Sodium channel blocking compounds, derivatives thereof, and methods of their use

Abstract

The invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel Nav1.8, and methods of treating a subject with those compounds for conditions such as pain, itch, and cough.

Description

[0001]LTGO-017 / 01WO 36088 / 98 Patent Application SODIUM CHANNEL BLOCKING COMPOUNDS, DERIVATIVES THEREOF, AND METHODS OF THEIR USE Field of the Invention The application relates generally to sodium channel blocking compounds, derivatives 5 thereof, and the use of such compounds as pharmacological agents. Background Millions of people suffer from conditions associated with pain, itch, and / or cough. Pain can be a symptom or cause of conditions such as neuropathy, hyperalgesia, and opioid use disorders. In many cases, drugs used to treat such condition fail to provide relief or produce 10 intolerable side effects. Therefore, existing treatments are inadequate for many patients who suffer from a variety of conditions. Summary The invention provides compounds that are useful for treatment of conditions associated with aberrant activity of voltage gated sodium channel NaV1.8, such as pain, itch, and cough. 15 In one aspect, the invention provides a compound of Formula (I): (I) or a tautomer thereof, or a p , hydrate and solvate thereof, wherein: R1a, R1b , R2a, R2b R3a, R3b are independently H, D, halo, hydroxyl, C1-C8 alkyl, C3-C620 cycloalkyl, deuterated C1-C8alkyl wherein the alkyl chain may be fully or partially deuterated, C1- C8fluoroalkyl wherein the alkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the 1 LTGO-017 / 01WO 36088 / 98 Patent Application alkoxy may be fully or partially halogenated, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted aryloxy,C2-C6alkenyl, C2-C6alkynyl, -[C(R8)(R9)]m-C3-C8- cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8 cycloalkyl, -[C(R8)(R9)]m-C3-C8 cycloalkenyl, - [C(R8)(R9)]m- C6-C10 aryl,-[C(R8)(R9)]m-N(R8)(R9), or -[C(R8)(R9)]m-C3-C8 heterocycloalkyl 5 wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and with the proviso that at least one of R1a, R1b, R2a, R2b R3a, R3b is not H or D; wherein any of said alkyl, alkenyl, or alkoxy moieties above may be further substituted with one, two, three or four R5substituents, where R5is individually and independently selected from halo, C1-C8alkyl, C3-C6cycloalkyl, deuterated C1-C8alkyl 10 wherein the alkyl chain may be fully or partially deuterated, C1-C8 fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6 alkoxy, C1-C6 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated; wherein any of R1a, R1b, R2a, R2b, R3a, or R3b may be optionally connected to another of R1a, R1b, R2a, R2b, R3a, or R3b through individual alkyl, fluoroalkyl, or alkoxy moieties 15 to form a spirocyclic, fused bicyclic, or bridged bicyclic ring; R2aand R2bmay optionally together form a substituted or unsubstituted exocyclic alkene, wherein alkene substituents are H, fluoro, C1-C6alkyl, aryl or C3-C6 heteroaryl; R4a is H, -OH, halo, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl wherein the alkyl may be fully or partially halogenated, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy 20 wherein the alkoxy may be fully or partially halogenated, -L1-(C1-C8 alkyl), -L1-(C1-C8 cycloalkyl), -L1- (C1-C8 haloalkyl), -L1-(C1-C8 cyclohaloalkyl), -L1-(C1-C8 alkoxy), L1-(C1-C8 cycloalkoxy), -L1-L2-(C2-C6alkyl)-OR4b, -L1-(C1-C6alkenyl)-OR4b, -L1-(C1-C6alkyl)-NR4cR4d, or -L1-L2-R4e; R4b, R4c, and R4d are independently H, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 25 haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy; and R4eis C3-C6cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, - C(O)O(C1-C8 alkyl), -COOH, or C(O)NR4cR4d, wherein said C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted by one or more halo, - OH, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy; and 30 L1 is a bond or O; L2 is a bond, C1-C6 alkyl or C1-C6 alkenyl; 2 LTGO-017 / 01WO 36088 / 98 Patent Application X2a, X2b, X2c, and X2d are independently N or C-R4f; wherein each R4fon X2a, X2b, X2c, and X2dis independently H, -OH, halo, C1-C8alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 cycloalkoxy, C1-C8 haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, - 5 NR4cC(O)C1-C8alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8alkyl, -S(O)2NR4cR4d, -S(O)C1-C8alkyl, or —P(O)(C1-C8 alkyl)2, wherein said C1-C8 alkyl, C1-C8 alkoxy, 3-7 membered heterocycloalkyl, 5 or 6-membered heteroaryl, or -NR4cC(O)C1-C8 alkyl is optionally substituted by one or more R4c, C3-C8cycloalkyl, -NR4cR4d, -OR4b, -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R4c. 10 R5a is -[C(R6)(R7)]n-R5c; R5b is H, C1-C4 alkyl, or R5a and R5b together with the nitrogen to which they are attached form a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted by one or more R5d; R5c is 5-10 membered heteroaryl, pyridinyl, pyridazinyl, pyrimidinyl, phenyl, 6-10 15 membered aryl, 3-7 membered heterocycloalkyl, wherein the R5csubstituent is further optionally substituted by one or more R5d; R5d is hydrogen, deuterium, oxo, halo, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially 20 or fully deuterated, nitro, cyano, SR8, S(O)R8, S(O)2R8, NR8NR9, -(CH2)nS(O)2NR8R9 (n is 0, 1, or 2), -(CH2)nCO NR8R9, -NHS(O)2R8, -C(O)OR8, C(O)NR8R9, -NHC(=O)-alkyl - NH(C=O)NR8R9, -SO(=NH)R4, -SO(=NR7)R4,-O-(CH2)1-5C(=O)NR8R9, -C(R8)(R9)-cycloalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one 25 heteroatom independently selected from O, S, and N; R4is C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or C3-C7 cycloalkyl; R6 is H, D, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; 30 R7 is H, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; 3 LTGO-017 / 01WO 36088 / 98 Patent Application R8 is H, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R9 is H, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; and 5 m and n are independently 0, 1, or 2. In certain embodiments, all R1a, R1b, R2a, R2b R3a, R3b are H or D. In certain embodiments, all R1a, R1b, R2a, R2b R3a, R3b are H. In certain embodiments, the compound is a compound of Formula (II): II) 10 or a tautomer thereof, or a hydrate and solvate thereof, wherein: R1a, R1b, R2a, R2b R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. In certain embodiments, the compound is a compound of Formula (III): II) or a tautomer thereof, or a hydrate and solvate thereof, 15 wherein: R2a, R2b R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. In certain embodiments, the compound is a compound of Formula (IV): 4 LTGO-017 / 01WO 36088 / 98 Patent Application V) or a tautomer thereof, or a , hydrate and solvate thereof, wherein: R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above; p is 0, 1, or 2; 5 R6a and R6b are independently: hydrogen, -OH, deuterium, halo, cyano, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4 alkyl wherein the C1-C4alkyl may be fully or partially deuterated, or C1-C8fully or partially fluorinated fluoroalkyl; Y1 is C(R6a)(R6b) or N(R6);10Y2 = CH2, O or N(R6); and each Y3is independently CH2or OCH2. In certain embodiments, the compound is a compound of Formula (V): V) or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof,15wherein R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. In certain embodiments, the compound is a compound of Formula (VI): 5 LTGO-017 / 01WO 36088 / 98 Patent Application I) or a tautomer thereof, or a hydrate and solvate thereof, wherein R2b, R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2dare defined above. In certain embodiments, Y1is C(R6a)(R6b), R6aor R6bare independently H or CH3. 5 In certain embodiments, R5a is selected from the group consisting of: 6 LTGO-017 / 01WO 36088 / 98 Patent Application 5 In certain embodiments, R2a and R2b are independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, fluorinated cyclopropyl, cyclopentyl, -OCH3, - 7 LTGO-017 / 01WO 36088 / 98 Patent Application CF3, -OCD3, -OCH2-CH3, -CHF2, -CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, -OCH2- In certain embodiments, R2aand R2bare independently -CF3and -CH3. 5 In certain embodiments, R2a and R2b are both -CH3. In certain embodiments, R2a is CF3 and R2b is alkoxy. In certain embodiment, R2ais CF3and R2bis -OCH3. In certain embodiments, R2ais CF3and R2bis alkyl. In certain embodiments, wherein R2a and R2b combine to form 3-6 membered substituted 10 or unsubstituted cycloalkyl or heterocycloalkyl spiro ring, wherein one or more hetero atoms in the spiro ring are O or N. In certain embodiments, the spiro ring is substituted or unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R2aand R2bcombine to form the spirocycli , and spirocyclic . 15 In c diments, R1aand R1bare independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, cyclopentyl, -OCH3, -CF3, -OCD3, -OCH2-CH3, -CHF2, - CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, -OCH2-CF3, -CH2-CF3, -CH2-CF3, phenyl, or fluorinated phenyl. In certain embodiments, R1aand R1bcombine to form spirocyclic substituted or 20 unsubstituted cycloalkyl. In certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R1aand R1bare independently -CF3and -CH3. In certain embodiments, X2a, X2b, X2c, and X2d are independently C-R4f; wherein each R4f is independently selected from the group consisting of: H, -OH, halo, C1-C8 alkyl, C1-C8 25 cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, - 8 LTGO-017 / 01WO 36088 / 98 Patent Application NR4cC(O)C1-C8 alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8 alkyl, -S(O)2NR4cR4d, -S(O)C1-C8 alkyl, or —P(O)(C1-C8alkyl)2, wherein said C1-C8alkyl, C1-C8alkoxy, 3-7 membered heterocycloalkyl, 5 or 6-membered heteroaryl, or -NR4cC(O)C1-C8 alkyl is optionally substituted by one or more R4c, C3-C8 cycloalkyl, -NR4cR4d, -OR4b, -CN, and 3-7 membered heterocycloalkyl optionally 5 substituted by one or more R4c, wherein R4c, R4d, and R7are defined above. In certain embodiments, R4f is selected from the group consisting of hydrogen, fluoro, chloro, -COOH, -OCF2H, -OCH3, -O-CH2-CH3, -OCD3, -OCH(CH3)2, cyclopropyl, and -CF3. In certain embodiments, R5bis hydrogen. In certain embodiments, R5a is selected from the group consisting , 10 . In certain embodiments, R5a is selected from the group consistin . and . iments, R3a and R3b are both hydrogen. 15 In certain embodiments, R3aand R3bare not halogen, hydroxy, or alkoxy. In certain embodiments, R1a, R1b , R2a, R2b R3a, R3b are independently H, halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, 20 haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6 alkenyl, C2-C6 alkynyl, -[C(R8)(R9)]m-C3-C8-cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8cycloalkyl, -[C(R8)(R9)]m-C3-C8cycloalkenyl, -[C(R8)(R9)]m-N(R8)(R9), or -[C(R8)(R9)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; and 9 LTGO-017 / 01WO 36088 / 98 Patent Application when m is 0, R1a, R1b, R2a, R2b R3a, R3b are independently -C3-C8-cycloalkoxy, -C3-C8 cycloalkyl, -N(R8)(R9), or -C3-C8heterocycloalkyl, wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N. In certain aspects, the invention provides a compound selected from the compounds 5 provided in Table A. Table A: 10 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 12 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 16 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application In certain aspects, the invention provides a compound selected from the compounds provided in Table B. Table B: 19 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 21 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 23 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 25 LTGO-017 / 01WO 36088 / 98 Patent Application 26 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 31 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 33 LTGO-017 / 01WO 36088 / 98 Patent Application 34 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 36 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 40 LTGO-017 / 01WO 36088 / 98 Patent Application In another aspect, the invention provides inhibitors of a voltage gated sodium channel NaV1.8. The inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above. 5 In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above. The condition may be associated with aberrant activity of voltage gated sodium channels. The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, 10 acute itch, acute pain, acute pain in major trauma / injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, 15 chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy 20 (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry's disease, facet joint 41 LTGO-017 / 01WO 36088 / 98 Patent Application syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, 5 melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from 10 diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress 15 disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, 20 trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. In another aspect, the invention provides methods of making a medicament using a compound of the invention, such as any of those described above. In another aspect the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of 25 those described above, in a subject. Detailed Description Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this presently 30 described subject matter belongs. The definitions provided below are intended to supplement and 42 LTGO-017 / 01WO 36088 / 98 Patent Application illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure. Unless otherwise stated, the moieties described below are optionally substituted, i.e., they may be substituted at one or more positions. The terms substituted, whether preceded by the term 5 “optionally” or not, and substituent, as used herein, refer to the ability to change one or more functional groups for another functional group or groups on a molecule, provided that the valency of all atoms is maintained. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. The substituents also may be further substituted (e.g., an aryl 10 group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions). When the term “independently selected” is used, the substituents being referred to (e.g., R groups, such as groups R1, R2, and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R1 and R2 can be substituted alkyls, or R1 can be hydrogen and R2 can 15 be a substituted alkyl, and the like. The terms “a,” “an,” or “a(n),” when used in reference to a group of substituents herein, mean at least one. For example, where a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” 20 Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. A named “R” or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein. For the purposes of illustration, certain representative “R” groups as set forth above are defined below. 25 Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and / or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as 30 aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with 43 LTGO-017 / 01WO 36088 / 98 Patent Application principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds. Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein. 5 The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in the art, all valences must be satisfied in making any substitutions. The hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, 10 isopropyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like. The term “alkyl” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic saturated hydrocarbon group, or combination thereof, and can include di- and multivalent groups, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 15 carbons). In particular embodiments, the term “alkyl” refers to C1-20 inclusive, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons, linear (i.e., “straight-chain”), branched, or cyclic saturated hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom. Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, 20 n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologues and isomers thereof. “Branched” refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having 1 to about 25 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term “alkyl group substituent” includes 30 but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There 44 LTGO-017 / 01WO 36088 / 98 Patent Application can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl. Thus, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one 5 or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto. The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain having from 1 to 20 carbon atoms or 10 heteroatoms or a cyclic hydrocarbon group having from 3 to 15 carbon atoms or heteroatoms, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom, such as O, N, P, Si or S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl15 group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2- CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)- CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)- CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. 20 As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)NR’, -NR’R”, -OR’, -SR, -S(O)R, and / or -S(O2)R’. “Cycloalkyl” refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group also 25 can be optionally substituted with an alkyl group substituent as defined herein, oxo, and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. 30 Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyeiohexenyl, cycloheptyl, and the like. 45 LTGO-017 / 01WO 36088 / 98 Patent Application The term “cycloalkylalkyl,” as used herein, refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkylene moiety, also as defined above, e.g., a C1-20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. 5 The term “carbocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which all ring members are carbon atoms. Unless otherwise specified, a carbocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 10 to about 15 ring members in which at least one ring member is a heteroatom, such as N, O, or S. Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, 3-oxetanyl, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, 15 tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl, isothiozolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the aforementioned groups. 20 The terms “cycloheteroalkyl” and “heterocycloalkyl” refer to a saturated ring system, such as a 3- to 10-member cycloalkyl ring system, that include one or more heteroatoms. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocycloalkyl include, but are not limited to, 1-(l, 2,5,6-tetrahydropyridyi), 1- piperidmyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-3-yl, 25 tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having from one to three heteroatoms, such as oxygen, sulfur, and nitrogen, in which the nitrogen 30 and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused 46 LTGO-017 / 01WO 36088 / 98 Patent Application six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6- membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may 5 optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like. 10 An unsaturated hydrocarbon, carbocyclyl, or heterocyclyl has one or more double bonds or triple bonds. Examples of unsaturated hydrocarbons include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term “alkenyl” as used herein refers to a monovalent group derived from a C2-C20 15 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl. The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least 20 one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. The term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-C20 hydrocarbon of a designed number of carbon atoms containing at least one25 carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), l- propynyl, pentynyl, hexynyl, and heptynyl groups, and the like. The term “alkylene” by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The 30 alkylene group can be straight, branched, or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more “alkyl group substituents.” There can be optionally 47 LTGO-017 / 01WO 36088 / 98 Patent Application inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (- CH2-CH2-); propylene (CH2)3, cyclohexylene (-C6H10-, -CH=CH-CH=CH-, -CH=CH-CH2-, - 5 CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-N(R)-(CH2)r-, wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The term “heteroalkylene” by itself or as part of another substituent means a divalent group10 derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S- CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the 15 formula -C(O)OR’- represents both -C(O)OR’- and -R’OC(O)-. The term “spirocyclyl” refers to a polycyclic compound in which two rings have a single atom, e.g., carbon, as the only common member of two rings. Thus, a “spirocycloalkyl” refers to a cycloalkyl group with two rings having a single carbon in common, and a “spiroheterocycloalkyl” or “spiroheterocycloalkyl” refers to a cycloheteroalkyl group with two 20 rings having a single carbon or other atom, e.g., nitrogen, in common. The term “aryl” means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently. The term “heteroaryl” refers to and groups (or rings) that contain from one to four 25 heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl,30 pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- 48 LTGO-017 / 01WO 36088 / 98 Patent Application pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzoihiazolyl, purinyl, 2-benzimidazolyl, 5- indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-qumolyl, and 6-quinolyl. Substituents for each of above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the 5 divalent forms of aryl and heteroaryl, respectively. Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g., “3 to 7 membered”), the term “member” refers to a carbon atom or heteroatom. Each of the above terms is meant to include both substituted and unsubstituted forms of the indicated group. In some instances, the groups are explicitly defined as substituted, for 10 example, “substituted aryl.” The optional substituents are provided below. Substituents can be one or more of a variety of groups selected from, but not limited to: - OR’, =O, =NR’, =N-OR’, -NR’R” -SR’, -halogen, -SiR’R”R”, -OC(O)R, -C(O)R, -CO2R - C(O)NR’R”, -OC(O)NR’R”, -NR”C(O)R, -NR’-C(O)NR”R’”, -NR”C(O)OR’, -NR- C(NR’R”)=NR”’, -S(O)R, -S(O)2R’, -S(O)2NR’R”, -NRSO2R’, -CN, CF3, fluorinated C1-C4 alkyl, 15 and -NO2in a number ranging from zero to (2m’ +1), where m’ is the total number of carbon atoms in such groups. R’, R”, R’” and R”” each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Other non- 20 limiting examples of substituents include (C1-C6)alkyl, (C2-C8)alkenyl, (C3-C8)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -O(C1-C6)alkyl, halo(C1-C6)alkoxy, (C3-C8)cycloalkyl, (C6-C10)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1- C6)alkyl(C6-C10)aryl, -C(O)(C1-C6)alkyl, -C(O)NR’R”, -S(O)(C1-C6)alkyl, -S(O)NR’R”, - S(O)2(C1-C6)alkyl, -S(O)2NR’R”, -O(C1-C6)alkyl-S(O)(C1-C6)alkyl, -O(C1-C6)alkyl-S(O)NR’R”, 25 -O(C1-C6)alkyl-S(O)2(C1-C6)alkyl, and -O(C1-C6)alkyl-S(O)2NR’R”. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen. When a compound of the disclosure includes more than one R group, for example, each of the R groups is independently selected as are each R’, R”, R’” and R”” groups when more than one of these groups is present. When R’ and R” are attached to the same nitrogen atom, they can 30 be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR’R” is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above 49 LTGO-017 / 01WO 36088 / 98 Patent Application discussion of substituents, one of ordinary skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e. g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). 5 Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)q-U-, wherein T and U are independently -NR-, -O-, -CRR’- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A- (CH2)r-B-, wherein A and B are independently -CRR’-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, - 10 S(O)2NR’- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR’)s-X’-(C”R’”)d-, where s and d are independently integers of from 0 to 3, and X’ is -O-, -NR’-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR’-. 15 The substituents R, R’, R” and R” may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. As used herein, the term “acyl” refers to an organic acid group wherein the -OH of the carboxyl group has been replaced with another substituent and has the general formula RC(=O)-, 20 wherein R is an alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic, or aromatic heterocyclic group as defined herein). As such, the term “acyl” specifically includes aryl acyl groups, such as a 2-(furan-2-yl)acetyl)- and a 2-phenylacetyl group. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also are intended to include amides, -RC(=O)NR, esters, -RC(=O)OR’, ketones, -RC(=O)R’, and aldehydes, -RC(=O)H. 25 The terms “alkoxyl” or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C1-C20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, 30 isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like. 50 LTGO-017 / 01WO 36088 / 98 Patent Application The term “alkoxy alkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group. “Aryloxyl” refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or 5 hexyloxyl, and alkyl, substituted alkyl, halo, or alkoxyl substituted phenyloxyl or hexyloxyl. “Aralkyl” refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously 10 described. An exemplar)' aralkyloxyl group is benzyloxyl, i.e., C6H5CH2-O-. An aralkyloxyl group can optionally be substituted. “Alkoxycarbonyl” refers to an alkyl-O-C(=O)- group. Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl. “Aryloxycarbonyl” refers to an aryl-O-C(=O)- group. Exemplary aryloxy carbonyl groups 15 include phenoxy- and naphthoxy-carbonyl. “Aralkoxycarbonyl” refers to an aralkyl -O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl. “Carbamoyl” refers to an amide group of the formula -C(=O)NH2. “Alkylcarbamoyl” refers to a R’RN -C(=O) group wherein one of R and R’ is hydrogen 20 and the other of R and R’ is alkyl and / or substituted alkyl as previously described. “Dialkylcarbamoyl” refers to a R'RN-C(=O)- group wherein each of R and R’ is independently alkyl and / or substituted alkyl as previously described. The term “carbonyldioxyl,” as used herein, refers to a carbonate group of the formula - OC(=O)-OR. 25 “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described. The term “amino” refers to the -NH2group and refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic groups. For example, the terms “acyl amino” and “alkylamino” refer to specific N- substituted organic groups with acyl and alkyl substituent groups respectively. 30 An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein 51 LTGO-017 / 01WO 36088 / 98 Patent Application refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR’ wherein R’ is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR’R”, wherein R’ and R” are each 5 independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, wherein R’, R”, and R’” are each independently selected from the group consisting of alkyl groups. Additionally, R’, R”, and / or R’” taken together may optionally be –(CH2)kwhere k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, 10 methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine. The amino group is -NR'R”, wherein R' and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 15 The terms alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like. “Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. 20 “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described. The term “carbonyl” refers to the -C(=O)- group, and can include an aldehyde group represented by the general formula R-C(=O)H. The term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety. 25 The term “cyano” refers to the -CN group. The terms “halo,” “halide,” and “halogen” refer to fluoro, chloro, bromo, and iodo groups. The term “haloalkyl” refers to an alkyl group substituted with one or more halogens. Additionally, the term “haloalkyl,” includes monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-4)alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- 30 chlorobutyl, 3-bromopropyl, and the like. 52 LTGO-017 / 01WO 36088 / 98 Patent Application The terms “halocycloalky” and “cyclohaloalkyl” refer to a cycloalkly group with one or more halogens. The term “hydroxyl” refers to the -OH group. The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group. 5 The term “mercapto” refers to the -SH group. The term “oxo” refers to an oxygen atom that is double bonded to a carbon atom or to another element. The term “nitro” refers to the -NO2group. The term “thio” refers to a compound described previously herein wherein a carbon or 10 oxygen atom is replaced by a sulfur atom. The term “sulfate” refers to the - SO4 group. The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH. More particularly, the term “sulfide” refers to compound having a group of the formula - SR. 15 The term “sulfone” refers to compound having a sulfonyl group -S(O2)R’. The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R The term ureido refers to a urea group of the formula -NH-CO-NH2. Throughout the specification and claims, a given chemical formula or name shall encompass all tautomers, congeners, and optical- and stereoisomers, as well as racemic mixtures 20 where such isomers and mixtures exist. Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that may be defined, m terms of absolute stereochemistry, as (R)-or (S)- or, as D- or L- for amino acids, and individual isomers are encompassed within the 25 scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic, and optically pure forms. Optically active (R)- and (S)-, or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefenic bonds or 30 other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. 53 LTGO-017 / 01WO 36088 / 98 Patent Application Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. 5 It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one isomeric form to another. Unless otherwise stated, structures depicted herein are also meant to include compounds 10 which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures with the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic 15 isotopes at one or more of atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example, tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. The compounds of the present disclosure may exist as salts, and particularly as 20 pharmaceutically acceptable salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. Also included 25 are base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or m a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include those derived from inorganic 30 acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or 54 LTGO-017 / 01WO 36088 / 98 Patent Application phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or 5 galactunoric acids and the like. Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow' the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. 10 The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain 15 compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. In addition to salt forms, the present disclosure provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo 20 chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. 25 The term “protecting group” refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective 30 group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. 55 LTGO-017 / 01WO 36088 / 98 Patent Application For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. 5 Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically 10 removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4- dimethoxybenzyl, while co existing amino groups may be blocked with fluoride labile silyl carbamates. 15 Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. 20 As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Compounds: The invention provides compounds that modulate, e.g., inhibit, the activity of voltage gated 25 sodium channels. In one aspect, the invention provides a compound of Formula (I): 56 LTGO-017 / 01WO 36088 / 98 Patent Application (I) or a tautomer thereof, or a p , hydrate and solvate thereof, wherein: R1a, R1b, R2a, R2bR3a, R3bare independently H, D, halo, hydroxyl, C1-C8alkyl, C3-C65 cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1- C8 fluoroalkyl wherein the alkyl chain may be fully or partially halogenated, C1-C6 alkoxy, C1-C6 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted aryloxy,C2-C6 alkenyl, C2-C6 alkynyl, -[C(R8)(R9)]m-C3-C8-10 cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8cycloalkyl, -[C(R8)(R9)]m-C3-C8cycloalkenyl, - [C(R8)(R9)]m- C6-C10aryl,-[C(R8)(R9)]m-N(R8)(R9), or -[C(R8)(R9)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and with the proviso that at least one of R1a, R1b, R2a, R2b R3a, R3b is not H or D; wherein any of said alkyl, alkenyl, or alkoxy moieties above may be further 15 substituted with one, two, three or four R5 substituents, where R5 is individually and independently selected from halo, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6 alkoxy, C1-C6 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated; 20 wherein any of R1a, R1b, R2a, R2b, R3a, or R3bmay be optionally connected to another of R1a, R1b, R2a, R2b, R3a, or R3bthrough individual alkyl, fluoroalkyl, or alkoxy moieties to form a spirocyclic, fused bicyclic, or bridged bicyclic ring; R2a and R2b may optionally together form a substituted or unsubstituted exocyclic alkene, wherein alkene substituents are H, fluoro, C1-C6alkyl, aryl or C3-C6heteroaryl; 57 LTGO-017 / 01WO 36088 / 98 Patent Application R4a is H, -OH, halo, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl wherein the alkyl may be fully or partially halogenated, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy wherein the alkoxy may be fully or partially halogenated, -L1-(C1-C8 alkyl), -L1-(C1-C8 cycloalkyl), -L1- (C1-C8 haloalkyl), -L1-(C1-C8 cyclohaloalkyl), -L1-(C1-C8 alkoxy), L1-(C1-C8 5 cycloalkoxy), -L1-L2-(C2-C6alkyl)-OR4b, -L1-(C1-C6alkenyl)-OR4b, -L1-(C1-C6alkyl)-NR4cR4d, or -L1-L2-R4e; R4b, R4c, and R4d are independently H, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy; and R4eis C3-C6cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, - 10 C(O)O(C1-C8 alkyl), -COOH, or C(O)NR4cR4d, wherein said C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted by one or more halo, - OH, C1-C8alkyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy; and L1 is a bond or O; L2 is a bond, C1-C6 alkyl or C1-C6 alkenyl; X2a, X2b, X2c, and X2d are independently N or C-R4f; 15 wherein each R4fon X2a, X2b, X2c, and X2dis independently H, -OH, halo, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, - NR4cC(O)C1-C8alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8alkyl, -S(O)2NR4cR4d, -S(O)C1-C8alkyl, or —P(O)(C1-C8alkyl)2, wherein said C1-C8alkyl, C1-C8alkoxy, 3-7 membered heterocycloalkyl, 5 20 or 6-membered heteroaryl, or -NR4cC(O)C1-C8 alkyl is optionally substituted by one or more R4c, C3-C8 cycloalkyl, -NR4cR4d, -OR4b, -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R4c. R5a is -[C(R6)(R7)]n-R5c; R5b is H, C1-C4 alkyl, or R5a and R5b together with the nitrogen to which they are attached 25 form a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted by one or more R5d; R5c is 5-10 membered heteroaryl, pyridinyl, pyridazinyl, pyrimidinyl, phenyl, 6-10 membered aryl, 3-7 membered heterocycloalkyl, wherein the R5c substituent is further optionally substituted by one or more R5d; 30 R5d is hydrogen, deuterium, oxo, halo, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain 58 LTGO-017 / 01WO 36088 / 98 Patent Application may be fully or partially deuterated, C1-C8 fluoroalkyl wherein the C1-C8 fluoroalkyl is partially or fully deuterated, nitro, cyano, SR8, S(O)R8, S(O)2R8, NR8NR9, -(CH2)nS(O)2NR8R9(n is 0, 1, or 2), -(CH2)nCO NR8R9, -NHS(O)2R8, -C(O)OR8, C(O)NR8R9, -NHC(=O)-alkyl - NH(C=O)NR8R9, -SO(=NH)R4, -SO(=NR7)R4, -O-(CH2)1-5C(=O)NR8R9, -C(R8)(R9)-cycloalkyl, 5 substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R4is C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or C3-C7cycloalkyl; 10 R6 is H, D, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R7is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R8 is H, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially 15 deuterated, hydroxyalkyl, or alkoxyl alkyl; R9is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; and m and n are independently 0, 1, or 2. In certain embodiments, all R1a, R1b, R2a, R2bR3a, R3bare H or D. 20 In certain embodiments, all R1a, R1b, R2a, R2b R3a, R3b are H. In certain embodiments, the compound is a compound of Formula (II): II) or a tautomer thereof, or a p , hydrate and solvate thereof, wherein: R1a, R1b, R2a, R2b R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. 25 In certain embodiments, the compound is a compound of Formula (III): 59 LTGO-017 / 01WO 36088 / 98 Patent Application II) or a tautomer thereof, or a hydrate and solvate thereof, wherein: R2a, R2b R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. In certain embodiments, the compound is a compound of Formula (IV): 5 V) or a tautomer thereof, or a p y , hydrate and solvate thereof, wherein: R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above; p is 0, 1, or 2; R6aand R6bare independently: hydrogen, -OH, deuterium, halo, cyano, C1-C6alkyl, 10 branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4alkyl wherein the C1-C4 alkyl may be fully or partially deuterated, or C1-C8 fully or partially fluorinated fluoroalkyl; Y1is C(R6a)(R6b) or N(R6); Y2 = CH2, O or N(R6); and15each Y3 is independently CH2 or OCH2. In certain embodiments, the compound is a compound of Formula (V): 60 LTGO-017 / 01WO 36088 / 98 Patent Application V) or a tautomer thereof, or a hydrate and solvate thereof, wherein R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2dare defined above. In certain embodiments, the compound is a compound of Formula (VI): 5 I) or a tautomer thereof, or a p y p , hydrate and solvate thereof, wherein R2b, R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above. In certain embodiments, Y1 is C(R6a)(R6b), R6a or R6b are independently H or CH3. In certain embodiments, R5ais selected from the group consisting of: 61 LTGO-017 / 01WO 36088 / 98 Patent Application 5 In certain embodiments, R2aand R2bare independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, fluorinated cyclopropyl, cyclopentyl, -OCH3, - 62 LTGO-017 / 01WO 36088 / 98 Patent Application CF3, -OCD3, -OCH2-CH3, -CHF2, -CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, -OCH2- In certain embodiments, R2aand R2bare independently -CF3and -CH3. 