , 3-dione

[0888] To a solution of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (390.00 mg, 1 Eq, 1.2220 mmol) in 1 ,4-Dioxane (9.0 mL) in a microwave tube were added 2- ((3S,6S)-6-(trifluoromethyl)piperidin-3-yl)isoindoline-1 ,3-dione (437.38 mg, 1 .2 Eq, 1 .4664 mmol), sodium 2-methylpropan-2-olate (293.6 mg, 2.5 Eq, 3.0550 mmol), Tris(dibenzylideneacetone)dipalladium (111.90 mg, 0.1 Eq, 122.20 pmol) and dicyclohexyl(2',6'- diisopropoxy-[1 ,1'-biphenyl]-2-yl)phosphane (114.05 mg, 0.2 Eq, 244.40 pmol), and the reaction mixture was degassed by bubbling N2 and then stirred at 85 °C for 40h. The reaction mixture was cooled to rt, treated with saturated NH4CI aq. solution, and extracted with EtOAc (3x). The extract 70311W001 was dried (Na2SC>4), filtered and concentrated. The residue was purified using column chromatography (ISCO, 24g prepacked silica gel column, 0 to 80% EtOAc / DCM) to give rac-2- ((3S,6S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-6- (trifluoromethyl)piperidin-3-yl)isoindoline-1, 3-dione as an off-white solid (420 mg, 61% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 1.10 - 1.45 (m, 4 H) 1.99 - 2.16 (m, 1 H) 2.22 - 2.37 (m, 1 H) 2.41 - 2.62 (m, 1 H) 2.67 - 2.89 (m, 2 H) 3.23 - 3.38 (m, 1 H) 4.28 - 4.53 (m, 2 H) 4.65 - 5.12 (m, 1 H) 7.45 - 7.77 (m, 2 H) 7.95 - 8.15 (m, 4 H) 10.82 - 11.05 (m, 1 H). LC-MS (ES) m / z = 537.1 [M+H]+, rt 0.99 min, Method 1.

[0889] Step 3 rac-5-((2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1- dioxide

[0890] To a solution of rac-2-((3S,6S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H- benzo[e][1 , 2 ,4]th iadiazi n-5-y l)-6-(trif I uoromethy I) pi perid i n-3-y I) isoi ndol i ne- 1 ,3-dione (100.00 mg, 1 Eq, 186.39 pmol) in EtOH (2.0 mL) was added hydrazinehydrate (186.6 mg, 181.5 pL, 20 Eq, 3.7279 mmol), and the reaction mixture stirred at 100 °C for 3h. The reaction mixture was concentrated and the residue was purified using MDAP under basic conditions (High pH Method B) to give rac-5-((2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide as a white solid (49 mg, 62% yield).1H NMR (400 MHz, METHANOL-d4) 5 ppm 1.00 - 1.10 (m, 2 H) 1.13 - 1.28 (m, 2 H) 1.72 - 1.88 (m, 1 H) 1.99 - 2.26 (m, 4 H) 3.10 - 3.22 (m, 1 H) 3.23 - 3.31 (m, 1 H) 3.36 - 3.44 (m, 1 H) 4.24 - 4.48 (m, 1 H) 7.23 - 7.50 (m, 2 H). LC-MS (ES) m / z = 407.1 [M+HJ+, rt 0.63 min, Method 1.

[0891] Example 154 was synthesized in an analogous manner to Example 153. 70311W001

[0892] Intermediate 12

[0893] 5-(((1s,4s)-4-aminocyclohexyl)amino)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide, 2Hydrochloride tert-butyl ((1s,4s)-4-((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)carbamate

[0894] A mixture of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (1.10 g, 1 Eq, 3.4467 mmol), tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (1.1080 g, 1.5 Eq, 5.1700 mmol), tBuBrettPhos Pd G3 (294.50 mg, 0.1 Eq, 344.67 pmol) and N,N,N',N'-Tetramethyl- N"-[tris(dimethylamino)phosphoranylidene]phosphoric triamide ethylimine (4.0944 g, 4.01 mL, 3.5 Eq, 12.063 mmol) in DMSO (10.0 mL) was degassed for 15 minutes. The mixture was then stirred for 66 h at RT under N2. The reaction mixture was checked by LCMS and showed new peak matching product. Water (100 mL) was added and then extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine and then dried over Na2SO4, filtered and then concentrated. The crude material was purified by normal phase chromatography (Combiflash, 120 g golden column, 85 mL / min, 0-8 % MeOH in DCM) to afford the desired product tert-butyl ((1s,4s)-4-((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)carbamate (1.20 g, 2.6 mmol, 76 %, 99% purity) as a light-brown solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 6.73 - 6.77 (m, 1 H) 6.71 (dd, J=12.23, 2.45 Hz, 1 H) 6.53 (br s, 1 H) 3.59 - 3.68 (m, 1 H) 3.49 - 3.58 (m, 1 H) 1.99 - 2.07 (m, 1 H) 1.69 - 1 .96 (m, 8 H) 1.47 (s, 9 H) 1.22 - 1.28 (m, 2 H) 1.09 - 1.16 (m, 2 H). LC-MS (ES) m / z = 453.2, [M+HJ+, rt 0.85 min, Method 1. 70311W001

[0895] Step 2

[0896] 5-(((1s,4s)-4-aminocyclohexyl)amino)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide, 2Hydrochloride

[0897] HCI (4M in dioxane) (9.5293 mL, 4.0 molar, 15 Eq, 38.117 mmol) was added to a suspension of tert-butyl ((1s,4s)-4-((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H- benzo[e][1 ,2,4]thiadiazin-5-yl)amino)cyclohexyl)carbamate (1.1500 g, 1 Eq, 2.5412 mmol) in 1 ,4- Dioxane (10.0 mL). The mixture was heated to 50 °C to form a clear solution and then stirred for 16 h. The light-brown suspension was cooled down to RT, filtered. The filter cake was washed with EtOAc (2x10 mL), ether (3x10 mL) and then dried in vacuo to afford the product 5-(((1s,4s)- 4-aminocyclohexyl)amino)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide, 2Hydrochloride (0.9800 g, 2.3 mmol, 89 %, 98% Purity) as an off-white solid.1H NMR (400 MHz, METHANOL-d4) 5 ppm 6.79 (dd, J=7.34, 2.45 Hz, 1 H) 6.73 (dd, J=12.23, 2.45 Hz, 1 H) 3.68 - 3.74 (m, 1 H) 3.34 - 3.40 (m, 1 H) 2.24 (tt, J=7.83, 4.40 Hz, 1 H) 1.89 - 2.03 (m, 8 H) 1.21 - 1.27 (m, 2 H) 1.10 - 1.16 (m, 2 H). LC-MS (ES) m / z = 353.2, [M+HJ+, rt 0.52 min, Method 1.

[0898] Example 155

[0899] N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)oxazole-4-carboxamide

[0900] EDC (27.375 mg, 1.5 Eq, 176.33 pmol) was added to a stirring mixture of carboxylic acid (1.1. Eq), 5-(((1s,4s)-4-aminocyclohexyl)amino)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1-dioxide, 2Hydrochloride (50 mg, 1 Eq, 117.55 pmol), HOBt (21.602 mg, 1.2 Eq, 141.06 pmol) and DIPEA (53.177 mg, 71.7 pL, 3.5 Eq, 411.43 pmol) in DMF (0.50 mL) at 25°C under N2. The mixture was stirred for 16 h, then filtered through a syringe filter, and purified by MDAP (High pH Method B) (XSelect CSH Prep C18 5um OBD column, 15-55%, acetonitrile / water with 10mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 17 min run time or 27 min run time). HPLC fractions with the desired product were combined and lyophilized to afford the desired product N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1 ,1- dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)amino)cyclohexyl)oxazole-4-carboxamide (46mg, 88% yield).1H NMR (400 MHz, DMSO-d6) 5 11.20 (br s, 1 H), 8.66 (d, J = 1.0 Hz, 1 H), 8.53 (d, J = 1.0 Hz, 1 H), 7.85 - 7.69 (m, 1 H), 6.87 - 6.58 (m, 2H), 6.17 - 5.97 (m, 1 H), 4.05 - 3.91 (m, 1 H), 3.69 70311W001

[0901] -3.56 (m, 1H), 2.08 (s, 1H), 1.95-1.62 (m, 8H), 1.19-1.03 (m, 4H). LCMS m / z 448.2 [M+H]+, rt =0.62 min, Method 1.

[0902] Examples 156-167 were synthesized in an analogous manner to Example 155. 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001 70311W001

[0903] Example 168 tert-butyl 3-(((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate

[0904] A mixture of 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (1.10 g, 1 Eq, 3.4467 mmol), tert-butyl 3-(aminomethyl)morpholine-4-carboxylate (1.1182 g, 1.5 Eq, 5.1700 mmol), tBuBrettPhos Pd G3 (294.50 mg, 0.1 Eq, 344.67 pmol) and N,N,N',N'- T etramethyl-N"-[tris(dimethylamino)phosphoranylidene]phosphoric triamide ethylimine (4.0944 g, 4.01 mL, 3.5 Eq, 12.063 mmol) in DMSO (10.0 mL) was degassed for 15 minutes. The mixture was then stirred for 18 h at RT under N2. Water (15 mL) was added and then extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine and then dried over Na2SO4, filtered, and concentrated. The crude material was purified by normal phase chromatography (Combiflash, 120 g RediSep Gold column, 85 mL / min, 0-8 % MeOH in DCM) to give a brown oil which was further purified by normal phase chromatography (Combiflash, 80 g Gold column, 60 mL / min, 0-70 % EtOAc in DCM) to afford the desired product tert-butyl 3-(((3-cyclopropyl-7-fluoro- 1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)amino)methyl)morpholine-4-carboxylate as a lightbrown foam (1.15 g, 73%).1H NMR (400 MHz, METHANOL-d4) 6 ppm 6.90 (br s, 1 H) 6.79 (dd, J=7.34, 2.45 Hz, 1 H) 4.19 - 4.33 (m, 1 H) 3.79 - 4.01 (m, 3 H) 3.61 (br dd, J=11.98, 3.18 Hz, 2 H) 3.49 (td, =11.86, 3.18 Hz, 1 H) 3.25 (td, J=13.08, 3.67 Hz, 1 H) 1.91 - 2.01 (m, 1 H) 1.15 - 1.54 (m, 12 H) 1.10 - 1.15 (m, 2 H). LCMS (ES) = 455.2 [M+H]+, rt 0.93 min, Method 2. 70311W001

[0905] Examples 169-175 were synthesized in an analogous manner to Example 168 as shown by the general reaction scheme below: 70311W001 70311W001 70311W001 70311W001 70311W001

[0906] Example 176

[0907] 2,2,2-trifluoroethyl 3-(((3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate formic acid salt

[0908] 3-cyclopropyl-7-fluoro-5-((morpholin-3-ylmethyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (118.00 mg, 1 Eq, 332.96 pmol) was dissolved in DMF (1.6648 mL) and treated with potassium carbonate (138.04 mg, 3 Eq, 998.87 pmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (85.007 mg, 1.1 Eq, 366.25 pmol). The reaction was stirred at rt for 18 h. The reaction was then diluted with EtOAc and filtered through celite. The solids were washed with EtOAc, and the combined organics were concentrated. The concentrated DMF solution was purified on the MDAP (Formic acid Method C). Desired fractions were concentrated to provide 3- cyclopropyl-7-fluoro-5-(((4-(2,2,2-trifluoroethyl)morpholin-3-yl)methyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide, formic acid salt as a white solid (37 mg, 22%).1H NMR (CHLOROFORM-d ,700MHz): 5 (ppm) 9.29 (br s, 1 H), 7.00 (br s, 1 H), 6.75 (br d, J=9.2 Hz, 1 H), 6.67 - 6.70 (m, 1 H), 4.85 - 5.25 (m, 1 H), 4.55 (br dd, J=7.9, 5.5 Hz, 2H), 4.28 - 4.16 (m, 1 H), 4.04 (br d, J=12.3 Hz, 1 H), 3.92 - 4.02 (m, 1 H), 3.84 - 3.98 (m, 1 H), 3.68 (br d, J=9.9 Hz, 1 H), 3.53 - 3.61 (m, 1 H), 3.54 (br d, J=10.5 Hz, 1 H), 3.45 (br d, J=Q.2 Hz, 1 H), 3.25 - 3.37 (m, 1 H), 1.60 (br s, 1 H), 1.09 (br s, 2H), 0.90 (br d, J=4.5 Hz, 2H). LC-MS (481.1 , M+H), rt 0.90 min, Method 2.