5 In certain embodiments, R2a and R2b are both -CH3. In certain embodiments, R2a is CF3 and R2b is alkoxy. In certain embodiment, R2ais CF3and R2bis -OCH3. In certain embodiments, R2ais CF3and R2bis alkyl. In certain embodiments, wherein R2a and R2b combine to form 3-6 membered substituted 10 or unsubstituted cycloalkyl or heterocycloalkyl spiro ring, wherein one or more hetero atoms in the spiro ring are O or N. In certain embodiments, the spiro ring is substituted or unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R2aand R2bcombine to form the spirocycli , and spirocyclic . 15 In c diments, R1aand R1bare independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, cyclopentyl, -OCH3, -CF3, -OCD3, -OCH2-CH3, -CHF2, - CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, -OCH2-CF3, -CH2-CF3, -CH2-CF3, phenyl, or fluorinated phenyl. In certain embodiments, R1aand R1bcombine to form spirocyclic substituted or 20 unsubstituted cycloalkyl. In certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. In certain embodiments, R1aand R1bare independently -CF3and -CH3. In certain embodiments, X2a, X2b, X2c, and X2d are independently C-R4f; wherein each R4f is independently selected from the group consisting of: H, -OH, halo, C1-C8 alkyl, C1-C8 25 cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, - 63 LTGO-017 / 01WO 36088 / 98 Patent Application NR4cC(O)C1-C8 alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8 alkyl, -S(O)2NR4cR4d, -S(O)C1-C8 alkyl, or —P(O)(C1-C8alkyl)2, wherein said C1-C8alkyl, C1-C8alkoxy, 3-7 membered heterocycloalkyl, 5 or 6-membered heteroaryl, or -NR4cC(O)C1-C8 alkyl is optionally substituted by one or more R4c, C3-C8 cycloalkyl, -NR4cR4d, -OR4b, -CN, and 3-7 membered heterocycloalkyl optionally 5 substituted by one or more R4c, wherein R4c, R4d, and R7are defined above. In certain embodiments, R4f is selected from the group consisting of hydrogen, fluoro, chloro, -COOH, -OCF2H, -OCH3, -O-CH2-CH3, -OCD3, -OCH(CH3)2, cyclopropyl, and -CF3. In certain embodiments, R5bis hydrogen. In certain embodiments, R5a is selected from the group consisting , 10 . In certain embodiments, R5a is selected from the group consistin . and . iments, R3a and R3b are both hydrogen. 15 In certain embodiments, R3aand R3bare not halogen, hydroxy, or alkoxy. In certain embodiments, R1a, R1b , R2a, R2b R3a, R3b are independently H, halo, hydroxyl, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, 20 haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6 alkenyl, C2-C6 alkynyl, -[C(R8)(R9)]m-C3-C8-cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8cycloalkyl, -[C(R8)(R9)]m-C3-C8cycloalkenyl, -[C(R8)(R9)]m-N(R8)(R9), or -[C(R8)(R9)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; and 64 LTGO-017 / 01WO 36088 / 98 Patent Application when m is 0, R1a, R1b, R2a, R2b R3a, R3b are independently -C3-C8-cycloalkoxy, -C3-C8 cycloalkyl, -N(R8)(R9), or -C3-C8heterocycloalkyl, wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N. In certain aspects, the invention provides a compound selected from the compounds 5 provided in Table A. In certain aspects, the invention provides a compound selected from the compounds provided in Table B. In another aspect, the invention provides inhibitors of a voltage gated sodium channel NaV1.8. The inhibitors may have a defined chemical structure, such as the structure of any of the 10 compounds described above. Voltage-gated sodium channels, or NaV channels, control the excitability of neurons in the peripheral and central nervous systems (Catterall 2000). There are 9 members of the NaV family: NaV1.1, NaV1.2 and NaV1.3 are involved in central nervous system function, NaV1.4 is involved in respiratory function, NaV1.5 is involved in cardiac function, NaV1.6 is involved in motor 15 neuron function, and NaV1.7, NaV1.8 and NaV1.9 are involved in nociceptor function. From a closed state, sodium channels open briefly upon membrane depolarization to let sodium ions into the cell and then rapidly inactivate to prevent sustained sodium influx (Ahern et al 2016). Sodium currents entering pain sensing neurons, termed nociceptors, through NaV channels drive the upstroke of an action potential, the electrical means of sensory information transfer in the nervous 20 system. In the peripheral nervous system, sensory neurons in the dorsal root ganglion (DRG) are responsible for pain signaling. Action potentials are transmitted along peripheral afferent nerve fiber axons to the spinal cord and then to the central nervous system for pain signal processing and integration (Basbaum et al 2009). Painful heat, chemical, or mechanical stimuli increased action potential firing in human nociceptive fibers and firing increased with the intensity of pain reported 25 in healthy subjects (Torebjork et al 1984; Yarnitsky et al 1992; Van and Gybels 1981). DRG neurons isolated from patients with neuropathic pain as well as nociceptive nerve fibers in patients with painful neuropathies exhibited spontaneous action potential firing (North et al 2019; North et al 2022; Serra et al 2012; Kleggetveit et al 2012). NaV1.8 is a member of the voltage-gated sodium channel family specifically expressed in 30 DRG neurons in the peripheral nervous system (Bennett et al 2019; Shiers et al 2020; Han et al 65 LTGO-017 / 01WO 36088 / 98 Patent Application 2016). NaV1.8 nociceptor expression spans from afferent nerve terminals in the skin to first order pre-synaptic regions in the dorsal horn of the spinal cord (Bennett et al 2019; Shields et al 2012; Gautron et al 2011). The biophysical properties of NaV1.8, specifically the right-shifted voltage- dependence of inactivation coupled with rapid recovery from inactivation, support NaV1.8- 5 mediated high-frequency action potential firing in DRG neurons (Han et al 2015). NaV1.8 is both a genetically and pharmacologically validated pain target in humans. Rare gain of function genetic mutations in SCN10A, the gene encoding NaV1.8 protein, are associated with or drive pain phenotypes in small fiber neuropathy, diabetic peripheral neuropathy, and trigeminal neuralgia (Stefano et al 2020; Huang et al 2013; Han et al 2018; Faber et al 2012; Han et al 2014). In contrast, 10 more common single nucleotide polymorphisms are linked to reduced pain in inflammatory bowel disease, post-surgical pain and experimentally-induced mechanical pain (Duan et al 2018; Duan et al 2016; Gonzalez-Lopez et al 2018; Coates et al 2019). Pharmacological block of NaV1.8 with small molecules inhibited native NaV1.8 current (termed tetrodotoxin-resistant or TTX-R current) and action potential firing in DRG neurons as 15 well as pain behavioral endpoints in preclinical rodent model systems (Jarvis et al 2007; Payne et al 2015; Qin et al 2023; Scanio et al 2010; Zhang et al 2010; Kort et al 2008; McGaraughty et al 2008). VX-150, a NaV1.8-selective small molecule inhibitor developed by Vertex Pharmaceuticals, was the first NaV selective inhibitor to impart significant analgesia in the clinic in Phase 2 studies. VX-150 inhibited nociceptive cold pain in healthy volunteers, acute post- 20 operative bunionectomy surgical pain, musculoskeletal osteoarthritis pain as well as chronic neuropathic pain in small fiber neuropathy (Vertex Pharmaceuticals 2021; Vertex Pharmaceuticals 2017; Hijma et al 2021). Thus, pharmacological inhibition of NaV1.8 is clinically validated as a novel analgesic mechanism of action targeting the peripheral nervous system for both acute and chronic pain disorders. 25 In another aspect, the invention provides methods of treating a condition in a subject by providing to a subject having a condition a compound of the invention, such as any of those described above. The condition may be associated with aberrant activity of voltage gated sodium channels. The condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, 30 acute itch, acute pain, acute pain in major trauma / injury, airways hyperreactivity, allergic 66 LTGO-017 / 01WO 36088 / 98 Patent Application dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, 5 chronic cough, chronic itch, chronic low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy 10 (DSP) associated with highly active antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry's disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel 15 syndrome, irritable bowel syndrome, itch, juvenile idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia 20 congenita, pain, pain resulting from cancer, pain resulting from chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative 25 pain, post-stroke pain, post-surgical pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous 30 pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. In another 67 LTGO-017 / 01WO 36088 / 98 Patent Application aspect, the invention provides methods of making a medicament using a compound of the invention, such as any of those described above. In another aspect the invention provides products comprising a compound of the invention, such as any of those described above, for treatment of a condition, such as any of 5 those described above, in a subject. Compositions The invention provides pharmaceutical compositions containing compounds of the inventions, such as those described above. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily 10 suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, to provide pharmaceutically elegant and palatable preparations. Tablets contain the compounds in 15 admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc. The 20 tablets may be uncoated, or they may be coated by known techniques to delay disintegration in the stomach and absorption lower down in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874, the contents of which are incorporated herein 25 by reference, to form osmotic therapeutic tablets for control release. Preparation and administration of compounds is discussed in U.S. Patent No. 6,214,841 and U.S. Pub. No. 2003 / 0232877, the contents of which are incorporated herein by reference. Formulations for oral use may also be presented as hard gelatin capsules in which the compounds are mixed with an inert solid diluent, for example calcium carbonate, calcium 68 LTGO-017 / 01WO 36088 / 98 Patent Application phosphate or kaolin, or as soft gelatin capsules in which the compounds are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. An alternative oral formulation, where control of gastrointestinal tract hydrolysis of the compound is sought, can be achieved using a controlled-release formulation, where a compound 5 of the invention is encapsulated in an enteric coating. Aqueous suspensions may contain the compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such 10 as a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such a polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for 15 example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for 20 example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid. 25 Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the compounds in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavoring, and coloring agents, may also be present. 69 LTGO-017 / 01WO 36088 / 98 Patent Application The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for 5 example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene 10 glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and agents for flavoring and / or coloring. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable 15 solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic 20 acid find use in the preparation of injectables. In certain embodiments, the formulation is a sustained release formulation. In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles having a D50 (volume weighted median diameter) of less than 10 microns. In certain 25 embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension. The composition may be formulated for administration by a particular mechanism. The composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The composition may be formulated for administration by 70 LTGO-017 / 01WO 36088 / 98 Patent Application injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents). The composition may be formulated a single daily dosage. The composition may be formulated for multiple daily dosages, e.g., two, three, four, five, six or more daily dosages. 5 Methods of treating conditions The invention provides methods of treating a condition in a subject using compounds of the invention. The methods are useful for treating any condition associated with aberrant, e.g., increased, activity of voltage gated sodium channel NaV1.8. Conditions associated with increased activity at voltage gated sodium channels and the use of inhibitors to treat such conditions is known 10 in the art and described in, for example, International Patent Publication Nos. WO 2020 / 014243, WO 2020 / 014246, WO 2020 / 092187, the contents of each of which are incorporated herein by reference. For example and without limitation, the condition may be abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute itch, acute pain, acute pain in major 15 trauma / injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic 20 low back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pain with additional attacks, contact dermatitis, cough, dental pain, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active 25 antiretroviral therapy (HAART), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythromelalgia, Fabry's disease, facet joint syndrome, failed back surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, inherited erythromelalgia, irritable bowel syndrome, irritable bowel syndrome, itch, juvenile 30 idiopathic arthritis, mastocytosis, melorheostosis, migraine, multiple sclerosis, musculoskeletal 71 LTGO-017 / 01WO 36088 / 98 Patent Application damage, myofascial orofacial pain, neurodegeneration following ischemia, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, pachyonychia congenita, pain, pain resulting from cancer, pain resulting from 5 chemotherapy, pain resulting from diabetes, pain syndrome, painful joint arthroplasties, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, post-surgical pain, post- 10 thoracotomy pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, stump pain, subacute cough, 15 temporomandibular joint disorders, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder. Methods of treating a condition in a subject may include providing a composition of the invention to a subject. The composition may be provided to a subject by any suitable route or mode of administration. For example and without limitation, the composition may be provided buccally, 20 dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or with or on an implantable medical device. The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration. 25 Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every 72 LTGO-017 / 01WO 36088 / 98 Patent Application five days, once every week, twice per week, three times per week, four times per week, or five times per week. The dose may be provided in a single dosage, i.e., the dose may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be provided in a divided dosage, i.e., the dose 5 may be provided as multiple tablets, capsules, pills, etc. The dosing may continue for a defined period. For example and without limitation, doses may be provided for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months or more. 10 Examples Methods of making the compounds of the present invention, and intermediates used in their synthesis, are provided in the General Synthetic Schemes and Specific Syntheses Procedures below. Chemicals were purchased from standard commercial vendors and used as received unless 15 otherwise noted. Otherwise, their preparation is facile and known to one of ordinary skill in the art, or it is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “dry” glassware means oven / desiccator dried. Solvents were ACS grade unless otherwise noted. All reactions were performed in flame-dried or oven-dried glassware under a positive 20 pressure of dry nitrogen or dry argon and were stirred magnetically unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise noted. Yields are not optimized. The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chemAxon. Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 25 60 F254 plates purchased from EMD MILLIPORE™. Purification was performed with Biotage Isolera One Flash Chromatography Instrument or purified using one of the preparative HPLC methods mentioned below. Prep Method 1 Equipment: Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: 30 Gemini 5 um C18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 73 LTGO-017 / 01WO 36088 / 98 Patent Application 0.1% HCOOH, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm; Prep Method 2 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18 5 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 0.1% TFA, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Prep Method 3 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C1810 column, 150x21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 0.05% ammonia, gradient may be slight adjusted for specific compound; Flow rate: 20 mL / min; Column temperature: ambient temperature; UV Wavelength: 214 and 254 nm. Analytical LCMC were collected using one of following methods. Analytical Method 1 15 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C182.7 µm, 3.0 mm × 30 mm; Mobile Phase: MeCN (0.05% HCOOH) - Water (0.05% HCOOH); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50oC; Wavelength: 214 and 254 nm PDA. Analytical Method 2 20 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; XBridge BEH C182.5µm, 3.0 mm × 30 mm Mobile Phase: MeCN - Water (0.1% NH4OH); Gradient: MeCN from 5% to 95% over 1.8 min, hold 0.7 min, total run time is 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 oC; Wavelength: 214 and 254 nm PDA. Analytical Method 3 25 Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C182.7 µm, 3.0 mm × 30 mm Mobile Phase: MeCN (0.05% TFA) - Water (0.05% TFA); Gradient: MeCN from 5% to 95% over 1.4 min, hold 0.6 min, total run time is 2.5 min; Flow rate: 1.8 mL / min; Column temperature: 50oC; Wavelength: 214 and 254 nm PDA. SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System 30 (SFE-30A, LC-30ADSF, SFC-30A) using following methods: Analytical Method 4 74 LTGO-017 / 01WO 36088 / 98 Patent Application Column: Daicel chiralpak-AS-H 5 um 250x20 mm; Mobile Phase: CO2 / MeOH [0.1% NH3 (7M in MeOH)], CO2 / MeOH ratio varies for different compounds; Oven temperature: 40oC; Flow rate: 38 mL / min. Analytical Method 5 5 Column: Daicel chiralpak-OJ-H 5 um 250 * 20 mm; Mobile Phase: CO2 / MeOH (0.1% HCOOH), CO2 / MeOH ratio varies for different compounds; Oven temperature: 40oC; Flow rate: 38 mL / min. Analytical Method 6 Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CO2 / MeOH, ratio 10 varies for different compounds; Oven temperature: 40oC; Flow rate: 38 mL / min. Analytical Method 7 Column: Daicel chiralpak-AD-H 5 um 250x20 mm; Mobile Phase: CO2 / i-PrOH, ratio varies for different compounds; Oven temperature: 40oC; Flow rate: 38 mL / min. Analytical Method 8 15 Column: Daicel chiralpak-IC 5 um 250x20 mm; Mobile Phase: CO2 / EtOH, ratio varies for different compounds; Oven temperature: 40oC; Flow rate: 38 mL / min. Unless otherwise stated,1H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz Digital NMR Spectrometer. Chemical shifts, δ, are quoted in parts per million (ppm) relative to tetramethylsilane and calibrated using residual un- 20 deuterated solvent as an internal reference. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz. 25 Abbreviations and Acronyms When the following abbreviations are used herein, they have the following meaning: Ac2O acetic anhydride 75 LTGO-017 / 01WO 36088 / 98 Patent Application br broad n-BuOH n-butanol 76 LTGO-017 / 01WO 36088 / 98 Patent Application LiHMDS Lithium bis(trimethylsilyl)amide m-CPBA meta-Chloroperoxybenzoic acid 77 LTGO-017 / 01WO 36088 / 98 Patent Application TMS trimethylsilyl p-TsOH p-Toluenesulfonic acid Gener Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The present invention further provides processes for the 5 preparation of compounds of structural Formula I as defined above. In some cases, the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention. General Synthetic Schemes 10 Scheme A om the substituted proline ester by copper / palladium mediated coupling reaction or thermo- displacement reaction with an appropriated aryl bromide or iodide to afford intermediate A1. 15 Intermediate A1 can be converted to corresponding acid A2 by treating A1 with base such as LiOH in aqueous THF or MeOH. Reacting A2 with R5-substituted amines utilizing appropriate amide coupling afforded the desired compounds A3. If R5a or R5b involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others. Scheme B 78 LTGO-017 / 01WO 36088 / 98 Patent Application om the substituted proline acid by copper / palladium mediated coupling reaction or thermo- displacement reaction with an appropriated aryl bromide or iodide to afford intermediate acid A2. 5 Reacting A2 with ring-hand site amine utilizing appropriate amide coupling afforded the desired compounds A3. If R5a or R5b involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others. Scheme C 10 s ustrate n c eme , n genera , compoun s o t e nvent on can e prepared by coupling of appropriate aryl bromide or iodide with substituted pyrrolidine to afford B1. Reacting B1 with appropriate cyanation reagents to give B2. Intermediate B2 can be converted to corresponding carboxamide B3 by treating B2 with base such as K2CO3or LiOH, optionally in the presence of aqueous H2O2in DMSO. Intermediate B3 can then be brought together with materials 15 of variously substituted Br compounds, utilizing Xantphos-Pd-G2 mediated coupling conditions 79 LTGO-017 / 01WO 36088 / 98 Patent Application to deliver A4. When required, R5 could be further functionalized with appropriate reagents (e.g. N-oxide formation with m-CPBA). If R5involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others. Scheme D 5 As illustrated in Scheme D, in general, compounds of the invention can be prepared by functionalizing the keto group of the Boc-pyrrolidinone with an appropriate nucleophile to afford 10 C1. Alkylating the hydroxyl of C1 affords C2. Removing the Boc-protecting group of C2 affords C3. Coupling of appropriate aryl bromide or iodide with C3 furnishes C4. Reacting C4 with an appropriate cyanation reagent gives C5. Intermediate C5 can be converted to the corresponding carboxamide C6 by treating C5 with a base such as K2CO3 or LiOH in the presence of aqueous H2O2 in DMSO. Intermediate C6 can then be brought together with materials of variously 15 substituted Br compounds, utilizing Xantphos-Pd-G2 mediated coupling conditions to deliver A5. R5could be further functionalized with appropriate reagents (e.g. N-oxide formation with m- 80 LTGO-017 / 01WO 36088 / 98 Patent Application CPBA). If R5 involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others. The above schemes are intended to be illustrative and not limiting in any way. Those skilled in the art are able to prepare the Compounds of the invention using these general schemes as a 5 guideline but other methods are available to accomplish the synthesis of compounds of the invention. Specific methods are provided for each of the Examples to further illustrate the synthesis of Compounds of the invention. Intermediate 1 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxylic acid 10 Reagents & c To a solution of 4,4-dimethylpyrrolidine-2-carboxylic acid 1 (500 mg, 3.49 mmol) in NMP (15 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (934 mg, 4.19 mmol), (1S,2S)- N1,N2-dimethylcyclohexane-1,2-diamine (49 mg, 0.34 mmol) and copper(I) iodide (133 mg, 0.69 15 mmol) and Cs2CO3 (3413 mg, 10.47 mmol) under N2. The mixture was heated at 150 ℃ for 6 hours. After cooled to room temperature. The aqueous solution was adjusted to pH 2-3 with 2N HCl. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography20 (eluting with EtOAc / PE=1 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylpyrrolidine-2-carboxylic acid (70 mg, 6.68% yield) as a brown oil. LCMS (ESI) calcd. for C14H18F2NO3 [M + H]+m / z 286.12, found 285.7. Intermediate 2 81 LTGO-017 / 01WO 36088 / 98 Patent Application 1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine-2-carboxylic acid Step 1: A solution of (S)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic 5 acid (900 mg, 3.70 mmol) in HCl-dioxane (10 mL) was stirred at 25 ℃ for 2 h. After the reaction was completed, the mixture was concentrated under vacuum to provide 4,4-dimethylpyrrolidine- 2-carboxylic acid hydrochloride (800 mg) which was used directly in the next step without further purification. Step 2: A solution of 4,4-dimethylpyrrolidine-2-carboxylic acid hydrochloride (300 mg, 10 1.67 mmol), 2-chloro-1-fluoro-4-iodobenzene (643 mg, 2.51 mmol), K2CO3 (691 mg, 5.01 mmol) and CuI (64 mg, 0.33 mmol) in DMF (8 mL) were heated at 100 ℃ for 8 h under a N2 atmosphere. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on15 silica gel (DCM / MeOH = 10 / 1) to provide 1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine- 2-carboxylic acid (130 mg, 28.63 % yield) as a yellow solid. LCMS (ESI) calcd. for C13H16ClFNO2 [M + H]+m / z 272.09, found 272.2. Intermediate 3 82 LTGO-017 / 01WO 36088 / 98 Patent Application 5-(2-ethoxy-3,4-difluorophenyl)-5-azaspiro[2.4]heptane-6-carboxylic acid Reag )3, BINAP, Cs2CO3, toluene, 110 ℃; d) LiOH, THF / MeOH / H2O 5 Step 1: To a solution of 2,3-difluorophenol (10 g, 7 mmol) in DCM (50 mL) was added NBS (8.21 g, 4 mmol) and diisopropylamine (7.78 g, 7 mmol). The mixture was stirred at 0 ℃ for 2 hours. Then the resulting mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography 10 (eluting with PE / EtOAc =20 / 1) to give 6-bromo-2,3-difluorophenol (1.6 g, 9.49% yield) as a clear oil.1H NMR (400 MHz, CDCl3, ppm) δ 7.21 (ddd, J = 9.0, 5.1, 2.5 Hz, 1 H), 6.70 (td, J = 9.3, 7.5 Hz, 1 H), 5.67 (s, 1 H). Step 2: To a solution of 6-bromo-2,3-difluorophenol (800 mg, 3.82 mmol) in DMF (10 mL) was added EtI (716 mg, 4.59 mmol) and K2CO3 (1058 mg, 7.6 mmol). The mixture was heated at 50 15 ℃ for 3 hours. The organic solvent was removed under reduced pressure. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =20 / 1) to give 1-bromo-2-ethoxy-3,4-difluorobenzene (690 mg, 72.2% yield) as a clear oil.1H NMR (400 20 MHz, CDCl3, ppm) δ 7.26 (d, J = 4.2 Hz, 1 H), 6.82 (td, J = 9.3, 7.6 Hz, 1 H), 4.22 (q, J = 7.0 Hz, 2 H), 1.45 (t, J = 7.0 Hz, 3 H). Step 3: To a solution of 1-bromo-2-ethoxy-3,4-difluorobenzene (500 mg, 2.10 mmol) in toluene (10 mL) was added methyl (S)-5-azaspiro[2.4]heptane-6-carboxylate (654 mg, 4.21 mmol) and CsCO3 (1030 mg, 3.16 mmol) and Pd2(dba)3 (193 mg, 0.21 mmol) and 2,2’- 83 LTGO-017 / 01WO 36088 / 98 Patent Application bis(diphenylphosphino)-1,1’-binaphthyl (262 mg, 0.42 mmol) under N2. The mixture was heated at 110 ℃ for 6 hours. Then the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column 5 chromatography (eluting with PE / EtOAc = 20 / 1) to give methyl 5-(2-ethoxy-3,4-difluorophenyl)- 5-azaspiro[2.4]heptane-6-carboxylate (280 mg, 40.5% yield) as a yellow oil. LCMS (ESI) calcd. for C16H20F2NO3 [M + H]+m / z 312.14, found 311.8. Step 4: To a solution of methyl 5-(2-ethoxy-3,4-difluorophenyl)-5-azaspiro[2.4]heptane-6- carboxylate (270 mg, 0.86 mmol) in MeOH / THF / H2O = 1 / 1 / 1 (9 mL) was added LiOH (208 mg, 10 8.6 mmol). The mixture was stirred at 25 ℃ for 2 hours. Then the organic solvent was removed under reduced pressure. The aqueous solution was adjusted to pH 2-3 with 2N HCl. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 15 DCM / MeOH=20 / 1) to give 5-(2-ethoxy-3,4-difluorophenyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (230 mg, 84.7% yield) as a yellow oil. LCMS (ESI) calcd. for C15H18F2NO3[M + H]+m / z 298.13, found 297.7. Intermediate 4 5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylic acid 20 R g , , , ; ; , P, Cs2CO3, toluene, 110 ℃; d) LiOH, THF / MeOH / H2O 84 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: A mixture of 1-(tert-butyl) 2-methyl (S)-4-methylenepyrrolidine-1,2-dicarboxylate (15 g, 62.2 mmol), NaI (4.66 g, 31.1 mmol) and (trifluoromethyl)trimethylsilane (22.1 g, 155 mmol) in THF (200 mL) was stirred at 75 ℃ for 4 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under vacuum. The residue was triturated 5 with PE to provide 5-(tert-butyl) 6-methyl-1,1-difluoro-5-azaspiro[2.4]heptane-5,6-dicarboxylate (12 g, 66.2% yield) as a yellow oil.1H NMR (400 MHz, CDCl3, ppm) δ 4.60-4.32 (m, 1 H), 3.77- 3.64 (m, 4 H), 3.55-3.43 (m, 1 H), 2.59-2.34 (m, 1 H), 2.13-1.90 (m, 1 H), 1.48-1.32 (m, 11 H). Step 2: A solution of 5-(tert-butyl) 6-methyl -1,1-difluoro-5-azaspiro[2.4]heptane-5,6- dicarboxylate (12 g, 41.2 mmol) was added 6 N HCl in EtOAc solution (20 mL) at room 10 temperature. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was concentrated under vacuum to provide methyl-1,1-difluoro-5- azaspiro[2.4]heptane-6-carboxylate (6.2 g, 78.6% yield) as a yellow oil. LCMS (ESI) calcd. for C8H12F2NO2 [M + H]+m / z 192.09, found 192.15. Step 3: A mixture of methyl-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (600 mg, 15 3.14 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (350 mg, 1.57 mmol), BINAP (98 mg, 0.16 mmol), Pd2(dba)3(144 mg, 0.16 mmol) and Cs2CO3(1.5 g, 4.71 mmol) in toluene (10 mL) was stirred at 110 ℃ for 3 hours. After the reaction was completed, the mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by20 flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide methyl 5-(3,4-difluoro- 2-methoxyphenyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylate (280 mg, 26.8% yield) as a yellow oil. LCMS (ESI) calcd. for C15H16F4NO3[M + H]+m / z 334.11, found 334.15. Step 4: To a solution of methyl 5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro-5- azaspiro[2.4]heptane-6-carboxylate (280 mg, 0.84 mmol) in THF / MeOH / H2O (1 / 1 / 1, 10 mL) was 25 added LiOH (201 mg, 8.40 mmol). The mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the mixture adjusted to pH 2-3 with 2N HCl then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to give 5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro-5-azaspiro[2.4]heptane-6- carboxylic acid (210 mg, 78.3% yield) as a yellow solid. LCMS (ESI) calcd. for C14H14F4NO3[M 30 + H]+m / z 320.09, found 320.10. Intermediate 5 85 LTGO-017 / 01WO 36088 / 98 Patent Application 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxylic acid Reagents & c To a s olution of (S)-4,4-dimethylpyrrolidine-2-carboxylic acid (500 mg, 3.49 mmol) in 5 NMP (15 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (934 mg, 4.19 mmol), (1S,2S)- N1,N2-dimethylcyclohexane-1,2-diamine (49 mg, 0.34 mmol), Copper(I) iodide (133 mg, 0.69 mmol) and Cs2CO3(3413 mg, 10.47 mmol) under N2. The mixture was heated at 150 ℃ for 6 hours. After cooled to room temperature. The reaction solution was adjusted to pH 2-3 with 2N HCl, diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic 10 layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE=1 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (40 mg, 3.81 yield) as a brown oil. LCMS (ESI) calcd. for C14H18F2NO3[M + H]+m / z 286.13, found 285.70. Intermediate 6 15 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylic acid Re g , , - ; ; , 3 , O, 100 ℃ 86 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: To a solution of 1-(tert-butyl) 2-ethyl (R)-5-oxopyrrolidine-1,2-dicarboxylate (7 g, 27.2 mmol) in THF (100 mL) was added LiHMDS (1M, 22 mL) at -78 ℃. The mixture was stirred at -78 ℃ for 0.5 h. Then MeI (9.6 g, 68 mmol) was added. The mixture was stirred at -78 ℃ for 3 h. The mixture was quenched with ice water (100 mL) and extracted with EtOAc (100 mL x 3). 5 The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide 1-(tert-butyl) 2-ethyl-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (2.3 g, 45.7 % yield) as a yellow oil. LCMS (ESI) calcd. for C9H16NO3[M - Boc + H]+m / z 186.12, found 185.7. 10 Step 2: A solution of 1-(tert-butyl) 2-ethyl-4,4-dimethyl-5-oxopyrrolidine-1,2- dicarboxylate (2.3 g, 8.04 mmol) in 4M HCl dioxane / dioxane 1 / 10 (30 mL) was stirred at 25 ℃ for 3 h. After the reaction was completed, the solution was adjusted to pH = 8-9 with saturated aqueous NaHCO3. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated 15 under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide ethyl 4,4-dimethyl-5-oxopyrrolidine-2-carboxylate (1.2 g, 80.2 % yield) as a yellow oil. LCMS (ESI) calcd. for C9H16NO3 [M + H]+m / z 186.12, found 186.3. Step 3: A solution of ethyl 4,4-dimethyl-5-oxopyrrolidine-2-carboxylate (260 mg, 1.39 mmol), 1,2-difluoro-4-iodo-3-methoxybenzene (386 mg, 1.43 mmol), CuI (51 mg, 0.27 mmol) 20 and K3PO4 (884 mg, 4.17 mmol) in DMSO (5 mL) was heated at 100 ℃ for 3 h. After the reaction was completed, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-5-oxopyrrolidine-2-carboxylic 25 acid (280 mg, 67.3% yield) as a yellow oil. LCMS (ESI) calcd. for C14H16F2NO4[M + H]+m / z 300.11, found 299.7. Intermediate 7 87 LTGO-017 / 01WO 36088 / 98 Patent Application 5-(5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide Rea 4Cl, DMF, 50 ℃ 5 Step 1: To a solution of (S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid (2 g, 8.25 mmol) in dioxane (10 mL) was added HCl-dioxane (4M, 10 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was concentrated under vacuum to provide 5-azaspiro[2.4]heptane-6- carboxylic acid hydrochloride (1.4 g, 95.2% yield) as white solid. LCMS (ESI) calcd. for 10 C7H12ClNO2 [M + H]+m / z 142.09, found 142.3. Step 2: A mixture of 5-azaspiro[2.4]heptane-6-carboxylic acid hydrochloride (800 mg, 4.50 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.07 g, 4.73 mmol) and K2CO3(1.87 g, 13.5 mmol) in DMF (10 mL) was heated at 100 ℃ for 2 hours. After the reaction was completed, the mixture was quenched with 2M HCl aq. (50 mL) and extracted with EtOAc (50 mL x 3). The 15 combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide 5-(5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxylic acid (680 mg, 52.7% yield) as a yellow oil. LCMS (ESI) calcd. for C13H14F3N2O2 [M + H]+m / z 287.10, found 287.0. 20 Step 3: A mixture of 5-(5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6- carboxylic acid (500 mg, 1.75 mmol) and NH4Cl (374 mg, 6.99 mmol) in DMF (10 mL) was added HATU (996 mg, 2.62 mmol) and DIEA (1.13 g, 8.73 mmol). The mixture was heated at 70 °C for 2 hours. The reaction was monitored by LCMS. After the reaction was completed, the resulting solution was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined 88 LTGO-017 / 01WO 36088 / 98 Patent Application organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide 5-(5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (320 mg, 64.2% yield) as yellow oil. LCMS (ESI) calcd. For C13H15F3N3O [M + H]+m / z 286.12, found 286.0. 5 Intermediate 8 and 9 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3-carboxamide and 2-(3,4-difluoro-2- methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide 10TBHP; c) K2CO3, H2O2, DMSO Step 1: To a solution of 2-azaspiro[4.4]nonane (1000 mg, 6.18 mmol) in toluene (20 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (1655 mg, 7.42 mmol), Pd(dba)2(355 mg, 0.61 mmol), BINAP (577 mg, 0.92 mmol) and t-BuONa (891 mg, 9.27 mmol). The mixture was stirred at 110 ℃ for 16 hours under N2. Then the resulting mixture was diluted with water (40 mL) 15 and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =10 / 1) to provide 2-(3,4-difluoro-2- methoxyphenyl)-2-azaspiro[4.4]nonane (1.6 g, 91.9% yield) as a yellow oil. LCMS (ESI) calcd. for C15H20F2NO [M + H]+m / z 268.15, found 267.70. 20 Step 2: To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane (800 mg, 2.99 mmol) in MeOH (10 mL) was added TMSCN (593 mg, 5.98 mmol), FeCl2(37 mg, 0.29 mmol) and tert-butyl hydroperoxide (674 mg, 7.48 mmol) under N2. The mixture was stirred at 25 ℃ for 16 hours. Then the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium 89 LTGO-017 / 01WO 36088 / 98 Patent Application sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 10 / 1) to provide a mixture of 2-(3,4-difluoro-2- methoxyphenyl)-2-azaspiro[4.4]nonane-3-carbonitrile and 2-(3,4-difluoro-2-methoxyphenyl)-2- azaspiro[4.4]nonane-1-carbonitrile (530 mg, 57.5% yield) as a yellow oil. LCMS (ESI) calcd. for 5 C16H19F2N2O [M + H]+m / z 293.15, found 292.75. Step 3: To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3- carbonitrile and 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carbonitrile mixture (500 mg, 1.71 mmol) in DMSO / 30% aqueous H2O2= 3 / 1 (8 mL) was added K2CO3(1180 mg, 8.5 mmol). The mixture was stirred at 25 ℃ for 1 hours. Then the resulting mixture was diluted 10 with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 1 / 1) to give a mixture of 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3-carboxamide and 2-(3,4-difluoro-2- methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide (310 mg, 55.5% yield) as a clear oil. 15 LCMS (ESI) calcd. for C16H21F2N2O2[M + H]+m / z 311.16, found 311.10. Intermediate 10 and 11 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine-2-carboxamide LTGO-017 / 01WO 36088 / 98 Patent Application Reagents & conditions: a)NaH, MeI, DMF; b) HCl, EtOAC; c) t-BuONa, Pd(dba)2, BINAP, toluene, 100 ℃; d) TMSCN, FeCl2, TBHP; e) K2CO3, H2O2, DMSO Step 1: 60% NaH (5.34 g) was added to a solution of tert-butyl 3-hydroxy-3- (trifluoromethyl)pyrrolidine-1-carboxylate (19 g, 74.44 mmol) in DMF (200 mL) at 0oC. The 5 mixture was stirred for 30 minutes. Then CH3I (31.55 g, 222.50 mmol) was added to the reaction mixture at the same temperature. The reaction was stirred for 1 hour at room temperature. LCMS showed the reaction was completed. The mixture was diluted with water (600 mL) and extracted with EtOAc (600 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on10 silica gel (PE / EtOAc = 10 / 1) to provide tert-butyl 3-methoxy-3-(trifluoromethyl)pyrrolidine-1- carboxylate (16 g, 79.88% yield) as light yellow oil. Step 2: A solution of tert-butyl 3-methoxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (16 g, 59.45 mmol) in EtOAc (50 mL) was added 4M HCl dioxane (100 mL). The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture 15 was concentrated under vacuum to provide crude 3-methoxy-3-(trifluoromethyl)pyrrolidine (8 g) as a white solid. LCMS (ESI) calcd. for C6H11F3NO [M + H]+m / z 170.08, found 169.65. Step 3: A solution of crude 3-methoxy-3-(trifluoromethyl)pyrrolidine (8 g, 47.31 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (11.6 g, 52.26 mmol), t-BuONa (11.36 g, 118.25 mmol), Pd(dba)2 (2.72 g, 4.73 mmol) and BINAP (4.42 g, 7.09 mmol) in toluene (50 mL) was heated at 20 110 °C for 16 hours under N2atmosphere. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL) and extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-(3,4- difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine (6 g) as a yellow oil. LCMS 25 (ESI) calcd. for C13H15F5NO2 [M + H]+m / z 312.10, found 311.65. Step 4: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- (trifluoromethyl)pyrrolidine (6 g, 18.12 mmol), TMSCN (7.06 g, 55.70 mmol), FeCl2(0.23 g, 1.78 mmol) and TBHP (42 mL) in MeOH (50 mL) was stirred at 35 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (100 mL) and extracted with 30 EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on 91 LTGO-017 / 01WO 36088 / 98 Patent Application silica gel (PE / EtOAc = 10 / 1) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-4-(trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3- methoxy-3-(trifluoromethyl)pyrrolidine-2-carbonitrile (3 g, 46.30% yield) as a light yellow oil. LCMS (ESI) calcd. for C14H14F5N2O2 [M + H]+m / z 337.10, found 336.65. 5 Step 5: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- (trifluoromethyl)pyrrolidine-2-carbonitrile mixture (3 g, 8.93 mmol), K2CO3 (6.16 g, 44.63 mmol) and H2O2(3 mL) in DMSO (9 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc 10 (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy- 3-(trifluoromethyl)pyrrolidine-2-carboxamide (1.5 g, 47.47% yield) as a white solid. LCMS (ESI) 15 calcd. for C14H16F5N2O3[M + H]+m / z 355.11, found 354.65. Intermediate 12 and Intermediate 13 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide 92 LTGO-017 / 01WO 36088 / 98 Patent Application R ane, 60 ℃; d) (Bu)3SnH, AIBN, dioxane, 100 ℃; e) Pd / C, Pd(OH)2, HCl, H2, MeOH / t-BuOH, 80 ℃; f) t-BuONa, Pd(dba)2, BINAP, toluene, 110 ℃; g) TMSCN, FeCl2, TBHP; h) K2CO3, H2O2, 5 DMSO Step 1: A solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (50 g, 210.61 mmol) in DCM (500 mL) was added 2-(trifluoromethyl)acrylic acid (30.3 g, 214.82 mmol) and TFA (3.84 g, 33.70 mmol) at 0 ℃. The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was filtered, washed with DCM and dried 10 under vacuum to provide 1-benzyl-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid (35 g, 60.87% yield) as a white solid. LCMS (ESI) calcd. for C13H15F3NO2 [M + H]+m / z 274.11, found 273.65. Step 2: A solution of 1-benzyl-3-(trifluoromethyl)pyrrolidine-3-carboxylic acid (35 g, 128.16 mmol) in THF (185 mL) was added BH3-Me2S (10M in DMS, 30 mL) at 0 ℃. The reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The 93 LTGO-017 / 01WO 36088 / 98 Patent Application mixture was quenched with MeOH (150 mL) and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide (1-benzyl- 3-(trifluoromethyl)pyrrolidin-3-yl)methanol (16 g, 47.06% yield) as a colorless oil. LCMS (ESI) calcd. for C13H17F3NO [M + H]+m / z 260.13, found 259.65. 5 Step 3: A solution of (1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl)methanol (16 g, 61.75 mmol) in 1,4-dioxane (300 mL) was added SOCl2 (43.9 g, 369.00 mmol), pyridine (29.19 g, 369.00 mmol) and DMAP (0.75 g, 6.15 mmol) at 0 ℃. The reaction was stirred at 60 ℃ for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (600 mL) and extracted with EtOAc (600 mL x 3). The combined organic layers were washed with brine, dried 10 over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-benzyl-3-(chloromethyl)-3- (trifluoromethyl)pyrrolidine (8 g, 47.06% yield) as light yellow oil. LCMS (ESI) calcd. for C13H16ClF3N [M + H]+m / z 278.09, found 277.60. Step 4: A solution of 1-benzyl-3-(chloromethyl)-3-(trifluoromethyl)pyrrolidine (8 g, 28.87 15 mmol) in 1,4-dioxane (100 mL) was added tributylstannane (37.66 g, 129.15 mmol) and AIBN (7.07 g, 43.05 mmol). The reaction was heated at 100 ℃ for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc 20 = 10 / 1) to provide 1-benzyl-3-methyl-3-(trifluoromethyl)pyrrolidine (6 g, 85.47% yield) as colorless oil. LCMS (ESI) calcd. for C13H17F3N [M + H]+m / z 244.13, found 243.65. Step 5: A solution of 1-benzyl-3-methyl-3-(trifluoromethyl)pyrrolidine (6 g, 24.68 mmol) in t-BuOH (65 mL) and MeOH (65 mL) was added 10% Pd / C (6 g), 10% Pd(OH)2 / C (6 g) and conc HCl (1 mL). The reaction was heated at 80 ℃ for 48 hours under an atmosphere of H2. LCMS 25 showed the reaction was completed. The mixture was filtered through celite and washed with MeOH. The combined filtrate was concentrated under vacuum to provide 3-methyl-3- (trifluoromethyl)pyrrolidine hydrochloride (3.5g, 75.11% yield) as colorless oil. LCMS (ESI) calcd. for C6H11F3N [M + H]+m / z 154.09, found 153.60. Step 6: To a solution of 3-methyl-3-(trifluoromethyl)pyrrolidine hydrochloride (2 g, 13.0 30 mmol) in toluene (25 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (2.32 mg, 10.4 mmol), Pd(dba)2 (0.75 g, 1.3 mmol), BINAP (1.21 g, 1.9 mmol) and t-BuONa (3.8 g, 39.0 mmol) 94 LTGO-017 / 01WO 36088 / 98 Patent Application under N2. The mixture was stirred at 110 ℃ for 16 hours. Then the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 10 / 1) to provide 1-(3,4- 5 difluoro-2-methoxyphenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine (1.7 g, 43% yield) as a yellow solid. LCMS (ESI) calcd. for C13H15F5NO [M + H]+m / z 296.11, found 295.60. Step 7: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine (1.7 g, 5.7 mmol), TMSCN (1.13 g, 11.4 mmol) and FeCl2(70 mg, 0.5 mmol) in MeOH (20 mL) was added tert-Butyl hydroperoxide (5.5 mol in decane, 4 mL) 10 dropwise under N2. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was diluted with brine (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =10 / 1) to provide a 3:1 mixture of provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-15 (trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine-2-carbonitrile (1.35 g, 73% yield) as a yellow oil. LCMS (ESI) calcd. for C14H14F5N2O [M + H]+m / z 321.10, found 321.10. Step 8: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4- (trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- 20 (trifluoromethyl)pyrrolidine-2-carbonitrile mixture (1.35 g, 4.2 mmol) in DMSO (12 mL) was added K2CO3 (2.9 g, 20.9 mmol) and 30% H2O2 (4 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel25 column chromatography (eluting with DCM / MeOH = 20 / 1) to provide a mixture of 1-(3,4- difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4- difluoro-2-methoxyphenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide (1 g, 69% yield) as a white solid. LCMS (ESI) calcd. for C14H16F5N2O2 [M + H]+m / z 339.12, found 338.70. Intermediate 14 and 15 95 LTGO-017 / 01WO 36088 / 98 Patent Application 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2- carboxamide and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine-2-carboxamide 5 TBHP; c) K2CO3, H2O2, DMSO Step 1: A solution of 3-methyl-3-(trifluoromethyl)pyrrolidine hydrochloride (500 mg, 2.62 mmol), 1-bromo-2-(difluoromethoxy)-3,4-difluorobenzene (815 mg, 3.15 mmol), t-BuONa (378 mg, 3.93 mmol), Pd(dba)2 (151 mg, 0.26 mmol) and BINAP (245 mg, 0.39 mmol) in Toluene (10 10 mL) was heated to 110 °C and refluxed for 16 hours under N2atmosphere. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3-methyl-3- 15 (trifluoromethyl)pyrrolidine (500 mg, 57.10% yield) as a yellow oil. LCMS (ESI) calcd. for C13H13F7NO [M + H]+m / z 332.09, found 331.65. Step 2: A solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine (500 mg, 1.50 mmol), TMSCN (597 mg, 6.02 mmol), FeCl2 (38 mg, 0.30 mmol) and TBHP (4 mL) in MeOH (10 mL) was stirred at 40 °C for 16 hours. LCMS showed 20 the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide a mixture of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4- 96 LTGO-017 / 01WO 36088 / 98 Patent Application methyl-4-(trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(2-(difluoromethoxy)-3,4- difluorophenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2-carbonitrile (300 mg, 55.79% yield) as a yellow oil. LCMS (ESI) calcd. for C14H12F7N2O [M + H]+m / z 357.09, found 356.70. Step 3: A solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl-4- 5 (trifluoromethyl)pyrrolidine-2-carbonitrile and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3- methyl-3-(trifluoromethyl)pyrrolidine-2-carbonitrile mixture (300 mg, 0.84 mmol), K2CO3 (579 mg, 4.20 mmol) and 30% H2O2 (1 mL) in DMSO (3 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried 10 over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide 1-(2-(difluoromethoxy)-3,4- difluorophenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(2- (difluoromethoxy)-3,4-difluorophenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide (250 mg, 69.69% yield) as a white solid. LCMS (ESI) calcd. for C14H14F7N2O2 [M + H]+m / z 15 375.10, found 374.70. Intermediate 16 and 17 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamide and 1-(3,4-difluoro- 2-methoxyphenyl)-3,3-dimethylpyrrolidine-2-carboxamide 20 R g , , , , , , 2O2, HOAc; c) K2CO3, H2O2, DMSO Step 1: To a solution of 3,3-dimethylpyrrolidine hydrochloride (1 g, 7.40 mmol) in toluene (10 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (1.97 g, 8.87 mmol), Pd(dba)2(425 97 LTGO-017 / 01WO 36088 / 98 Patent Application mg, 0.74 mmol) and 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (691 mg, 1.11 mmol) and t- BuONa (1.06 g, 11.1 mmol) under N2. The mixture was stirred at 110 ℃ for 16 hours. Then the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated 5 under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =20 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine (1.2 g, 67.2% yield) as a clear oil. LCMS (ESI) calcd. for C13H18F2NO [M + H]+m / z 242.14, found 241.65. Step 2: To a solution of NaCN (121 mg, 2.48 mmol) and RuCl3(21 mg, 0.10 mmol) was 10 added 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine (500 mg, 2.07 mmol) in MeOH (5 mL) and AcOH (746 mg, 12.4 mmol) and 30% hydrogen peroxide (587 mg) under N2. The mixture was stirred at 25 ℃ for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The 15 combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =20 / 1) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine- 2-carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine-2-carbonitrile (350 mg, 60.2% yield) as a clear oil. LCMS (ESI) calcd. for C14H17F2N2O [M + H]+m / z 267.13, found 20 266.65. Step 3: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2- carbonitrile and 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine-2-carbonitrile mixture (340 mg, 1.27 mmol) in DMSO (6 mL) was added K2CO3 (882 mg, 6.38 mmol) and 30% H2O2 (2 mL). The mixture was stirred at 25 ℃ for 1 hour. Then the resulting mixture was diluted 25 with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamide and 1-(3,4- difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine-2-carboxamide (360 mg, 94.2% yield) as a 30 clear oil. LCMS (ESI) calcd. for C14H19F2N2O2 [M + H]+m / z 285.14, found 284.60. 98 LTGO-017 / 01WO 36088 / 98 Patent Application Intermediate 18 and 19 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamide and 1-(2- (difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2-carboxamide 5 R CO3, DMF, 125 ℃; d) TMSCN, FeCl2, TBHP; e) K2CO3, H2O2, DMSO Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine (2g, 8 mmol) in DCM (20 mL) was added BBr3 (1 g, 40 mmol) dropwise at -78oC. The reaction mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The 10 mixture was quenched with MeOH (40 mL), diluted with water (200 mL), and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide 6-(3,3-dimethylpyrrolidin-1-yl)-2,3-difluorophenol (1.2 g, 67% yield) as a light-yellow oil. LCMS (ESI) calcd. for C12H16F2NO [M + H]+m / z 228.12, found 15 228.9. Step 2: To a solution of 6-(3,3-dimethylpyrrolidin-1-yl)-2,3-difluorophenol (1.2 g, 5.2 mmol), sodium 2-chloro-2,2-difluoroacetate (1.2 g, 7.8 mmol), K2CO32.1 g, 15 mmol) in DMF (20 mL). The mixture was heated at 125 ℃ for 4 hours under N2. After the reaction was completed, the mixture was diluted with brine (50 mL) and extracted with DCM (50 mL x 3). The combined 20 organic layers were dried over sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 10 / 1) to provide 1-(2- (difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine (1.0 g, 69% yield) as a yellow oil. LCMS (ESI) calcd. for C13H16F4NO [M + H]+m / z 278.12, found 277.7. 99 LTGO-017 / 01WO 36088 / 98 Patent Application Step 3: To a solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3- dimethylpyrrolidine (1 g, 3.6 mmol), TMSCN (890 mg, 9 mmol) and FeCl2(21 mg, 0.4 mmol) in MeOH (10 mL) was added tert-butylhydroperoxide (~5.5M in decane, 1.8 mL, 9 mmol) dropwise under N2. The mixture was stirred at room temperature for 16 hours. After the reaction was 5 completed, the mixture was diluted with brine (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =10 / 1) to provide a mixture of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carbonitrile and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2-carbonitrile (610 mg, 10 56% yield) as a yellow oil. LCMS (ESI) calcd. for C14H15F4N2O [M + H]+m / z 303.11, found 302.60. Step 4: To a solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4- dimethylpyrrolidine-2-carbonitrile and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3- dimethylpyrrolidine-2-carbonitrile mixture (610 mg, 2 mmol) in DMSO (3 mL) was added K2CO3 15 (820 mg, 6 mmol) and 30% H2O2(3 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide a mixture of 1-(2-(difluoromethoxy)-20 3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamide and 1-(2-(difluoromethoxy)-3,4- difluorophenyl)-3,3-dimethylpyrrolidine-2-carboxamide (580 mg, 78% yield) as a yellow solid. LCMS (ESI) calcd. for C14H17F4N2O2[M + H]+m / z 321.12, found 321.00. Intermediate 20 and 21 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane-3-carboxamide and 2-(2- 25 (difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane-1-carboxamide 100 LTGO-017 / 01WO 36088 / 98 Patent Application Re TBHP; c) K2CO3, H2O2, DMSO Step 1: To a solution of 2-azaspiro[4.4]nonane (500 mg, 3.99 mmol) in toluene (10 mL) 5 was added 1-bromo-2-(difluoromethoxy)-3,4-difluorobenzene (1241 mg, 4.79 mmol) and Pd(dba)2(229 mg, 0.39 mmol) and 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (372 mg, 0.59 mmol) and t-BuONa (575 mg, 5.98 mmol) under N2. The mixture was stirred at 110 ℃ for 16 hours. After the reaction was completed, the organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 20 / 1) to 10 provide 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane (440 mg, 36.3% yield) as a yellow oil. LCMS (ESI) calcd. for C15H18F4NO [M + H]+m / z 304.13, found 303.70. Step 2: To a solution of FeCl2 (18 mg, 0.14 mmol) under N2 was added 2-(2- (difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane (440 mg, 1.45 mmol) and TMSCN (431 mg, 4.35 mmol) in MeOH (5 mL) and TBHP (1.31 g, 5.5 M in decane). The mixture was 15 stirred at 25 ℃ for 16 hours. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =10 / 1) to provide a mixture of 2-(2-(difluoromethoxy)- 3,4-difluorophenyl)-2-azaspiro[4.4]nonane-3-carbonitrile and 2-(2-(difluoromethoxy)-3,4- 20 difluorophenyl)-2-azaspiro[4.4]nonane-1-carbonitrile (320 mg, 67% yield) as a yellow oil. LCMS (ESI) calcd. for C16H17F4N2O [M + H]+m / z 329.13, found 328.65. Step 3: To a solution of 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-3-carbonitrile and 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-1-carbonitrile mixture (300 mg, 0.91 mmol) in DMSO / 30% H2O2= 3 / 1 (8 101 LTGO-017 / 01WO 36088 / 98 Patent Application mL) was added K2CO3 (251 mg, 1.82 mmol). The mixture was stirred at 25 ℃ for 1 hours Then the resulting mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 5 DCM / MeOH = 20 / 1) to provide a mixture of 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-3-carboxamide and 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-1-carboxamide (255 mg, 79% yield) as a yellow oil. LCMS (ESI) calcd. for C16H19F4N2O2[M + H]+m / z 347.14, found 346.65. Intermediate 22 10 (Cis)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid Re a, Pd(dba)2, BINAP, toluene, 110 ℃; e) TMSCN, FeCl2, TBHP, MeOH, 30 ℃; f) KOH, 15 THF / H2O / MeOH; g) EtOAC / PE Step 1: To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (16 g, 85.9 mmol) in THF (160 mL) was added TMSCF3(24.4 g, 172 mmol)) and TBAF (1 mol / L in THF, 258 mL) slowly at 0 °C under an atmosphere of N2. The mixture was stirred at room temperature for 16 hours. Then the mixture was quenched and diluted with aqueous NH4Cl (100 mL) and extracted 20 with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was triturated in PE (40 mL), filtered and 102 LTGO-017 / 01WO 36088 / 98 Patent Application dried under vacuum to provide tert-butyl 3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (10 g, 45% yield) as a viscous yellow oil. Step 2: 60% NaH (4.67 g) was slowly added to a stirred solution of tert-butyl 3-hydroxy- 3-(trifluoromethyl)pyrrolidine-1-carboxylate (10 g, 38.9 mmol) in NMP (50 mL) at 0oC. The 5 mixture was stirred for 30 minutes 0oC. Then CH3I (16.6 g, 117 mmol) was added to the reaction mixture at the same temperature. The reaction mixture was stirred for 1 hour at room temperature. LCMS showed the reaction was completed. The mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL), dried over sodium sulfate, concentrated under vacuum to provide crude 10 tert-butyl 3-methoxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (9.5 g) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) calcd. for C9H14F3N2O3 [M - t-Bu + MeCN + H]+m / z 255.09, found 254.65. Step 3: A solution of crude tert-butyl 3-methoxy-3-(trifluoromethyl)pyrrolidine-1- carboxylate (9.5 g) in EtOAc (10 L) was added 4M HCl dioxane (20 mL). The reaction was stirred 15 at room temperature for 2 hours. LCMS showed the reaction was completed. The mixture was concentrated under vacuum. The residue was triturated in PE (20 mL), filtered and dried under vacuum to provide 3-methoxy-3-(trifluoromethyl)pyrrolidine hydrochloride (6.5 g) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.11 (s, 2 H), 3.59-3.53 (m, 1 H), 3.44-3.35 (m, 5 H), 3.32-3.24 (m, 1 H), 2.46-2.37 (m, 1 H), 2.23-2.13 (m, 1 H). 20 Step 4: A solution of 3-methoxy-3-(trifluoromethyl)pyrrolidine hydrochloride (6 g, 29.2 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (6.5 g, 29.2 mmol), t-BuONa (7.01 g, 73.0 mmol), Pd(dba)2(503 mg, 0.88 mol) and BINAP (2.73 g, 4.38 mmol) in toluene (60 mL) was heated at 110 °C for 16 hours under N2 atmosphere. LCMS showed the reaction was completed. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined 25 organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine (4.7 g, 52% yield) as a yellow oil. LCMS (ESI) calcd. for C13H15F5NO2 [M + H]+m / z 312.10, found 312.00. Step 5: To a stirred solution of 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- 30 (trifluoromethyl)pyrrolidine (6.5 g, 20.9 mmol), TMSCN (6.2 g, 62.7 mmol) and FeCl2 (265 mg, 2.09 mmol) in MeOH (50 mL) was added TBHP (5.5 M in decane, 17 mL) dropwise under N2 103 LTGO-017 / 01WO 36088 / 98 Patent Application atmosphere. The mixture was stirred at 35 °C for 16 hours. LCMS showed the reaction was completed. The mixture was quenched with sodium thiosulfate aqueous solution (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column 5 chromatography on silica gel (PE / EtOAc = 10 / 1) to provide a 1-(3,4-difluoro-2-methoxyphenyl)- 4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carbonitrile (4.7 g, 67% yield) as light yellow oil. LCMS (ESI) calcd. for C14H14F5N2O2 [M + H]+m / z 337.10, found 336.95. Step 6: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carbonitrile (4.7 g, 14.0 mmol) in 30 wt% KOH aqueous solution 10 (30 mL) and DMSO (3 mL) was heated at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was cooled to 0 °C and adjusted pH to 4-5 by slowly addition of 1M HCl. The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1) to provide 1-(3,4- 15 difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (3.6 g, 73% yield) as a yellow oil. LCMS (ESI) calcd. for C14H15F5NO4[M + H]+m / z 356.09, found 355.95. Step 7: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxylic acid (3.6 g, 10.1 mmol) in EtOAc (1 mL) was added PE 20 (11 mL) was stirred at 25 °C for 0.5 hours. Then the temperature cooled to 0 °C and the mixture was stirred for another 2 hours. The precipitate was collected by filtration. The obtained solid was triturated in EtOAc / PE (0.3 / 6, 23 mL) for 2 hours at room temperature. Then the mixture was filtered. The obtained solid was dried under vacuum to provide (cis)-1-(3,4-difluoro-2- methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (950 mg, 26.6% 25 yield) as a white solid.1H NMR (400 MHz, CDCl3, ppm) δ 6.80 (td, J = 9.4, 8.2 Hz, 1 H), 6.47 (ddd, J = 9.2, 4.9, 2.3 Hz, 1 H), 4.71 (t, J = 8.0 Hz, 1 H), 3.94 (d, J = 11.4 Hz, 1 H), 3.89 (d, J = 1.5 Hz, 3 H), 3.49 (d, J = 11.4 Hz, 1 H), 3.41 (q, J = 1.2 Hz, 3 H), 2.74-2.64 (m, 1 H), 2.40 (dd, J = 13.8, 8.3 Hz, 1 H). Intermediate 23 30 (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2- carboxylic acid 104 LTGO-017 / 01WO 36088 / 98 Patent Application Reagent A solution of (cis)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxylic acid (950 mg, 2.67 mmol) and (R)-1-(2- 5 naphthyl)ethylamine (458 mg, 2.67 mmol) in i-PrOH (9.5 mL) was heated to 80 °C and stirred for 2 hours. The mixture was cooled to 25 °C and stirred for another 2 hours. The precipitate was collected by filtration. The obtained solid was added into i-PrOH (4.5 mL) and heated to 80 °C and stirred for 2 hours. The mixture was cooled to 25 °C and stirred for another 2 hours. The precipitate was collected by filtration. The obtained solid was added into i-PrOH (3.6 mL) and 10 heated to 80 °C and stirred for 2 hours. The mixture was cooled to 25 °C and stirred for another 2 hours. The precipitate was collected by filtration. The obtained solid was diluted with 1M HCl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 4 / 1) to provide (2S,4R)-1-(3,4-difluoro-2- 15 methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (260 mg) as a yellow oil. Intermediate 24 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide 20 Reagents & conditions: a) K2CO3, H2O2, DMSO 105 LTGO-017 / 01WO 36088 / 98 Patent Application A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carbonitrile (3 g, 8.93 mmol), K2CO3(6.16 g, 44.63 mmol) and H2O2 (3 mL) in DMSO (9 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc 5 (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide (1.5 g, 47.47% yield) as a yellow oil. LCMS (ESI) calcd. for C14H16F5N2O3[M + H]+m / z 355.11, found 354.65. 10 Intermediate 25 (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethoxy)pyrrolidine-2-carboxylic acid Reagents & conditions: a) AgOTf, Selectfluor, TMSCF3, 2-fluoropyridine; b) H2, Pd / C, Pd(OH)2, MeOH / t-BuOH; c) Pd2(dba)3, BINAP, Cs2CO3, xylene, 140 ℃; d) LiOH, THF / H2O / MeOH 15 Step 1: To a mixture of AgOTf (27.7 g, 107 mmol), KF (2.56 g, 44 mmol) and Selectfluor (19.1 g, 53.7 mmol) was added 1-benzyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (10.0 g, 35.8 mmol) in EtOAc (200 mL) under N2. Then the mixture was added 2-fluoropyridine (10.5 g, 107 mmol) and TMSCF3(15.4 g, 107 mmol) dropwise at 0 °C. The reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The mixture was 20 diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was 106 LTGO-017 / 01WO 36088 / 98 Patent Application purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-benzyl 2- methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-1,2-dicarboxylate (3.48 g, 28.0% yield) as a colorless oil. LCMS (ESI) calcd. for C15H17F3NO5 [M + H]+m / z 348.11, found 348.00. Step 2: A mixture of 1-benzyl 2-methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-1,2- 5 dicarboxylate (3.48 g, 10.0 mmol), 10% Pd / C (3.48 g) and 20% Pd(OH)2(3.48 g) in MeOH (50 mL) and t-BuOH (50 mL) was stirred at room temperature under an atmosphere of H2 (3 bar) for 16 h. Then the mixture was filtered through celite. The filtrate was added HCl dioxane solution (4M, 30 mL) and stirred for 0.5 hour. The final solution was concentrated under vacuum to give crude methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-2-carboxylate hydrochloride (1.79 g) as a 10 white solid, which was used directly in next step without further purification. LCMS (ESI) calcd. for C7H11F3NO3 [M + H]+m / z 214.07, found 213.95. Step 3: A mixture of methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-2-carboxylate hydrochloride (700 mg, 2.81 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (753.3 mg, 3.38 mmol), Cs2CO3 (2751.4 mg, 8.44 mmol), Pd2(dba)3 (257.8 mg, 0.28 mmol) and BINAP (350.6 15 mg, 0.56 mmol) in xylenes (20 mL) was heated at 140 ℃ for 16 hours under N2. After the reaction was completed, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 10%) to give methyl (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- 20 (trifluoromethoxy)pyrrolidine-2-carboxylate (275 mg, 27.5% yield) as a yellow oil. LCMS (ESI) calcd. for C14H15F5NO4 [M + H]+m / z 356.09, found 355.70. Step 4: To a solution of methyl (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- (trifluoromethoxy)pyrrolidine-2-carboxylate (275 mg, 0.77 mmol) in MeOH / THF / H2O (1 / 1 / 1, 24 mL) was added LiOH (0.3 g, 7.7 mmol). The mixture was stirred at 25 ℃ for 2 hours. Then the 25 resulting mixture was adjusted pH = 4-5 with 2N HCl and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum to give crude (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- (trifluoromethoxy)pyrrolidine-2-carboxylic acid (200 mg) as a yellow oil. LCMS (ESI) calcd. for C13H13F5NO4[M + H]+m / z 342.08, found 341.95. 107 LTGO-017 / 01WO 36088 / 98 Patent Application Intermediate 26 (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethoxy)pyrrolidine-2-carboxamide Rea 5 pyr / HFDCM, -60 °C; d) H2 (3 bar), Pd / C, Pd(OH)2, HCl, MeOH, e) t-BuONa, Pd(dba)2, BINAP, toluene, 110 °C; f) TMSCN, FeCl2, TBHP, MeOH; g) K2CO3, H2O2, DMSO Step 1: To a mixture of (R)-pyrrolidin-3-ol (10 g, 114.8 mmol) and K2CO3(31.7g, 229.6 mmol) in THF (100 mL) and water (20 mL) was added CbzCl (21.5 g, 126.0 mmol) dropwise at 0 ℃. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, 10 the reaction mixture was diluted with water (400 mL) and extracted with EtOAc (300 mL × 2). The organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM, 0% to 3%) to give benzyl (R)-3-hydroxypyrrolidine-1-carboxylate (24.2 g, 95% yield) as a colorless oil. LCMS (ESI) calcd. for C12H16NO3 [M + H]+m / z 222.11, found 222.00. 15 Step 2: To a solution of benzyl (R)-3-hydroxypyrrolidine-1-carboxylate (24.0 g, 108.5 mmol) in THF (200 mL) was added NaH (60% in mineral oil, 8.68 g) in portions at 0 ℃. The mixture was stirred for 3 hours at room temperature. Then the mixture was cooled to 0 ℃ and CS2(33.04 g, 434.7 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 10 hours. Then CH3I (23.11 g, 162.8 mmol) was added dropwise at room temperature and 20 stirred for 3 hours. After the reaction was completed, the mixture was quenched with ice water 108 LTGO-017 / 01WO 36088 / 98 Patent Application (400 mL) and extracted with EtOAc (300 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 15%) to give benzyl (R)-3-(((methylthio)carbonothioyl)oxy)pyrrolidine-1-carboxylate (24.1 g, 71% yield) as a yellow oil. LCMS (ESI) calcd. for C14H18NO3S2 [M + H]+m / z 312.07, found 5 311.90. Step 3: To a suspension of 1,3-Dibrom-5,5-dimethylhydantoin (66.13 g, 231.3 mmol) in DCM (200.0 mL) was added pyridine hydrofluoric acid solution (30 / 70, 50 mL) dropwise at - 60 °C under an atmosphere of N2. The mixture was stirred for 0.5 hours at the same temperature. Then a solution of benzyl (R)-3-(((methylthio)carbonothioyl)oxy)pyrrolidine-1-carboxylate (24.0 10 g, 77.1 mmol) in DCM (100.0 mL) was added dropwise at -60 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (500 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 5%) to 15 give benzyl (R)-3-(trifluoromethoxy)pyrrolidine-1-carboxylate (3.6 g, 16% yield) as a yellow oil. LCMS (ESI) calcd. for C13H15F3NO3[M + H]+m / z 290.10, found 290.05. Step 4: A mixture of benzyl (R)-3-(trifluoromethoxy)pyrrolidine-1-carboxylate (3.6 g, 12.4 mmol), 10% Pd / C (0.72 g) and 20% Pd(OH)2(0.72 g) in MeOH (30 mL) and concentrated HCl (2 mL) was stirred at room temperature under an atmosphere of H2(3 bar) for 3 days. Then 20 the mixture was filtered through celite. HCl dioxane solution (4M, 30 mL) was added to the filtrate and stirred for 0.5 hours. The final solution was concentrated under vacuum to give crude (R)-3- (trifluoromethoxy)pyrrolidine hydrochloride (1.6 g) as a white solid, which was used directly in next step without further purification.1H NMR (400 MHz, DMSO-d6, ppm) δ 9.90-9.77 (m, 2 H), 5.24 (s, 1 H), 3.56 -3.22 (m, 4 H), 2.21 (s, 2 H). 25 Step 5: A mixture of crude (R)-3-(trifluoromethoxy)pyrrolidine hydrochloride (1.60 g), 1- bromo-3,4-difluoro-2-methoxybenzene 6 (1.86 g, 8.35 mmol), Pd(dba)2(0.48 g, 0.84 mmol), BINAP (1.04 g, 1.67 mmol) and t-BuONa (3.21 g, 33.41 mmol) in toluene (10.0 mL) was heated at 110 ℃ under an atmosphere of N2 for 16 hours. After the reaction was completed, the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL). The organic layer 30 was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 2%) to give (R)-1-(3,4-difluoro-2- 109 LTGO-017 / 01WO 36088 / 98 Patent Application methoxyphenyl)-3-(trifluoromethoxy)pyrrolidine (1.05 g, 38% yield) as a yellow oil. LCMS (ESI) calcd. for C12H12F5NO2[M + H]+m / z 298.09, found 298.05. Step 6: To a mixture of (R)-1-(3,4-difluoro-2-methoxyphenyl)-3- (trifluoromethoxy)pyrrolidine (0.75 g, 2.52 mmol) and FeCl2 (0.48 g, 3.79 mmol) in MeOH (20.0 5 mL) was added TMSCN (1.0 g, 10.09 mmol) slowly at 0 ℃ under an atmosphere of N2. After 2 minutes, 70% TBHP aqueous solution (1.3 g) was added dropwise at 0 ℃. The final mixture was stirred at that temperature for 2 hours. After the reaction was completed, the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue 10 was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 3%) to give (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethoxy)pyrrolidine-2-carbonitrile (0.19 g, 23% yield) as a yellow oil. LCMS (ESI) calcd. for C13H12F5N2O2[M + H]+m / z 323.08, found 323.05. Step 7: To a solution of (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- 15 (trifluoromethoxy)pyrrolidine-2-carbonitrile (190.0 mg, 0.59 mmol) in DMSO (5.0 mL) was added K2CO3(81.5 mg, 0.59 mmol) and 30% hydrogen peroxide (400 mg) slowly at 0 ℃. Then the mixture was allowed to warm to room temperature and stirred for 3 hours. After the reaction was completed. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL × 2). The organic layer was washed with water (100 mL × 2), dried over sodium sulfate, and 20 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM, 0% to 2%) to give (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- (trifluoromethoxy)pyrrolidine-2-carboxamide (140.1 mg, 70% yield) as a yellow solid. LCMS (ESI) calcd. for C13H14F5N2O3 [M + H]+m / z 341.09, found 340.95. 25 Intermediate 27 (4R)-1-(3,4-difluoro-2-methylphenyl)-4-(trifluoromethoxy)pyrrolidine-2-carboxamide LTGO-017 / 01WO 36088 / 98 Patent Application Reagents & conditions: a) (COCl)2, NH3-H2O Step 1: To a solution of (4R)-1-(3,4-difluoro-2-methylphenyl)-4- (trifluoromethoxy)pyrrolidine-2-carboxylic acid (260 mg, 0.8 mmol) in DMF (5 mL) was added HATU (455 mg, 1.2 mmol), DIEA (310 mg, 2.4 mmol) and NH4Cl (128 mg, 2.4 mmol). The 5 mixture was stirred at 25 ℃ for 1 hours. LCMS showed the reaction was completed. The mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 20 / 1) to provide (4R)- 1-(3,4-difluoro-2-methylphenyl)-4-(trifluoromethoxy)pyrrolidine-2-carboxamide (200 mg, 77% 10 yield) as a yellow oil. LCMS (ESI) calcd. for C13H14F5N2O2 [M + H]+m / z 325.10, found 325.00. Intermediate 28 1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide Re , , , , Cl, 15 dioxane; e) Cs2CO3, Pd2(dba)3, BINAP, o-xylene, 140 °C; f) LiOH, MeOH, THF, H2O; g) HATU, DIEA, NH4Cl Step 1: To a solution of 1-(tert-butyl) 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate 1 (40 g, 0.164 mol) in THF (200 mL) was added TMSCF3 (35 g, 0.24 mol) and TBAF (1 mol / L in THF, 6 ml) under N2. The mixture was stirred at 25 ℃ for 22 hours. Then the mixture was quenched and 111 LTGO-017 / 01WO 36088 / 98 Patent Application diluted with aqueous NH4Cl (200 mL), the mixture was stirred at 25 ℃ for 1 hours. Then TBAF (1 mol / L in THF, 190 ml) was added dropwise. The resulting solution was stirred at 25 ℃ for 1 hours. Then the resulting mixture was diluted with water (600 mL) and extracted with EtOAc (600 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, and 5 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE = 3 / 1) to provide 1-(tert-butyl) 2-methyl 4-hydroxy-4- (trifluoromethyl)pyrrolidine-1,2-dicarboxylate (40 g, 77% yield) as a white solid. LCMS (ESI) calcd. for C7H11F3NO3[M + H - Boc]+m / z 214.07, found 213.60. 10 Step 2: To a solution of 1-(tert-butyl) 2-methyl 4-hydroxy-4-(trifluoromethyl)pyrrolidine- 1,2-dicarboxylate (12 g 0.0383 mol) in pyridine (250 mL) was added SOCl2 (36 g, 0.31 mol) dropwise at room temperature. Then the mixture was heated at 80 °C for 4 hours. After the reaction was completed. The mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with 2N HCl and brine, dried over sodium sulfate, 15 concentrated under vacuum. The residue was first purified by flash column chromatography on silica gel (eluting with EtOAc / PE, 0% to 15%) to provide 1-(tert-butyl) 2-methyl 4- (trifluoromethyl)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate (3.2 g, 28% yield) as a yellow oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 6.78-6.62 (m, 1 H), 5.29-5.10 (m, 1 H), 4.33 (d, J = 7.2 Hz, 2 H), 3.70 (d, J = 11.3 Hz, 3 H), 1.39 (d, J = 26.2 Hz, 9 H). 20 Step 3: A mixture of 1-(tert-butyl) 2-methyl 4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole- 1,2-dicarboxylate (3.2 g, 10.85 mmol) and 10% Pd / C (1 g) in MeOH (60 mL) was stirred at room temperature under an atmosphere of H2for 8 hours. Then the mixture was filtered through celite. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 20%) to give 1-(tert-butyl) 2-methyl 4- 25 (trifluoromethyl)pyrrolidine-1,2-dicarboxylate (3 g, 93% yield) as a yellow oil. LCMS (ESI) calcd. for C7H11F3NO2[M + H - Boc]+m / z 198.07, found 197.55. Step 4: A solution of 1-(tert-butyl) 2-methyl 4-(trifluoromethyl)pyrrolidine-1,2- dicarboxylate (3 g, 10.10 mmol) in HCl-dioxane (40 mL) was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under vacuum to give crude 30 methyl 4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride (1.8 g) which was used 112 LTGO-017 / 01WO 36088 / 98 Patent Application directly in the next step without further purification. LCMS (ESI) calcd. for C7H11F3NO2 [M + H]+m / z 198.08, found 197.55. Step 5: To a solution of crude methyl 4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride (1 g, about 4 mmol) in O-xylene (20 mL) was added 1-bromo-3,4-difluoro-2- 5 methoxybenzene (1.1 g, 5.12 mmol), Pd2(dba)3(392 mg, 0.42 mmol), 2,2’- bis(diphenylphosphino)-1,1’-binaphthyl (533 mg, 0.85 mmol) and Cs2CO3 (5.58 g, 17.12 mmol) under N2. The mixture was stirred at 140 ℃ for 16 hours. LCMS showed the reaction was completed. Then the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 2). The combined organic layers were washed with brine, dried over sodium sulfate, and 10 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE = 10 / 1) to provide methyl 1-(3,4-difluoro-2-methoxyphenyl)-4- (trifluoromethyl)pyrrolidine-2-carboxylate (790 mg) as a yellow oil. LCMS (ESI) calcd. for C14H15F5NO3 [M + H]+m / z 340.10, found 339.70. Step 6: To a solution of methyl 1-(3,4-difluoro-2-methoxyphenyl)-4- 15 (trifluoromethyl)pyrrolidine-2-carboxylate (780 mg, 2.30 mmol) in MeOH / THF / H2O = 1 / 1 / 1 (18 mL) was added LiOH (546 mg, 23.0 mol). The mixture was stirred at 25 ℃ for 1 hours. The filtrate was adjusted to pH 5-6 with 4N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to 20 provide 1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (510 mg, 68.2% yield) as a yellow oil. LCMS (ESI) calcd. for C13H13F5NO3 [M + H]+m / z 326.08, found 326.00. Step 7: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)pyrrolidine- 2-carboxylic acid (510 mg, 1.56 mmol) in DMF (20 mL) was added HATU (894 mg, 2.35 mmol), 25 DIEA (608 mg, 4.70 mmol) and NH4Cl (335 mg, 6.27 mmol). The mixture was stirred at 25 ℃ for 1 hours. Then the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE =3 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4- 30 (trifluoromethyl)pyrrolidine-2-carboxamide (410 mg, 80.6% yield) as a yellow oil. LCMS (ESI) calcd. for C13H14F5N2O2 [M + H]+m / z 325.10, found 324.70. 