[0909] Example 177

[0910] Cyclopropyl(3-(((3-cyclopropyl-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholino)methanone

[0911] EDC (25.601 mg, 29 pL, 1.5 Eq, 164.90 pmol) was added to a stirring mixture of carboxylic acid (1.1. Eq), 3-cyclopropyl-5-((morpholin-3-ylmethyl)amino)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide, 2Hydrochloride (45.0 mg, 1 Eq, 109.94 pmol), HOBt (20.203 mg, 1.2 Eq, 131.92 pmol) 70311W001 and DIPEA (49.732 mg, 67.0 pL, 3.5 Eq, 384.78 pmol) in DMF (0.50 mL) at RT under N2. The mixture was stirred for 16 h, reaction complete by LC-MS. Purified by MDAP (XSelect CSH Prep C18 5um OBD column, 15-55%, acetonitrile / water with 10mM ammonium bicarb and 0.075% ammonium hydroxide, 40mL / min flow rate, 27 min run time) to afford cyclopropyl(3-(((3- cyclopropyl-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)amino)methyl)morpholino)methanone as a white solid (40.3 mg, 91%).1H NMR (400 MHz, DMSO-d6) 5 ppm 10.82 - 11.04 (m, 1 H) 7.00 - 7.35 (m, 2 H) 6.94 (br d, J=6.85 Hz, 1 H) 6.20 (br d, =1.47 Hz, 1 H) 4.26 - 4.46 (m, 1 H) 3.81 - 4.21 (m, 3 H) 3.54 - 3.72 (m, 2 H) 3.35 - 3.52 (m, 2 H) 2.95 - 3.17 (m, 1 H) 1.84 - 2.12 (m, 2 H) 0.93 - 1.18 (m, 4 H) 0.63 - 0.88 (m, 3 H) 0.39 - 0.60 (m, 1 H). LC-MS (405.2, M+H), rt 0.52 min, Method i .

[0912] Example 178 was synthesized in an analogous manner to Example 177. 70311W001

[0913] Example 179

[0914] 3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)piperidin-4-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide hydrochloride

[0915] Step 1 tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)piperidine-1- carboxylate

[0916] A 2mL vial was charged with tert-butyl 4-(trifluoro-A4-boraneyl)piperidine-1-carboxylate, potassium salt (50.176 mg, 1.1 Eq, 172.33 pmol), 5-bromo-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 ,1-dioxide (50.0 mg, 1 Eq, 156.67 pmol), 2,6-Lutidine (50.365 mg, 54.7 pL, 3.0 Eq, 470.00 pmol), [4,4'-Bis(1 , 1 -dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride (6.24 mg, 0.10 Eq, 15.667 pmol), and (4,4'-Di-t-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-(5- trifluoromethyl-2-pyridinyl-kN)phenyl-kC]iridium(lll) hexafluorophosphate (4.3942 mg, 0.025 Eq, 3.9167 pmol). The vessel was purged with nitrogen and then Acetonitrile (1.5667 mL) was added to the vessel under nitrogen. Nitrogen was gently bubbled through the solution for 5 min. The reaction was then parafilmed and irradiated at 450nM at 50% intensity in PennReactor for 18 hours. The reaction mixture was purified by MDAP [Method C extended, Low pH] to afford the desired product tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)piperidine-1 -carboxylate (12.0 mg, 28.335 pmol, 18.086 %) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 11.05 - 11.14 (m, 1 H) 7.55 - 7.63 (m, 1 H) 7.45 - 7.52 (m, 1 H) 4.07 - 4.19 (m, 2 H) 3.43 - 3.53 (m, 2 H) 2.84 - 2.99 (m, 2 H) 1 .72 - 1.80 (m, 2 H) 1 .52 - 1.59 (m, 2 H) 1 .42 - 1.46 (m, 9 H) 1.10 - 1.18 (m, 2 H) 1.03 - 1.09 (m, 2 H). LCMS (ES) = 422.3 [M-H]+, rt 1.09 min, Method 3.

[0917] Step 2

[0918] 3-cyclopropyl-7-fluoro-5-(piperidin-4-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide hydrochloride,

[0919] Tert-butyl 4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)piperidine-1 -carboxylate (12.0 mg, 28.335 pmol) was dissolved in DCM (2mL) and treated with 3M HCI in CMPE (3mL) and stirred for 1h at RT. Upon completion, the reaction was concentrated in vacuo to afford 3-cyclopropyl-7-fluoro-5-(piperidin-4-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide (9.40 mg, 29.067 pmol, 18.554%) as a white solid.1H NMR (400 MHz, DMSO-d6) 5 ppm 11.21 - 11.34 (m, 1 H) 8.65 - 8.76 (m, 1 H) 8.44 - 8.60 (m, 1 H) 7.53 - 7.61 (m, 1 H) 7.36 - 7.44 70311W001

[0920] (m, 1 H) 3.69 - 3.79 (m, 1 H) 3.43 (br d, J=12.72 Hz, 2 H) 3.03 - 3.14 (m, 2 H) 1.92 - 2.01 (m, 2 H) 1.77 - 1.90 (m, 2 H) 1.56 - 1.65 (m, 1 H) 1.04 - 1.16 (m, 4 H). LCMS (ES) = 324.1 [M+H]+, rt 0.50 min, Method 3.

[0921] Example 180

[0922] 3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide

[0923] 3-cyclopropyl-7-fluoro-5-iodo-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (75.0 mg, 1 Eq, 204.83 pmol) was weighed into a microwave vial with dimethylglycine (4.2245 mg, 0.2 Eq, 40.967 pmol), cesium carbonate (200.22 mg, 3 Eq, 614.50 pmol), and Cui (3.9011 mg, 0.1 Eq, 20.483 pmol). The solid mixture was covered with tetrahydro-2H-pyran-4-ol (20.920 mg, 1 Eq, 204.83 pmol) (~2 mL). This mixture was stirred for 2 min and then heated in the microwave at 110 °C for 2h. The reaction mixture turned greenish-blue quickly with microwave heating. LCMS showed the product. The reaction was heated to 110 °C for another 12h. The reaction showed no progression from the 2h timepoint. The reaction was heated in a heating block to 150°C for 18 h. Good progression was observed. The reaction was cooled to rt, filtered through a syringe filter, and purified directly on the MDAP (Formic Acid Prep LCMS Method B). The concentrated product was afforded as a tan solid (13 mg, 17% yield).1H NMR (400 MHz, METHANOL-d4) 5 7.30 (dd, J = 10.5, 2.7 Hz, 1 H), 7.13 - 7.09 (m, 1 H), 4.85 - 4.75 (m, 1 H), 4.06 (dt, J = 11.9, 3.9 Hz, 2H), 3.62 (td, J = 11.4, 2.2 Hz, 2H), 2.28 - 2.22 (m, 1 H), 2.19 - 2.11 (m, 2H), 1.97 - 1.88 (m, 2H), 1.28 - 1.22 (m, 3H), 1.16 - 1.10 (m, 3H). LCMS (ES) = 341.0 [M+H]+, rt 0.75 min, Method 2.

[0924] Example 181

[0925] 3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1- dioxide

[0926] AdCyBrettPhos, 0.1 eq

[0927] 5-bromo-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide (100.00 mg, 1

[0928] Eq, 313.33 pmol) was weighed into an 8 mL vial. The alcohol was also weighed into a 4 mL high recovery vial. The AdCyBrettPhos (20.296 mg, 0.11 Eq, 34.467 pmol) and Allylpalladium (II) 70311W001 chloride dimer (5.7323 mg, 0.05 Eq, 15.667 pmol) for each reaction were weighed into a single 8 mL vial. All vials were brought into the glovebox. The ligand and palladium vial was charged with 1.8 mL 1 ,4-Dioxane (1.5667 mL) and allowed to stir for 20 min till all of the Pd-salts were dissolved into a deep yellow-colored solution. The bromide vial was charged with sodium tert-butoxide (60.2 mg, 2 Eq, 626.66 pmol). The alcohol vial was each charged with 1 mL 1 ,4-Dioxane (1.5667 mL).

[0929] The alcohol solution was added to the bromide vial. The reaction vial was then treated with 0.6 mL of the catalyst solution. The vial was capped, removed from the glovebox, and parafilmed. The reaction was heated to 40 °C for 18 h and then cooled to rt and were allowed to stir for 48 h. The reaction was diluted with 1 mL DMSO, filtered through a syringe filter, and purified on the MDAP (Formic Acid Prep LCMS Method B) to afford the desired product as a tan solid (37 mg, 30% yield).1H NMR (400 MHz, DMSO-d6) 5 11.35 (s, 1 H), 7.38 (dd, J = 10.8, 2.4 Hz, 1 H), 7.14 (dd, J = 7.6, 2.7 Hz, 1 H), 4.09 (d, J = 6.8 Hz, 2H), 3.91 (br dd, J = 11 .2, 2.9 Hz, 2H), 3.40 - 3.34 (m, 2H), 2.47 - 2.38 (m, 1 H), 2.24 - 2.11 (m, 1 H), 1.79 (br dd, J = 12.7, 2.0 Hz, 2H), 1.40 - 1.28 (m, 2H), 1.13 - 1.06 (m, 2H), 1.06 - 1.01 (m, 2H). LCMS (ES) = 355.0 [M+H]+, rt 0.81 min, Method 2.

[0930] Example 182 was synthesized in an analogous manner to Example 181. 70311W001

[0931] Example 183 was synthesized in an analogous manner to Example 106.

[0932] Examples 184-187 were synthesized in an analogous manner to Example 116. 70311W001 70311W001 70311W001

[0933] Examples 188-191 were synthesized in an analogous manner to Example 116, with an additional HPLC purification step under high pH conditions (High pH MDAP Extended Method C) and a final chiral purification step using Chiral Method XQ. 70311W001 70311WG01

[0934] Examples 31 and 192 were synthesized using methods described for previous Examples 19, 20, and 7 to generate a racemic product mixture which was then separated using chiral separation method XR. Biological Data

[0935] A Ca2+mobilization assay was used to assess the activity of the compounds of this invention. A HEK293 cell line with stably expressing human MRGPRX2 and mouse Galpha15 70311W001 genes was used in the assay. Briefly, cells were seeded into black clear-bottomed 384-well plates at 1 .5 x 104cells / well and culture at 37°C for 24 hours prior to assay. On the day of assay, cells were loaded with Ca2+indicator dye in 20 pL Hank's buffered saline solution containing 25 mmol / L HEPES, pH 7.2 (assay buffer) supplemented with 2 pmol / L Fluo-4 dye (Molecular Probes), 2.5 mmol / L probenecid (Sigma) and 0.5 mmol / L Brilliant Black (MP Biomedicals). Activation of human MRGPRX2 by a peptide agonist, Cortistatin-14 (PCKNFFWKTFSSCK, Disulfide Bridge. 2-13, TFA salt, GeneScript), was measured on FLIPRTETRA(Molecular Devices) instrument as increased fluorescence intensity (488 nm excitation / 530 nm emission) upon receptor binding, leading to G-protein activation and Ca2+mobilization. An activation dose response curve was produced for Cortistatin-14 to determine the EC50 value of the agonist on the day of assay.