113 LTGO-017 / 01WO 36088 / 98 Patent Application Intermediate 29 (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(2-fluorophenoxy)pyrrolidine-2-carboxamide a) D F 5 Step 1: A solution of methyl (4S)-1-(3,4-difluoro-2-methoxyphenyl)-4- hydroxypyrrolidine-2-carboxylate (1 g, 3.48 mmol), 2-fluorophenol (1.17 g, 10.44 mmol), PPh3(1.55 g, 5.92 mmol), DEAD (1.03 g, 5.92 mmol) in THF (15 mL) was heated to 55 °C and stirred for 4 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, 10 dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide methyl (4R)-1-(3,4-difluoro-2- methoxyphenyl)-4-(2-fluorophenoxy)pyrrolidine-2-carboxylate (700 mg, 53.03% yield) as yellow oil. LCMS (ESI) calcd. for C19H19F3NO4[M + H]+m / z 382.13, found 381.8. Step 2: A solution of methyl (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(2- 15 fluorophenoxy)pyrrolidine-2-carboxylate (700 mg, 1.84 mmol) in THF / MeOH / H2O (1 / 1 / 1, 15 mL) was added LiOH (440 mg, 18.36 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 3-4 with aqueous HCl (1M). Then the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium20 sulfate, concentrated under vacuum to provide crude (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- (2-fluorophenoxy)pyrrolidine-2-carboxylic acid (550 mg) as a yellow oil. LCMS (ESI) calcd. for C18H17F3NO4 [[M + H]+m / z 368.11, found 367.7. Step 3: A solution of crude (4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(2- fluorophenoxy)pyrrolidine-2-carboxylic acid (550 mg), HATU (1.14 g, 2.99 mmol), DIEA (774 114 LTGO-017 / 01WO 36088 / 98 Patent Application mg, 5.99 mmol) and NH4Cl (801 mg, 14.97 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by 5 flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide (4R)-1-(3,4-difluoro-2- methoxyphenyl)-4-(2-fluorophenoxy)pyrrolidine-2-carboxamide (480 mg) as a yellow solid. LCMS (ESI) calcd. for C18H18F3N2O3 [M + H]+m / z 367.13, found 366.7. Intermediate 30 (2S)-1-(5-(benzyloxy)-3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine- 10 2-carboxamide NaOH, H2O2, THF; d) BnBr, K2CO3, DMF; e) Fe, NH4Cl, MeOH / H2O; f) NaNO2, CuBr, HBr, THF, H2O; g) Cs2CO3, Pd2(dba)3, BINAP, o-xylene, 140 °C; f) LiOH, THF, H2O; g) HATU, 15 DIEA, NH4Cl, DMF Step 1: To a solution of 1-bromo-2,3-difluoro-4-methoxybenzene (40 g, 0.18 mol) in H2SO4(500 mL) was added KNO3(18.2 g, 0.18 mol) slowly at 0 °C. The mixture was stirred at 0 °C for 3 hours. Then the mixture was poured into ice water (1500 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine, dried with sodium sulfate, 20 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 10%) to give 1-bromo-2,3-difluoro-4-methoxy-5-nitrobenzene (37 115 LTGO-017 / 01WO 36088 / 98 Patent Application g, 77% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 8.29 (dd, J = 6.8, 2.4 Hz, 1 H), 4.06 (d, J = 2.1 Hz, 3 H). Step 2: A solution of 1-bromo-2,3-difluoro-4-methoxy-5-nitrobenzene (20 g, 0.075 mol), KOAc (22 g, 0.22 mol), Bis(pinacolato)diboron (28.5 g, 0.11 mol) and Pd(dppf)Cl2 (5.5 g, 0.0075 5 mol) in dioxane (300 mL) was heated at 100°C for 8 hours under N2. Then the mixture was diluted with water (600 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated udder vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 10%) to give 2-(2,3- difluoro-4-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.5 g, 40% yield) as 10 yellow solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 8.08 (dd, J = 8.7, 2.1 Hz, 1 H), 4.05 (d, J = 2.6 Hz, 3 H), 1.33 (s, 12 H). Step 3: To a solution of 2-(2,3-difluoro-4-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (20 g, 0.063 mol) and NaOH (1.78 g, 0.044 mol) in THF (200 mL) was added 30% H2O2 (60 mL) dropwise at room temperature. The mixture was stirred at room temperature 15 for 3 hours. Then the mixture was adjusted to pH = 3-4 with 2N HCl and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 40%) to give 2,3-difluoro-4-methoxy-5-nitrophenol (10 g, 77% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 11.15 (s, 1 H), 7.36 (dd, J = 8.5, 2.3 20 Hz, 1 H), 3.92 (d, J = 0.8 Hz, 3 H). Step 4: To a solution of 2,3-difluoro-4-methoxy-5-nitrophenol (10 g, 0.049 mol) and K2CO3(20 g, 0.15 mol) in DMF (100 mL) was added BnBr (12.4 g, 0.073 mol) at room temperature. The mixture was stirred at room temperature for 8 hours. Then the mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers 25 were washed with brine, dried with sodium sulfate, concentrated udder vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 30%) to give 1- (benzyloxy)-2,3-difluoro-4-methoxy-5-nitrobenzene (9.1 g, 64% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6, ppm) δ 7.80 (dd, J = 8.2, 2.2 Hz, 1 H), 7.48-7.38 (m, 5 H), 5.28 (s, 2 H), 3.96 (d, J = 0.8 Hz, 3 H). 30 Step 5: To a solution of 1-(benzyloxy)-2,3-difluoro-4-methoxy-5-nitrobenzene (9.1 g, 0.031 mol) and NH4Cl (6.5 g, 0.12 mol) in EtOH / H2O (1 / 1, 200 mL) was added Fe power (8.7 g, 116 LTGO-017 / 01WO 36088 / 98 Patent Application 0.16 mol) at room temperature. The mixture was heated at 75 °C for 8 hours. Then the mixture was diluted with water (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried with sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 60%) to give 5- 5 (benzyloxy)-3,4-difluoro-2-methoxyaniline (7 g, 86% yield) as yellow solid. LCMS (ESI) calcd. for C14H14F2NO2 [M + H]+m / z 266.10, found 265.60. Step 6: To a solution of 5-(benzyloxy)-3,4-difluoro-2-methoxyaniline (5 g, 0.019 mol) and CuBr (0.80 g, 0.0057 mol) in THF (60 mL) was added 40% aqueous HBr (60 mL) and NaNO2(3.3 g, 0.048 mol) in H2O (30 mL) dropwise at 0 °C. Then the mixture was stirred at room 10 temperature for 8 hours. Then the mixture was adjusted to pH = 8-9 with saturated aqueous NaHCO3 and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / DCM, 0% to 80%) to give 1-(benzyloxy)- 5-bromo-2,3-difluoro-4-methoxybenzene (1.8 g, 29% yield) as yellow oil.1H NMR (400 MHz, 15 DMSO-d6, ppm) δ 7.53-7.28 (m, 6 H), 5.17 (s, 2 H), 3.86 (s, 3 H). Step 7: A mixture of 1-(benzyloxy)-5-bromo-2,3-difluoro-4-methoxybenzene (876 mg, 2.66 mmol), methyl (2S)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride (700 mg, 2.66 mmol), Pd2(dba)3(243 mg, 0.26 mmol), BINAP (330 mg, 0.53 mmol) and Cs2CO3(3027 mg, 9.29 mmol) in o-Xylene (7 mL) was heated at 140 ℃ for 18 hours under an atmosphere 20 of N2. After the reaction was completed, the mixture was diluted with water (150 mL) and extracted with EtOAc (100 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 5%) to give methyl (2S)-1-(5-(benzyloxy)-3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxylate (302 mg, 21% yield) as a yellow oil. LCMS (ESI) 25 calcd. for C22H23F5NO5[M + H]+m / z 476.15, found 476.30. Step 8: To a solution of methyl (2S)-1-(5-(benzyloxy)-3,4-difluoro-2-methoxyphenyl)-4- methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate (300 mg, 0.63 mmol) in THF (4 mL) and water (1 mL) was added Lithium hydroxide monohydrate (53 mg, 1.26 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed. Then the reaction 30 mixture was diluted with water (50 mL) and washed with EtOAc (50 mL). The aqueous phase was adjusted to pH 4-5 with 1N HCl and extracted with EtOAc (40 mL × 2). The organic layers were 117 LTGO-017 / 01WO 36088 / 98 Patent Application dried over sodium sulfate and concentrated under vacuum to provide crude (2S)-1-(5-(benzyloxy)- 3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (270 mg) as a yellow solid which was used directly in next step without further purification. LCMS (ESI) calcd. for C21H21F5NO5 [M + H]+m / z 462.13, found 462.05. 5 Step 9: To a solution of crude (2S)-1-(5-(benzyloxy)-3,4-difluoro-2-methoxyphenyl)-4- methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (250 mg), HATU (267 mg, 0.70 mmol) and DIPEA (630 mg, 4.88 mmol) in DMF (3 mL) was added NH4Cl (87 mg, 1.63 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (100 mL) and extracted with EtOAc (70 mL × 2). The organic layer was 10 washed with water (100 mL × 2), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM, 0% to 2%) to give (2S)-1-(5-(benzyloxy)-3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide (210 mg) as a yellow solid. LCMS (ESI) calcd. for C21H22F5N2O4 [M + H]+m / z 461.15, found 461.30. 15 Example 1 4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinamide Step 1: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2- 20 carboxylic acid (70 mg, 0.24 mmol) and methyl 4-aminopicolinate (40 mg, 0.26 mmol) in pyridine (5 mL) was added POCl3 (0.2 mL) dropwise. The mixture was stirred at 25 ℃ for 1 hour. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with25 EtOAc / PE=1 / 2) to provide methyl 4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine- 118 LTGO-017 / 01WO 36088 / 98 Patent Application 2-carboxamido)picolinate (50 mg, 46.2% yield) as a brown oil. LCMS (ESI) calcd. for C21H24F2N3O4[M + H]+m / z 420.18, found 419.8. Step 2: A solution of methyl 4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylpyrrolidine-2-carboxamido)picolinate (50 mg, 0.12 mmol) in 7M NH3.MeOH (6 mL) was 5 stirred at 25 ℃ for 4 hours. After the reaction was completed, the mixture was concentrated. The residue was directly purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to provide 4-(1-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinamide (12 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.47 (s, 1 H), 8.44 (d, J = 5.5 Hz, 1 H), 8.19 (d, J = 2.0 10 Hz, 1 H), 8.04 (s, 1 H), 7.74 (dd, J = 5.5, 2.1 Hz, 1 H), 7.59 (s, 1 H), 7.09-6.94 (m, 1 H), 6.51-6.39 (m, 1 H), 4.67 (t, J = 8.2 Hz, 1 H), 3.73 (s, 3 H), 3.45 (d, J = 9.1 Hz, 1 H), 3.03 (d, J = 9.0 Hz, 1 H), 2.19 (dd, J = 11.9, 7.6 Hz, 1 H), 1.76 (dd, J = 12.1, 8.7 Hz, 1 H), 1.17 (s, 3 H), 1.10 (s, 3 H). LCMS (ESI) calcd. for C20H23F2N4O3 [M + H]+m / z 405.18, found 405.1. Example 2 15 4-(1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinamide Step 1: A solution of 1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (180 mg, 0.66 mmol), methyl 4-aminopicolinate (150 mg, 0.99 mmol), TCFH (277 mg, 0.99 20 mmol) and NMI (108 mg, 1.32 mmol) in MeCN (8 mL) was stirred at room temperature for 2 hours. After the reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 3) to provide methyl 4-(1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinate (90 mg, 33.71 % yield) as a yellow solid. LCMS (ESI) calcd. for C20H22ClFN3O3[M + H]+m / z 406.14, found 25 406.2. Step 2: A solution of methyl 4-(1-(3-chloro-4-fluorophenyl)-4,4-dimethylpyrrolidine-2- carboxamido)picolinate (90 mg, 0.22 mmol) in 7M NH3-MeOH (5mL) was stirred at room 119 LTGO-017 / 01WO 36088 / 98 Patent Application temperature for 8h. After the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide 4-(1-(3-chloro-4-fluorophenyl)- 4,4-dimethylpyrrolidine-2-carboxamido)picolinamide (26 mg, 25.88% yield) as a white solid.1H 5 NMR (400 MHz, DMSO-d6, ppm) δ 10.56 (s, 1 H), 8.48 (d, J = 5.5 Hz, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.05 (s, 1 H), 7.84 (dd, J = 5.5, 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.19 (t, J = 9.1 Hz, 1 H), 6.57 (dd, J = 6.1, 3.0 Hz, 1 H), 6.40 (dt, J = 9.0, 3.3 Hz, 1 H), 4.33 (t, J = 7.6 Hz, 1 H), 3.40 (d, J = 9.2 Hz, 1 H), 3.15 (d, J = 9.1 Hz, 1 H), 2.30-2.21 (m, 1 H), 1.93-1.82 (m, 1 H), 1.17 (s, 3 H), 1.06 (s, 3 H). LCMS (ESI) calcd. for C19H21ClFN4O2[M + H]+m / z 391.14, found 391.05. 10 Example 3 N-(2-carbamoylpyridin-4-yl)-5-(3,4-difluoro-2-methoxyphenyl)-5-azaspiro[2.4]heptane-6- carboxamide R 15 Step 1: A mixture of 5-(3,4-difluoro-2-methoxyphenyl)-5-azaspiro[2.4]heptane-6- carboxylic acid (60 mg, 0.21 mmol) and methyl 4-aminopicolinate (39 mg, 0.25 mmol) in pyridine (5 mL) was added phosphoryl trichloride (42 mg, 0.28 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour. Then the mixture was quenched with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over sodium 20 sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide methyl 4-(5-(3,4-difluoro-2-methoxyphenyl)-5- azaspiro[2.4]heptane-6-carboxamido)picolinate (70 mg, 79.2% yield) as a yellow oil. LCMS (ESI) calcd. for C21H22F2N3O4[M + H]+m / z 418.16, found 418.2. Step 2: A mixture of methyl 4-(5-(3,4-difluoro-2-methoxyphenyl)-5-azaspiro[2.4]heptane- 25 6-carboxamido)picolinate (70 mg, 0.17 mmol) in 7 M NH3-MeOH solution (10 mL) was stirred at 70 °C for 2 hours. Then the mixture was concentrated under vacuum and the residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O 120 LTGO-017 / 01WO 36088 / 98 Patent Application containing 0.05% NH3) to provide N-(2-carbamoylpyridin-4-yl)-5-(3,4-difluoro-2- methoxyphenyl)-5-azaspiro[2.4]heptane-6-carboxamide (10 mg, 14.9% yield, white solid).1H NMR (400 MHz, DMSO-d6, ppm) δ 10.33 (s, 1 H), 8.48-8.38 (m, 1 H), 8.30 (s, 1 H), 8.05 (s, 1 H), 7.92-7.85 (m, 1 H), 7.60 (s, 1 H), 7.06-6.94 (m, 1 H), 6.46 (s, 1 H), 4.54-4.40 (m, 1 H), 3.70 5 (s, 3 H), 3.41-3.34 (m, 2 H), 2.44-2.40 (m, 1 H), 1.84-1.76 (m, 1 H), 0.71-0.48 (m, 4 H). LCMS (ESI) calcd. for C20H21F2N4O3 [M + H]+m / z 403.16, found 403.2. Example 4 Preparation of 5-(2-ethoxy-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)- 5-azaspiro[2.4]heptane-6-carboxamide 10 Step 1: To a solution 5-(2-ethoxy-3,4-difluorophenyl)-5-azaspiro[2.4]heptane-6- carboxylic acid (150 mg, 0.50 mmol) in pyridine (10 mL) was added [4-aminopyridine-2- (methane)sulfinylidene]amino tert-butyl formate (164 mg, 0.60 mmol) and POCl3(0.2 ml). The 15 mixture was stirred at 25 ℃ for 1 hour. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to give tert-butyl ((4-(5-(2-ethoxy-3,4- difluorophenyl)-5-azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- 20 sulfaneylidene)carbamate (90 mg, 30.7% yield) as a yellow oil. LCMS (ESI) calcd. for C21H25F2N4O3S [M + H - Boc]+m / z 451.16, found 450.8. Step 2: To a solution of tert-butyl ((4-(5-(2-ethoxy-3,4-difluorophenyl)-5- azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (90 mg, 0.16 mmol) in DCM / TFA=10 / 1 (11 mL). The mixture was stirred at 25 ℃ for 1 hour. 25 After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, 121 LTGO-017 / 01WO 36088 / 98 Patent Application concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide 5-(2- ethoxy-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5- azaspiro[2.4]heptane-6-carboxamide (38 mg, 49.1% yield) as a white solid.1H NMR (400 MHz, 5 DMSO-d6, ppm) δ 10.54 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.9 Hz, 1 H), 7.85 (dd, J = 5.5, 2.0 Hz, 1 H), 7.01-6.97 (m, 1 H), 6.52-6.40 (m, 1 H), 4.59 (dd, J = 8.3, 4.3 Hz, 1 H), 4.30 (s, 1 H), 4.09-3.85 (m, 2 H), 3.49 (d, J = 8.9 Hz, 1 H), 3.28 (d, J = 8.9 Hz, 1 H), 3.12 (s, 3 H), 2.39 (dd, J = 12.4, 8.4 Hz, 1 H), 1.89 (dd, J = 12.4, 4.3 Hz, 1 H), 1.24 (t, J = 7.0 Hz, 3 H), 0.71-0.47 (m, 4 H). LCMS (ESI) calcd. for C21H25F2N4O3S [M + H]+m / z 451.16, found 451.1. 10 Examples 5 and 6 (3S)-5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro-N-(2-((R)-S-methylsulfonimidoyl)pyridin- 4-yl)-5-azaspiro[2.4]heptane-6-carboxamide & (3R)-5-(3,4-difluoro-2-methoxyphenyl)-1,1- difluoro-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-azaspiro[2.4]heptane-6-carboxamide 15 Reagen , Step 1: A solution of 5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro-5- azaspiro[2.4]heptane-6-carboxylic acid (210 mg, 0.66 mmol) and tert-butyl (R)-((4-aminopyridin- 2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (179 mg, 0.66 mmol) in pyridine (5 mL) was added phosphoryl trichloride (303 mg, 1.98 mmol) at 0 °C. The resulting mixture was stirred at 25 20 °C for 1 hour. Then the mixture was quenched with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, 122 LTGO-017 / 01WO 36088 / 98 Patent Application concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl ((1R)-(4-(5-(3,4-difluoro-2-methoxyphenyl)-1,1- difluoro-5-azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (190 mg, 50.4% yield) as a yellow solid. LCMS (ESI) calcd. For 5 C20H21F4N4O3S [M - Boc + H]+m / z 473.13, found 473.10. Step 2: A solution of tert-butyl ((1R)-(4-(5-(3,4-difluoro-2-methoxyphenyl)-1,1-difluoro- 5-azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (190 mg, 0.33 mmol) in DCM (10 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture 10 was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide 2 isomers. 15 Example 5, Isomer 1 (major, 48 mg, white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.64 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.31 (d, J = 1.8 Hz, 1 H), 7.83 (dd, J = 5.5, 2.0 Hz, 1 H), 7.10- 7.00 (m, 1 H), 6.58-6.35 (m, 1 H), 4.66 (d, J = 7.0 Hz, 1 H), 4.31 (s, 1 H), 3.72 (s, 3 H), 3.63-3.54 (m, 2 H), 3.13 (s, 3 H), 2.66-2.59 (m, 1 H), 2.12-2.04 (m, 1 H), 1.76-1.58 (m, 2 H). LCMS (ESI) calcd. for C20H21F4N4O3S [M + H]+m / z 473.13, found 473.15. 20 Example 6, Isomer 2 (minor, 21 mg, white solid).1H NMR (400 MHz, DMSO-d6, ppm) δ 10.70 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.32 (d, J = 1.8 Hz, 1 H), 7.78 (dd, J = 5.5, 1.9 Hz, 1 H), 7.09- 6.97 (m, 1 H), 6.60-6.48 (m, 1 H), 4.72 (dd, J = 8.6, 4.1 Hz, 1 H), 4.30 (s, 1 H), 3.79-3.65 (m, 4 H), 3.55-3.49 (m, 1 H), 3.12 (s, 3 H), 2.72-2.64 (m, 1 H), 2.15-2.05 (m, 1 H), 1.75-1.60 (m, 2 H). LCMS (ESI) calcd. for C20H21F4N4O3S [M + H]+m / z 473.13, found 473.10. 25 Example 7 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)pyrrolidine-2-carboxamide 123 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2- carboxylic acid (40 mg, 0.14 mmol) and tert-butyl (R)-((4-aminopyridin-2-yl)(methyl)(oxo)-λ6- 5 sulfaneylidene)carbamate (45 mg, 0.16 mmol) in pyridine (5 mL) was added POCl3(0.15 mL). The mixture was stirred at 25 ℃ for 1 hour. Then the resulting mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE=1 / 2) to provide tert-butyl ((R)-(1-(3,4-difluoro-10 2-methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (30 mg, 39.8% yield) as a brown oil. LCMS (ESI) calcd. for C25H33F2N4O5S [M + H]+m / z 539.22, found 539.05. Step 2: To a solution of tert-butyl ((R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (30 15 mg, 0.05 mmol) in DCM / TFA (10 / 1, 11 mL). The mixture was stirred at 25 ℃ for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm,20 eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide 1-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2- carboxamide (5 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.67 (s, 1 H), 8.51 (d, J = 5.5 Hz, 1 H), 8.26 (dd, J = 4.8, 1.8 Hz, 1 H), 7.70 (dd, J = 5.4, 2.0 Hz, 1 H), 6.99-6.93 (m, 1 H), 6.51-6.41 (m, 1 H), 4.68 (t, J = 8.2 Hz, 1 H), 4.28 (s, 1 H), 3.73 (s, 3 H), 3.43 (d, J = 9.2 Hz, 25 1 H), 3.12-2.98 (m, 4 H), 2.26-2.11 (m, 1 H), 1.78-1.70 (m, 1 H), 1.18-1.09 (m, 6 H). LCMS (ESI) calcd. for C20H25F2N4O3S [M + H]+m / z 439.16, found 439.15. Examples 8 and 9 124 LTGO-017 / 01WO 36088 / 98 Patent Application (R)-1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin- 4-yl)-5-oxopyrrolidine-2-carboxamide & (S)-1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-N- (2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-oxopyrrolidine-2-carboxamide 5 Step 1: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-5-oxopyrrolidine- 2-carboxylic acid (280 mg, 0.93 mmol) and tert-butyl (R)-((4-aminopyridin-2-yl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (252 mg, 0.93 mmol) in pyridine (5 mL) was added POCl3(0.3 mL). The solution was stirred at 25 ℃ for 1 h. After the reaction was completed, the mixture was diluted 10 with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-5-oxopyrrolidine-2- carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (230 mg, 44.8% yield) as 15 a yellow oil. LCMS (ESI) calcd. for C25H31F2N4O6S [M + H]+m / z 553.20, found 553.2. Step 2: A solution of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl- 5-oxopyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (230 mg, 0.41 mmol) in DCM / TFA = 5 / 1 (5 mL) was stirred at 25 ℃ for 3 h. After the reaction was completed, the solution was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the 20 mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide 1-(3,4-difluoro-2- 125 LTGO-017 / 01WO 36088 / 98 Patent Application methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-oxopyrrolidine- 2-carboxamide (140 mg, 75.3 % yield) as a white solid. LCMS (ESI) calcd. for C20H23F2N4O4S [M + H]+m / z 453.14, found 453.2. Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S- 5 methylsulfonimidoyl)pyridin-4-yl)-5-oxopyrrolidine-2-carboxamide (140 mg, 0.30 mmol) was further purified by Chiral-Prep-SFC (Regis (R,R)-Whelk-O 120 mm I.D.*250 mm L, 5μm, eluting with 60 / 40 CO2 / MeOH containing 0.1% NH3) to provide 2 isomers. 8, First eluting isomer (92 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.93 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 7.67 (dd, J = 5.5, 2.0 Hz, 1 H), 7.18 10 (dd, J = 9.6, 6.8 Hz, 2 H), 4.71 (t, J = 7.5 Hz, 1 H), 4.32 (s, 1 H), 3.91 (d, J = 1.5 Hz, 3 H), 3.10 (s, 3 H), 2.45 (s, 1 H), 2.04 (m, 1 H), 1.22 (d, J = 4.6 Hz, 6 H). LCMS (ESI) calcd. for C20H23F2N4O4S [M + H]+m / z 453.14, found 452.9. 