[0936] Compounds of this invention were prepared as 1 mM or 10 mM solution in DMSO. Serial dilutions of 11 concentrations at 3-folds were made in DMSO for each compound and then diluted in assay buffer prior to addition onto the dye-loaded cells (final testing concentration range of 100 pmol / L-100 pmol / L for compounds with final 1% DMSO in assay buffer). After 30 min incubation at 37°C, agonist Cortistatin-14 was added to the cell culture at 4xEC50 final concentration. Fluorescence intensity was measured on FLIPRTETRAfor compounds’ ability to inhibit agonist mediated MRGPRX2 activation. Dose dependent inhibition curves were fitted in ActivityBase (I DBS) data analysis platform to report a plC50 value for each individual compound dilution series.

[0937] The plC50s for each compound of this invention were averaged to determine a mean value, for a minimum of 2 experiments.

[0938] The compounds of Examples 1-192 (except Examples 2, 34, and 139) inhibited MRGPRX2 activation in the above method with a plC50 value between approximately 4.6 and 9.

[0939] The compound of Example 92 exhibited a plC50 of 8.8. The compound of Example 99 exhibited a plC50 of 8.8. The compound of Example 117 exhibited a plC50 of 7.7. The compound of Example 144 exhibited a plC50 of 8.2. The compound of Example 105 exhibited a plC50 of >9.7. The compound of Examples 2, 87, 105, 107, 111 , 112, 138, and 143 exhibited plC50 > 8.7. The compound of Example 183 and 185 each exhibited a plC50 of 6. The compound of Example 184 exhibited a plC50 of 8.7. The compound of Example 186 exhibited a plC50 of 8.6. The compound of Example 187 exhibited a plC50 of 6.4. The compound of Example 188 exhibited a plC50 of 8.9. The compound of Example 189 exhibited a plC50 of 8.5. The compound of Example 190 exhibited a plC50 of 9.2. The compound of Example 191 exhibited a plC50 of 8.7. The compound of Example 192 exhibited a plC50 of 8.3.

Claims

1. 70311W001CLAIMS1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof,wherein:R1is a C3-7 cycloalkyl optionally substituted by 1 or 2 groups independently selected from halo or C1-5 alkyl, or R1is a C1-5 alkyl optionally substituted by a C3-7 cycloalkyl;X1, X2, and X3are each independently N or CR2wherein each R2is independently selected from the group consisting of hydrogen, halo, cyano, Ci-3alkyl, and halo(Ci-3)alkyl;L1is selected from the group consisting of a bond,-O-, -OCi-3alkylene-, -C1- salkyleneO-, -Ci-salkyleneNH-, -NHCi-salkylene-, and -NH-;Ring A is a C3-10 cycloalkyl ring or a 4- to 10- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S; n is 0, 1 , 2, 3, or 4; each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2-ealkynyl, thio(Ci-e)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-e)alkyl, halo(Ci-6)alkyl, halo(C2-e)alkenyl, halo(Ci-e)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci-3alkylene- NR3R4, -N(R3)C(O)R4, -NR3CO2R4,-NR3SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci- 3alkyleneNHCi-3alkyl, -Ci-3alkyleneNR3R4, -C(O)NR3R4, -C(O)SR3, -C(O)OR3, -C(O)- hydroxy(Ci.3)alkyl, -CO2-halo(Ci-3)alkyl, -C(O)R3, -Ci-2alkylene-C(O)OR3, -S(O)R3, - S(O)2R3, -OSO2R3, and -L2-Y;R3, R4and R5are each independently selected from hydrogen, Ci-4alkyl, and halo(Ci-4)alkyl;L2is selected from the group consisting of a bond, -NR3-, -NR3C(O)-, -CH2-, - C(O)NR3-, -C(O)O-, -C(O)OCH2-, and -SO2-;Y is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl containing one, two or three heteroatoms independently selected from N, O, and S, C3-870311W001 cycloalkyl and a 4- to 8- membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O, and S, wherein Y is optionally substituted by one, two or three groups independently selected from halo, Ci-3alkoxy, Ci-3alkyl and halo(Ci-3)alkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X1, X2, and X3are each independently CF or CH.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X1is CH.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein X2is CH or CF.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein X3is CH.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X1is CH, X2is CF, and X3is CH.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R1is Cs-ecycloalkyl or ethyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R1is a cyclopropyl group.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein L1is selected from the group consisting of a bond, -NH-, -NHCH2-, -CH2NH- , -O-, -CH2O-and -OCH2-.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein L1is a bond.11 . The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein each Z1is independently selected from the group consisting of halo, hydroxy, oxo, cyano, Ci-4alkyl, Ci-4alkoxy, Cs-scycloalkyl, Cs-scycloalkenyl, C2-ealkenyl, C2- ealkynyl, thio(Ci-4)alkyl, hydroxy(Ci-e)alkyl, cyano(Ci-4)alkyl, halo(Ci-4)alkyl, halo(C2- 4)alkenyl, halo(Ci-4)alkoxy, halo(C3-8)cycloalkyl, hydroxy(C2-e)alkynyl, -NR3R4, -NR5Ci- 3alkylene-NR3R4, -N(R3)CO2R4, -N(R3)SO2R4, -NR3-hydroxy(Ci-3)alkyl, -Ci-3alkyleneNHCi.70311W0013alkyl, -Ci.3alkyleneNR3R4, -C(O)NR3R4,-C(O)SR3, -CO2R3, -C(O)-hydroxy(Ci-3)alkyl, - CO2-halo(Ci.3)alkyl, -C(O)R3, -Ci-3alkylene-C(O)OR3, -S(O)R3, -S(O)2R3, and -OSO2R3.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims1 to 10, wherein each Z1is independently selected from the group consisting of oxo, cyano, -NH2, -CH2NH2, -CH2-NH-CH3, -CH2NHCH(CH3)2, -C(CH3)2NH2, -OH, -OCF2H, - OCF3, -CH3, -CH2CH3, -CH(CH3)2-F, -CH2CF3, -CHF2, -CF2CH3, -CF3, -CO2-CH2CF3, - CO2-C(CH3)3, -CONH2, -CON(CH3)2, -CONHCH3, -COCH(OH)CH3, -COCH3, -CH2OH, - CH2CH2OH, -C(CH3)2OH, -SO2CH3, -SO2CH2CH3, -N(CH2CH3)2, -NHCH3, -NHC(CH3)3, - NHCH(CH3)2, -N(CH3)CH2CH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH(CH3)2, -NHCH2CH2NH2, -NHCH(CH3)CH2OH, -NHCO2C(CH3)3, -NHSO2CH3, -NHCH(CH3)CF3, cyclopropane, fluorocyclopropane, and -L2-Y;L2is selected from the group consisting of a bond, -NH-, -CO2CH2-, -CH2-, -SO2-, and -NHCO-; and Y is selected from the group consisting of phenyl, cyclopropyl, difluorocyclopropyl, cyclobutyl, oxetanyl, phenyl-OCH3, pyrrolidinyl, pyridinyl, imidazolyl, thiazolyl, and oxazolyl.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein n is 2.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims1 to 13, wherein the group representedselected from the group consisting of70311W00170311W001where * indicates the binding site; wherein Z1and n are as defined in accordance with claim 1 or any preceding claim, and wherein X4is selected from the group consisting of NH, O, and CH2, X5is selected from the group consisting of NH and O.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims1 to 14, wherein the compound of Formula (I) is a compound of Formula (II)wherein R1, X1, X2, X3, Z1, and n are as defined in accordance with claim 1 or any preceding claim, wherein p is 0, 1 , or 2, and each X6is independently selected from the group consisting of -CH2-, -NR6- and -O- wherein when p is 2, one X6is -CH2- and one X6is -NR6- or -O-; and70311W001R6are each independently selected from hydrogen and Ci-3alkyl which may be optionally substituted by one, two or three halo substituents.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims1 to 15, wherein the compound of Formula (I) is a compound of Formula (III)wherein R1, X1, X2, and X3are as defined in accordance with claim 1 or any preceding claim; wherein p is 0, or 1 ;X7is selected from the group consisting of CR7R8, C=O, NR9, and O; wherein R7is H or CH3;R8is selected from the group consisting of NHCH(CH3)2, C(CH3)2NH2, CH2NH2, CH2NHCH(CH3)2, NH2, N(CH3)CH2CH3, NHCH3, NHCH2CH2NH2, NHCH(CH3)CH2OH, C(O)NHCH3, C(O)NH2, NHCH2CH3, NH-cyclobutyl, pyrrolidinyl, NH-oxetanyl, NHSO2CH3, H, N(CH2CH3)2, OH, N(CH3)CH(CH3)2, and N(CH3)2; andR9is selected from the group consisting of C(O)CH3, oxetanyl, CH2CH2OH, CH3, H, C(O)CH(OH)CH3, SO2CH3, and C(O)OC(CH3)3.

17. The compound or pharmaceutically acceptable salt thereof according to claim 16, wherein X7is selected from the group consisting of CH2, CHOH, NH, and O.

18. The compound or pharmaceutically acceptable salt thereof according to claim 16 or 17, wherein R7is H, and R8is -CH2NH2, -CH2NHCH(CH3)2, -OH, -CH2NHCH3and - NHCH(CH3)CF3.70311W00119. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of: 3-cyclopropyl-7-fluoro-5-((1S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,3R,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;3-cyclopropyl-7-fluoro-5-((1R,5S)-2-(trifluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1);3-cyclopropyl-7-fluoro-5-((1R,5S)-2-(trifluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2);3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(2-hydroxyethyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-methyl-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1R,3R,4R)-5-methyl-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((1S,3S,4S)-5-ethyl-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(oxetan-3-yl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,2S,5R)-2-(trifluoromethyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; benzyl (1 R,4R,6R)-5-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-6-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;3-cyclopropyl-7-fluoro-5-((1R,3R,4R)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide;3-ethyl-7-fluoro-5-((1S,3S,4S)-3-(trifluoromethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((1R,5S,7R)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan- 6-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide; rac-3-cyclopropyl-7-fluoro-5-((1R,5S,7S)-7-(trifluoromethyl)-3,6-diazabicyclo[3.2.1]octan- 6-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide;3-cyclopropyl-7-fluoro-5-((1R,3S,4S)-3-(trifluoromethyl)-2-azabicyclo[2.2.1]heptan-2-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;70311W001 tert-butyl 4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-3-(trifluoromethyl)piperazine-l -carboxylate; rac-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(4-(2-hydroxyethyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-(4- methoxybenzyl)-5-(trifluoromethyl)piperazin-2-one;4-(3-cyclopropyl-7-fluoro-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thi ad iazi n-5-y l)-5- (trifluoromethyl)piperazin-2-one;3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine1 ,1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)azetidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine1 ,1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(4-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(4-hydroxy-2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine1 ,1 -dioxide;3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-(R)-3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,5R)-2-methyl-5-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide70311W0013-cyclopropyl-7-fluoro-5-((2R,5S)-2-methyl-5-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;Trans-rac-5-((2S,4R)-4-amino-2-(trifluoromethyl)pyrrolidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(7-(trifluoromethyl)-1 ,4-diazepan-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(2-(trifluoromethyl)pyrrolidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(2-methylpyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide;3-cyclopropyl-7-fluoro-5-(piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,3R)-3-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-1-ethyl-5-(trifluoromethyl)piperazin-2-one; rac-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-2-methyl-3-(trifluoromethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); cis-rel-1-(3-cyclopropyl-7-fluoro-1,1-dioxo-4H-1A6,2,4-benzothiadiazin-5-yl)-2- (trifluoromethyl)pyrrolidine-3-carboxylic acid;Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); trans-rel-3-cyclopropyl-7-fluoro-5-((2S,3S)-3-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);Trans-rel-3-cyclopropyl-7-fluoro-5-((2R,3R)-3-(2-hydroxypropan-2-yl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);70311W0013-cyclopropyl-7-fluoro-5-(4-hydroxy-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-(R)-3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-5-(3-(difluoromethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide; rel-(R)-3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-(R)-3-cyclopropyl-5-(3-(1,1-difluoroethyl)morpholino)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);3-cyclopropyl-7-fluoro-5-((2R,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,5R)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,5S)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide3-cyclopropyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-(6,6-difluoro-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-(piperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(3-methylpiperazin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;3-cyclopropyl-7-fluoro-5-(4-(isopropylamino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;5-(4-aminopiperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;70311W0013-ethyl-7-fluoro-5-((2R*,5S)-5-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-ethyl-7-fluoro-5-(3-(trifluoromethyl)morpholino)-4H-benzo[e][1 ,2,4]thiadiazine 1,1- dioxide;(S)-3-ethyl-7-fluoro-5-(2-(trifluoromethyl)piperazin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;(R)-3-ethyl-7-fluoro-5-(2-(2,2,2-trifluoroethyl)piperazin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;3-ethyl-7-fluoro-5-(3-(2,2,2-trifluoroethyl)morpholino)-4H-benzo[e][1,2,4]thiadiazine 1,1- dioxide;3-ethyl-7-fluoro-5-(2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-ethyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1); rel-3-ethyl-7-fluoro-5-((2R,5R)-2-methyl-5-(2,2,2-trifluoroethyl)morpholino)-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); rel-5-((2R,4R)-4-amino-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); rel-5-((2R,4R)-4-amino-4-methyl-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2); rac-5-((2R,4S)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2S,4R)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-ethyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2S,4R)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2R,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((1-hydroxypropan-2-yl)amino)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R*)-1-hydroxypropan-2-yl)amino)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1);70311W0013-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R*)-1-hydroxypropan-2-yl)amino)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);3-cyclopropyl-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((2R,4S)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((propan-2-yl-d7)amino)-2-(trifluoromethyl)piperidin-1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((2S,4R)-4-(ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((2S,4R)-4-(diethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((2S,4R)-4-(dimethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropyl(methyl)amino)-2-(trifluoromethyl)piperidin- 1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(pyrrolidin-1-yl)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2S,4R)-4-((2-aminoethyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methyl-d3)amino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((2S,4R)-4-(ethyl(methyl)amino)-2-(trifluoromethyl)piperidin-1-yl)-7- fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(R)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-one;(S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2-(trifluoromethyl)piperidin-4-one;3-cyclopropyl-7-fluoro-5-((2S,4S)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2S,4S)-4-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;70311W0015-((2S,4S)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1 -yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;5-((2S,4R)-4-(tert-butylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((R)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((S)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4S)-2-(trifluoromethyl)-4-(((S)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide;(R)-3-cyclopropyl-7-fluoro-5-(4-(methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(4-(methylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1S,3S,4S)-5-(methylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((1 R,3R,4R)-5-(methylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((1S,3S,4S)-5-(ethylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-5-((1S,3S,4S)-5-(cyclopropylsulfonyl)-3-(trifluoromethyl)-2,5- diazabicyclo[2.2.1 ]heptan-2-yl)-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidin-4-yl)methanesulfonamide;Cis-rel-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-2-(trifluoromethyl)piperidin-4-yl)methanesulfonamide (Isomer 1);Cis-rel-N-((2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)-2-(trifluoromethyl)piperidin-4-yl)methanesulfonamide (Isomer 2);(R)-1-(4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3-(trifluoromethyl)piperazin-1-yl)ethan-1-one;(S)-1-((R)-4-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-3- (trifluoromethyl)piperazin-1-yl)-2-hydroxypropan-1-one; rac-cis-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-N,N- dimethyl-2-(trifluoromethyl)pyrrolidine-3-carboxamide; rac-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide; rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1 ,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide (Isomer 1);70311W001 rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-2- (trifluoromethyl)piperidine-4-carboxamide (Isomer 2); rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-N- methyl-2-(trifluoromethyl)piperidine-4-carboxamide (Isomer 1); rel-(2R,4S)-1-(3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5-yl)-N- methyl-2-(trifluoromethyl)piperidine-4-carboxamide (Isomer 2);(R)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;(S)-3-cyclopropyl-7-fluoro-5-(4-(oxetan-3-yl)-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 1);3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2);5-((2S,4R)-4-(cyclobutylamino)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(oxetan-3-ylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1);3-cyclopropyl-7-fluoro-5-((2R,4S)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2);Cis-rac-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1 -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); rel-3-cyclopropyl-7-fluoro-5-((2R,3S)-3-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2); trans- rel-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1);Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 1); trans-rel-3-cyclopropyl-7-fluoro-5-((2R,4S)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Isomer 2);70311W001Cis-rel-3-cyclopropyl-7-fluoro-5-((2R,4R)-4-(hydroxymethyl)-2-(trifluoromethyl)pyrrolidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide (Isomer 2); rac-5-((2R,5R)-5-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; rac-5-((2R,3S)-3-amino-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)oxazole-4-carboxamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)cyclopropane carboxamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)benzamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)nicotinamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)-1 H-imidazole-5-carboxamide;(S)-N-((1s,4R)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)-2,2-difluorocyclopropane-1 -carboxamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)isoxazole-5-carboxamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)isoxazole-3-carboxamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)picolinamide;N-((1s,4s)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)thiazole-4-carboxamide;N-((1s,4s)-4-((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)benzamide;N-((1s,4s)-4-((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)cyclopropanecarboxamide;N-((1s,4s)-4-((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-5- yl)amino)cyclohexyl)picolinamide; tert-butyl 3-(((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate;3-cyclopropyl-7-fluoro-5-(((1-(2,2,2-trifluoroethyl)pyrrolidin-2-yl)methyl)amino)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; tert-butyl ((1R,3R)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate;70311W001 tert-butyl (4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)bicyclo[2.1.1 ]hexan-1 -yl)carbamate; tert-butyl ((1S,3S)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate; tert-butyl ((1S,3R)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclopentyl)carbamate; tert-butyl ((1r,4r)-4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)cyclohexyl)carbamate; rac-tert-butyl ((1R,3S)-3-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H- benzo[e][1,2,4]thiadiazin-5-yl)amino)cyclopentyl)carbamate; 2,2,2-trifluoroethyl 3-(((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholine-4-carboxylate; Cyclopropyl(3-(((3-cyclopropyl-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)amino)methyl)morpholino)methanone; (3-(((3-cyclopropyl-1 , 1 -dioxido-4H-benzo[e][1 , 2 , 4]thiadiazi n-5- yl)amino)methyl)morpholino)(2,2-difluorocyclopropyl)methanone;3-cyclopropyl-7-fluoro-5-(3-(trifluoromethyl)piperidin-4-yl)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide; 3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)oxy)-4H-benzo[e][1,2,4]thiadiazine 1 ,1 -dioxide;3-cyclopropyl-7-fluoro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; benzyl 4-((3-cyclopropyl-7-fluoro-1,1-dioxido-4H-benzo[e][1 ,2,4]thiadiazin-5- yl)oxy)piperidine-1 -carboxylate; 3-cyclopropyl-7-fluoro-5-((2S,4S)-4-(methylamino)-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; 3-cyclopropyl-5-((2S,4R)-4-(((R)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 3-cyclopropyl-5-((2S,4S)-4-(((R)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 3-cyclopropyl-5-((2S,4R)-4-(((S)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 3-cyclopropyl-5-((2S,4S)-4-(((S)-1 ,1-difluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-7-fluoro-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((R)-1-fluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide; 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((R)-2-methylaziridin-1-yl)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;70311W0013-cyclopropyl-7-fluoro-5-((2S,4R)-4-(((S)-1-fluoropropan-2-yl)amino)-2- (trifluoromethyl)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide;3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((S)-2-methylaziridin-1-yl)-2- (trifluoromethyl)piperidin-l -yl)-4H-benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; and (S)-3-cyclopropyl-7-fluoro-5-(4-methyl-2-(trifluoromethyl)piperazin-1-yl)-4H- benzo[e][1 ,2,4]thiadiazine 1 , 1 -dioxide; or a pharmaceutically acceptable salt thereof.

20. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 5-((2S,4R)-4-(aminomethyl)-2-(trifluoromethyl)piperidin-1-yl)-3-cyclopropyl-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide as represented by the following structure:or a pharmaceutically acceptable salt thereof.

21. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-5-((2S,4R)-4-(ethylamino)-2-(trifluoromethyl)piperidin-1-yl)-7-fluoro-4H- benzo[e][1,2,4]thiadiazine 1,1 -dioxide as represented by the following structure:or a pharmaceutically acceptable salt thereof.

22. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-7-fluoro-5-((2S,4R)-2-(trifluoromethyl)-4-(((S)-1 ,1 ,1-trifluoropropan-2- yl)amino)piperidin-1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide as represented by the following structure:70311W001or a pharmaceutically acceptable salt thereof.

23. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((methylamino)methyl)-2-(trifluoromethyl)piperidin-1- yl)-4H-benzo[e][1,2,4]thiadiazine 1,1 -dioxide as represented by the following structure:or a pharmaceutically acceptable salt thereof.

24. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-hydroxy-2-(trifluoromethyl)piperidin-1-yl)-4H- benzo[e][1,2,4]thiadiazine 1,1-dioxide as represented by the following structure:or a pharmaceutically acceptable salt thereof.

25. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-((isopropylamino)methyl)-2-(trifluoromethyl)piperidin- 1-yl)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide as represented by the following structure:70311W001or a pharmaceutically acceptable salt thereof.

26. The compound or pharmaceutically acceptable salt thereof according to claim 1 , which is 3-cyclopropyl-7-fluoro-5-((2S,4R)-4-(isopropylamino)-2-(trifluoromethyl)piperidin-1-yl)- 4H-benzo[e][1 ,2,4]thiadiazine 1 ,1 -dioxide as represented by the following structure:or a pharmaceutically acceptable salt thereof.

27. The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein the compound is in its free base or free acid form.

28. The compound or pharmaceutically acceptable salt thereof according to any preceding claim, wherein the compound is a pharmaceutically acceptable salt.

29. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 28 and a pharmaceutically acceptable excipient.

30. A compound or a pharmaceutically acceptable salt thereof according to any of claims 1 to 28, for use in therapy.31 . A compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 28, for use in the treatment of an MRGX2-mediated disease or disorder.70311W00132. The compound or pharmaceutically acceptable salt thereof for use according to claim 31 , wherein the disease or disorder is selected from the group consisting of Allergic rhinitis, Asthma, Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug- induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, and Pseudo anaphylaxis.

33. The compound or pharmaceutically acceptable salt thereof for use according to claim 31 , wherein the disease or disorder is chronic spontaneous urticaria.

34. A method of treating an MRGX2-mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 28 or the pharmaceutical composition of claim 29.

35. The method according to claim 34, wherein the disease or disorder is selected from the group consisting of Allergic rhinitis, Asthma, Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis.

36. The method according to claim 34, wherein the disease or disorder is chronic spontaneous urticaria.70311W00137. Use of the compound or pharmaceutically acceptable salt thereof according to any of claims 1 to 28, in the manufacture of a medicament for use in the treatment of an MRGX2- mediated disease or disorder.

38. The use according to claim 37, wherein the disease or disorder is Allergic rhinitis, Asthma,Atopic dermatitis, Bronchial asthma, Chronic inducible urticaria, Chronic obstructive pulmonary disease, Chronic pain, Chronic spontaneous urticaria, Cold urticaria, Contact urticaria, Cough, Crohn’s disease, Cutaneous mastocytosis, Drug-induced anaphylactoid reactions, Eosinophilic esophagitis (EOE), Fibromyalgia, Food allergy, idiopathic pulmonary fibrosis, Inflammatory pain, Interstitial cystitis, Irritable bowel syndrome, Mast cell activation syndrome (MCAS), Mastocytic enterocolitis, Mastocytosis, Metabolic syndrome, Microbial infection, Migraine, Nasal polyps, Neuropathic pain, Oesophagus reflux, Osteoarthritis, Prurigo nodularis, Pruritis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis, Rosacea, Systemic lupus erythematosus (SLE), Systemic mastocytosis, Ulcerative colitis, Urinary tract infection, Pseudo anaphylaxis.

39. The use according to claim 37, wherein the disease or disorder is chronic spontaneous urticaria.

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