9, Second eluting isomer (20 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.94 (s, 1 H), 8.54 (d, J = 5.4 Hz, 1 H), 8.26 (d, J = 1.7 Hz, 1 H), 7.66 (dd, J = 5.5, 2.0 Hz, 1 H), 15 7.18 (dd, J = 9.4, 6.7 Hz, 2 H), 4.72 (t, J = 7.5 Hz, 1 H), 4.32 (s, 1 H), 3.91 (d, J = 1.6 Hz, 3 H), 3.10 (s, 3 H), 2.46 (d, J = 4.6 Hz, 1 H), 2.04 (m, 1 H), 1.22 (d, J = 4.4 Hz, 6 H). LCMS (ESI) calcd. for C20H23F2N4O4S [M + H]+m / z 453.14, found 452.8. Examples 10 and 11 (S)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-(5-(trifluoromethyl)pyridin-2-yl)-5-20 azaspiro[2.4]heptane-6-carboxamide & (R)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-(5- (trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide 126 LTGO-017 / 01WO 36088 / 98 Patent Application R C Step 1: A mixture of 5-(5-(trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6- carboxamide (290 mg, 1.02 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6- 5 sulfaneylidene)carbamate (376 mg, 1.12 mmol), Cs2CO3 (828 mg, 2.54 mmol) and Xantphos-Pd- G2(45 mg, 0.05 mmol) in 1,4-dioxane (10 mL) was heated at 100 ℃ for 2 hours under nitrogen. After the reaction was completed, the mixture was filtered through celite. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl ((1R)-methyl(oxo)(4-(5-(5-(trifluoromethyl)pyridin-2-yl)- 10 5-azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)-λ6-sulfaneylidene)carbamate (210 mg, 38.2% yield) as a yellow solid. LCMS (ESI) calcd. for C24H29F3N5O4S [M + H]+m / z 540.19, found 540.2. Step 2: A solution of tert-butyl ((1R)-methyl(oxo)(4-(5-(5-(trifluoromethyl)pyridin-2-yl)- 5-azaspiro[2.4]heptane-6-carboxamido)pyridin-2-yl)-λ6-sulfaneylidene)carbamate (210 mg, 0.39 15 mmol) in DCM (10 mL) was added TFA (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by 20 prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-(5- 127 LTGO-017 / 01WO 36088 / 98 Patent Application (trifluoromethyl)pyridin-2-yl)-5-azaspiro[2.4]heptane-6-carboxamide (110 mg, 64.4% yield) as white solid. LCMS (ESI) calcd. for C19H21F3N5O2S [M + H]+m / z 440.14, found 440.1. Step 3: N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-5-(5-(trifluoromethyl)pyridin-2- yl)-5-azaspiro[2.4]heptane-6-carboxamide was further purified by Chiral-Prep-SFC (Daicel IH, 20 5 mm I.D.* 250 mm L, 5μm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3) to provide 2 isomers. 10, First eluting isomer (40 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.70 (s, 1 H), 8.56-8.27 (m, 3 H), 7.85-7.71 (m, 2 H), 6.60 (d, J = 8.5 Hz, 1 H), 4.85-4.70 (m, 1 H), 4.30 (s, 1 H), 3.62-3.45 (m, 2 H), 3.11 (s, 3 H), 2.55-2.51 (m, 1 H), 1.94-1.84 (m, 1 H), 0.72- 10 0.53 (m, 4 H). LCMS (ESI) calcd. for C19H21F3N5O2S [M + H]+m / z 440.14, found 440.1. 11, Second eluting isomer (40 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.71 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.41-8.28 (m, 2 H), 7.86-7.76 (m, 2 H), 6.61 (d, J = 8.9 Hz, 1 H), 4.79 (d, J = 5.9 Hz, 1 H), 4.31 (s, 1 H), 3.64-3.44 (m, 2 H), 3.11 (s, 3 H), 2.57-2.25 (m, 1 H), 1.94-1.84 (m, 1 H), 0.72-0.53 (m, 4 H). LCMS (ESI) calcd. for C19H21F3N5O2S [M + H]+15 m / z 440.14, found 440.1. Examples 12, 13, 14 and 15 (S)-N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3- carboxamide, (R)-N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-2- azaspiro[4.4]nonane-3-carboxamide, (S)-N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2-20 methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide and (R)-N-(2-carbamoylpyridin-4-yl)-2- (3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide 128 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3- carboxamide and 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide 5 mixture (300 mg, 0.96 mmol) in 1.4-dioxane (10 mL) was added methyl 4-bromopicolinate (250 mg, 1.16 mmol), Cs2CO3 (944 mg, 2.90 mmol) and Xantphos-Pd-G2 (85 mg, 0.09 mmol). The mixture was stirred at 100 ℃ for 3 hours under N2. After the reaction was completed, the organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide a mixture of methyl 4-(2-(3,4-difluoro-10 2-methoxyphenyl)-2-azaspiro[4.4]nonane-3-carboxamido)picolinate and methyl 4-(2-(3,4- difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamido)picolinate (290 mg, 63.9% yield) as white solid. LCMS (ESI) calcd. for C23H26F2N3O4 [M + H]+m / z 446.19, found 445.85. Step 2: To a solution of methyl 4-(2-(3,4-difluoro-2-methoxyphenyl)-2- azaspiro[4.4]nonane-3-carboxamido)picolinate and methyl 4-(2-(3,4-difluoro-2-methoxyphenyl)- 15 2-azaspiro[4.4]nonane-1-carboxamido)picolinate mixture (290 mg, 0.67 mmol) in MeOH (5 mL) was added 7M NH3.MeOH (5 mL). The mixture was stirred at 25 ℃ for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by prep- HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to give a mixture of N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2- 129 LTGO-017 / 01WO 36088 / 98 Patent Application methoxyphenyl)-2-azaspiro[4.4]nonane-3-carboxamide and N-(2-carbamoylpyridin-4-yl)-2-(3,4- difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide (170 mg, 55.7% yield) as a white solid. LCMS (ESI) calcd. for C22H25F2N4O3 [M + H]+m / z 431.19, found 431.45. Step 3: N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2-methoxyphenyl)-2- 5 azaspiro[4.4]nonane-3-carboxamide and N-(2-carbamoylpyridin-4-yl)-2-(3,4-difluoro-2- methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide mixture was further purified by Chiral- Prep-SFC (DAICEL AD-H 20 mm I.D.*250 mm L, 5 μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to give 4 isomers. Example 12, First eluting isomer (23 mg, white solid):1H NMR (400 MHz, DMSO-d6, 10 ppm) δ 10.32 (s, 1 H), 8.47 (d, J = 5.5 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 8.06 (s, 1 H), 7.90 (dd, J = 5.4, 2.0 Hz, 1 H), 7.60 (s, 1 H), 7.07-6.94 (m, 1 H), 6.55-6.44 (m, 1 H), 4.02 (s, 1 H), 3.64- 3.50 (m, 4 H), 3.37 (d, J = 6.8 Hz, 1 H), 1.93 (td, J = 10.2, 8.7 Hz, 1 H), 1.72 (dt, J = 18.0, 9.5 Hz, 5 H), 1.61-1.50 (m, 3 H), 1.36-1.28 (m, 1 H). LCMS (ESI) calcd. for C22H25F2N4O3 [M + H]+m / z 431.19, found 431.15. 15 Example 13, Second eluting isomer (35 mg, white solid):1H NMR (400 MHz, DMSO- d6, ppm) δ 10.44 (s, 1 H), 8.44 (d, J = 5.5 Hz, 1 H), 8.21 (d, J = 2.0 Hz, 1 H), 8.04 (s, 1 H), 7.77 (dd, J = 5.5, 2.2 Hz, 1 H), 7.59 (s, 1 H), 6.98 (dd, J = 18.6, 9.5 Hz, 1 H), 6.51-6.44 (m, 1 H), 4.58 (t, J = 7.8 Hz, 1 H), 3.71 (s, 3 H), 3.53 (d, J = 9.1 Hz, 1 H), 3.11 (d, J = 8.9 Hz, 1 H), 2.30 (dd, J = 12.0, 7.8 Hz, 1 H), 1.90 (dd, J = 12.1, 7.9 Hz, 1 H), 1.75-1.53 (m, 8 H). LCMS (ESI) calcd. for 20 C22H25F2N4O3 [M + H]+m / z 431.19, found 431.85. Example 14, Third eluting isomer (27 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.44 (s, 1 H), 8.44 (d, J = 5.5 Hz, 1 H), 8.21 (d, J = 1.8 Hz, 1 H), 8.04 (s, 1 H), 7.77 (dd, J = 5.5, 2.1 Hz, 1 H), 7.59 (s, 1 H), 6.98 (q, J = 9.3 Hz, 1 H), 6.47 (dd, J = 5.9, 3.6 Hz, 1 H), 4.58 (t, J = 7.7 Hz, 1 H), 3.71 (s, 3 H), 3.53 (d, J = 9.1 Hz, 1 H), 3.11 (d, J = 9.0 Hz, 1 H), 2.34-2.26 25 (m, 1 H), 1.90 (dd, J = 12.0, 8.0 Hz, 1 H), 1.76-1.53 (m, 8 H). LCMS (ESI) calcd. for C22H25F2N4O3[M + H]+m / z 431.19, found 431.05. Example 15, Fourth eluting isomer (21 mg, white solid):1H NMR (400 MHz, DMSO- d6, ppm) δ 10.32 (s, 1 H), 8.47 (d, J = 5.5 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 8.06 (s, 1 H), 7.90 (dd, J = 5.5, 2.1 Hz, 1 H), 7.60 (s, 1 H), 7.01 (dd, J = 18.7, 9.5 Hz, 1 H), 6.56-6.43 (m, 1 H), 4.02 30 (s, 1 H), 3.63 (s, 3 H), 3.53 (t, J = 8.1 Hz, 1 H), 3.43-3.34 (m, 1 H), 1.93 (dd, J = 19.4, 10.3 Hz, 1 130 LTGO-017 / 01WO 36088 / 98 Patent Application H), 1.79-1.51 (m, 8 H), 1.36-1.27 (m, 1 H). LCMS (ESI) calcd. for C22H25F2N4O3 [M + H]+m / z 431.19, found 431.20. Examples 16, 17, 18 and 19 (S)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2- 5 azaspiro[4.4]nonane-3-carboxamide, (R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3-carboxamide, (S)-2-(3,4-difluoro-2- methoxyphenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-1- carboxamide and (R)-2-(3,4-difluoro-2-methoxyphenyl)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-1-carboxamide 10 Step 1 : To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3- carboxamide and 2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamide mixture (300 mg, 0.96 mmol) in 1.4-dioxane (10 mL) was added tert-butyl (R)-((4-bromopyridin- 15 2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (390 mg, 1.16 mmol) and Xantphos-Pd-G2 (85 mg, 0.09 mmol) and Cs2CO3(944 mg, 2.90 mmol) under N2. The mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, the organic layers were concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide tert-butyl ((1R)-(4-(2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-3-20 carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and ((1R)-(4-(2-(3,4- 131 LTGO-017 / 01WO 36088 / 98 Patent Application difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamido)pyridin-2-yl)(methyl)(oxo)- λ6-sulfaneylidene)carbamate (400 mg, 69.5% yield) as white solid. LCMS (ESI) calcd. for C27H35F2N4O5S [M + H]+m / z 565.23, found 564.90. Step 2: To a solution of tert-butyl ((1R)-(4-(2-(3,4-difluoro-2-methoxyphenyl)-2- 5 azaspiro[4.4]nonane-3-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and ((1R)-(4-(2-(3,4-difluoro-2-methoxyphenyl)-2-azaspiro[4.4]nonane-1-carboxamido)pyridin- 2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (400 mg, 0.70 mmol) in DCM / TFA (10 / 1, 11 mL). The mixture was stirred at 25 ℃ for 1 hour. After the reaction was completed, the residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3.The organic layers were concentrated 10 under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to give 2-(3,4-difluoro-2- methoxyphenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3- carboxamide and 2-(3,4-difluoro-2-methoxyphenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin- 4-yl)-2-azaspiro[4.4]nonane-1-carboxamide (130 mg, 37.6% yield) as a white solid. LCMS (ESI) 15 calcd. for C22H27F2N4O3S [M + H]+m / z 465.18, found 465.05. Step 3: 2-(3,4-difluoro-2-methoxyphenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)-2-azaspiro[4.4]nonane-3-carboxamide was further purified by Chiral-Prep-SFC (DAICEL AD-H 20 mm I.D.*250 mm L, 5 μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to give 4 isomers. 20 Example 16, First eluting isomer (23 mg, white solid) :1H NMR (400 MHz, DMSO-d6, ppm) δ 10.49 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.34 (d, J = 1.9 Hz, 1 H), 7.91 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07-6.93 (m, 1 H), 6.51 (dd, J = 8.5, 4.1 Hz, 1 H), 4.33 (s, 1 H), 4.03 (s, 1 H), 3.64 (s, 3 H), 3.56-3.47 (m, 1 H), 3.41-3.34 (m, 1 H), 3.13 (s, 3 H), 1.91 (d, J = 10.9 Hz, 1 H), 1.80-1.66 (m, 5 H), 1.63-1.50 (m, 3 H), 1.33 (d, J = 7.9 Hz, 1 H). LCMS (ESI) calcd. for C22H27F2N4O3S [M 25 + H]+m / z 465.18, found 465.10. Example 17, Second eluting isomer (23 mg, white solid) :1H NMR (400 MHz, DMSO- d6, ppm) δ 10.49 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.34 (d, J = 1.9 Hz, 1 H), 7.92 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07-6.96 (m, 1 H), 6.57-6.46 (m, 1 H), 4.32 (s, 1 H), 4.03 (s, 1 H), 3.64 (s, 3 H), 3.52 (q, J = 7.9 Hz, 1 H), 3.41-3.35 (m, 1 H), 3.13 (s, 3 H), 1.91 (td, J = 10.2, 8.7 Hz, 1 H), 1.80-1.52 30 (m, 8 H), 1.36-1.29 (m, 1 H). LCMS (ESI) calcd. for C22H27F2N4O3S [M + H]+m / z 465.18, found 465.15. 132 LTGO-017 / 01WO 36088 / 98 Patent Application Example 18, Third eluting isomer (18 mg, white solid) :1H NMR (400 MHz, DMSO-d6, ppm) δ 10.63 (s, 1 H), 8.52 (d, J = 5.5 Hz, 1 H), 8.29 (d, J = 1.8 Hz, 1 H), 7.75 (dd, J = 5.5, 1.9 Hz, 1 H), 7.05-6.82 (m, 1 H), 6.52-6.43 (m, 1 H), 4.59 (t, J = 7.8 Hz, 1 H), 4.30 (s, 1 H), 3.71 (s, 3 H), 3.51 (d, J = 9.1 Hz, 1 H), 3.12 (d, J = 8.1 Hz, 4 H), 2.35-2.27 (m, 1 H), 1.94-1.86 (m, 1 H), 5 1.75-1.54 (m, 8 H). LCMS (ESI) calcd. for C22H27F2N4O3S [M + H]+m / z 465.18, found 465.15. Example 19, Fourth eluting isomer (16 mg, white solid) :1H NMR (400 MHz, DMSO- d6, ppm) δ 10.63 (s, 1 H), 8.52 (d, J = 5.5 Hz, 1 H), 8.28 (d, J = 1.7 Hz, 1 H), 7.76 (dd, J = 5.5, 1.8 Hz, 1 H), 7.05-6.93 (m, 1 H), 6.53-6.42 (m, 1 H), 4.59 (t, J = 7.8 Hz, 1 H), 4.30 (s, 1 H), 3.71 (s, 3 H), 3.51 (d, J = 9.0 Hz, 1 H), 3.12 (d, J = 9.4 Hz, 4 H), 2.34-2.27 (m, 1 H), 1.93-1.86 (m, 1 H), 10 1.76-1.54 (m, 8 H). LCMS (ESI) calcd. for C22H27F2N4O3S [M + H]+m / z 465.18, found 465.15. Examples 20, 21, 22 and 23 (2R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide, (2S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy- N-(6-oxo-1,6-dihydropyridazin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R)-1-15 (3,4-difluoro-2-methoxyphenyl)-3-methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide, and (2S)-1-(3,4-difluoro-2-methoxyphenyl)-3- methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide eage s co o s: a s3, a p os- - , o a e, ; c a, c , 20 ℃; c) SFC 133 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy- 3-(trifluoromethyl)pyrrolidine-2-carboxamide mixture (400 mg, 1.13 mmol), 5-bromo-3- chloropyridazine (240 mg, 1.24 mmol), Cs2CO3 (1.84 g, 5.65 mmol) and Xantphos-Pd-G2 (100 5 mg, 0.11 mmol) in dioxane (10 mL) was heated to 100 °C and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide N-(6-chloropyridazin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-10 4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide and N-(6-chloropyridazin-4-yl)-1-(3,4- difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine-2-carboxamide (450 mg, 85.55% yield) as a yellow oil. LCMS (ESI) calcd. for C18H17ClF5N4O3[M + H]+m / z 467.09, found 466.75. Step 2: A solution of N-(6-chloropyridazin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-4-15 methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide and N-(6-chloropyridazin-4-yl)-1-(3,4- difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine-2-carboxamide mixture (450 mg, 0.96 mmol) and AcONa (237 mg, 2.89 mmol) in AcOH (5 mL) was heated at 120 °C for 1 hour. LCMS showed the reaction was completed. The mixture was quenched with saturated aqueous NaHCO3and extracted with DCM (15 mL x 3). The combined organic layers were washed 20 with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-3- 25 (trifluoromethyl)pyrrolidine-2-carboxamide (70 mg, 15.98% yield) as a white solid. LCMS (ESI) calcd. for C18H18F5N4O4[M + H]+m / z 449.13, found 448.75. Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(6-oxo-1,6-dihydropyridazin-4- yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3- methoxy-N-(6-oxo-1,6-dihydropyridazin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide 30 mixture (70 mg, 0.16 mmol) was further purified by Chiral-Prep-SFC (DAICEL IG, 20 mm I.D.* 250 mm L, 5μm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3) and Chiral-Prep-SFC 134 LTGO-017 / 01WO 36088 / 98 Patent Application (DAICEL IH, 20 mm I.D.* 250 mm L, 5μm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) to provide 4 isomers. Example 20, First eluting isomer (8.00 mg, white solid):1H NMR (400 MHz, CD3OD, ppm) δ 8.05 (d, J = 2.3 Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H), 6.89 (dd, J = 18.2, 9.5 Hz, 1 H), 6.61 5 (ddd, J = 9.4, 4.9, 2.3 Hz, 1 H), 4.70 (s, 1 H), 3.79 (t, J = 8.2 Hz, 1 H), 3.72 (d, J = 1.0 Hz, 3 H), 3.55-3.49 (m, 1 H), 3.46 (s, 3 H), 2.68-2.58 (m, 1 H), 2.55-2.46 (m, 1 H). LCMS (ESI) calcd. for C18H18F5N4O4 [M + H]+m / z 449.13, found 448.75. Example 21, Second eluting isomer (8.00 mg, white solid):1H NMR (400 MHz, CD3OD, ppm) δ 8.05 (d, J = 2.3 Hz, 1 H), 7.39 (d, J = 2.3 Hz, 1 H), 6.89 (dd, J = 18.2, 9.5 Hz, 1 H), 6.65- 10 6.57 (m, 1 H), 4.70 (s, 1 H), 3.79 (t, J = 7.9 Hz, 1 H), 3.72 (d, J = 1.1 Hz, 3 H), 3.54-3.49 (m, 1 H), 3.46 (s, 3 H), 2.68-2.57 (m, 1 H), 2.55-2.46 (m, 1 H). LCMS (ESI) calcd. for C18H18F5N4O4 [M + H]+m / z 449.13, found 448.80. Example 22, Third eluting isomer (19.00 mg, white solid):1H NMR (400 MHz, DMSO- d6, ppm) δ 12.75 (s, 1 H), 10.28 (s, 1 H), 7.97 (d, J = 2.2 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.06 15 (dd, J = 18.5, 9.5 Hz, 1 H), 6.72-6.63 (m, 1 H), 4.62 (dd, J = 9.3, 3.2 Hz, 1 H), 3.93 (d, J = 11.1 Hz, 1 H), 3.74 (s, 3 H), 3.56 (d, J = 11.3 Hz, 1 H), 3.36 (s, 3 H), 2.74 (dd, J = 13.9, 9.4 Hz, 1 H), 2.41-2.35 (m, 1 H). LCMS (ESI) calcd. for C18H18F5N4O4 [M + H]+m / z 449.13, found 448.75. Example 23, Fourth eluting isomer (18.00 mg, white solid):1H NMR (400 MHz, DMSO- d6, ppm) δ 12.75 (s, 1 H), 10.27 (s, 1 H), 7.97 (d, J = 2.2 Hz, 1 H), 7.16 (d, J = 2.2 Hz, 1 H), 7.06 20 (dd, J = 18.5, 9.4 Hz, 1 H), 6.72-6.62 (m, 1 H), 4.62 (dd, J = 9.1, 3.2 Hz, 1 H), 3.93 (d, J = 11.2 Hz, 1 H), 3.74 (s, 3 H), 3.56 (d, J = 11.3 Hz, 1 H), 3.36 (s, 3 H), 2.73 (dd, J = 13.9, 9.4 Hz, 1 H), 2.42-2.34 (m, 1 H). LCMS (ESI) calcd. for C18H18F5N4O4[M + H]+m / z 449.13, found 448.80. Examples 24, 25, 26, 27, 28 and 29 (2R)-1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-25 yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide, (2S)-1-(3,4-difluoro-2-methoxyphenyl)-3- methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2- carboxamide , (2R,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4S)-1- (3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-30 (trifluoromethyl)pyrrolidine-2-carboxamide, (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2- 135 LTGO-017 / 01WO 36088 / 98 Patent Application carboxamide, and (2S,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide 5 Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- (trifluoromethyl)pyrrolidine-2-carboxamide mixture (600 mg, 1.69 mmol), tert-butyl (R)-((4- bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (569 mg, 1.69 mmol), Cs2CO3 (2.76 g, 8.47 mmol) and Xantphos-Pd-G2 (151 mg, 0.17 mmol) in dioxane (10 mL) was heated at 10 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide a mixture of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2- 136 LTGO-017 / 01WO 36088 / 98 Patent Application carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1- (3,4-difluoro-2-methoxyphenyl)-3-methoxy-3-(trifluoromethyl)pyrrolidine-2- carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (700 mg, 67.96% yield) as a yellow oil. LCMS (ESI) calcd. for C25H29F5N4O6SNa [M + Na]+m / z 631.16, found 631.00. 5 Step 2: A solution of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy- 3-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate mixture (700 mg, 1.15 mmol) in DCM (10 mL) was added TFA (1 mL) 10 at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting15 with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide a mixture of 1-(3,4-difluoro- 2-methoxyphenyl)-4-methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy- N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide (150 mg, 25.68% yield) as a white solid. LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 20 509.13, found 508.90. Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4- difluoro-2-methoxyphenyl)-3-methoxy-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide mixture (150 mg, 0.29 mmol) was further purified by 25 Chiral-Prep-SFC (DAICEL IC, 20 mm I.D.* 250 mm L, 5 μm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3), Chiral-Prep-SFC (DAICEL IH, 20 mm I.D.* 250 mm L, 5 μm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) and ) and Chiral-Prep-SFC (DAICEL IB N-5, 20 mm I.D.* 250 mm L, 5μm, eluting with 75 / 25 CO2-MeOH containing 0.1% NH3) to obtain 6 isomers. Example 24, First eluting isomer (7.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 30 δ 10.72 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.30 (d, J = 1.8 Hz, 1 H), 7.83 (dd, J = 5.5, 2.0 Hz, 1 H), 7.05 (dd, J = 18.5, 9.5 Hz, 1 H), 6.62-6.56 (m, 1 H), 4.78 (s, 1 H), 4.33 (s, 1 H), 3.80 (d, J = 137 LTGO-017 / 01WO 36088 / 98 Patent Application 3.9 Hz, 1 H), 3.68 (s, 3 H), 3.48 (dd, J = 15.8, 7.3 Hz, 1 H), 3.39 (s, 3 H), 3.12 (d, J = 0.8 Hz, 3 H), 2.65-2.55 (m, 1 H), 2.47 -2.41 (m, 1H). LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 509.13, found 509.35. Example 25, Second eluting isomer (8.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 5 δ 10.72 (s, 1 H), 8.55 (d, J = 5.4 Hz, 1 H), 8.30 (s, 1 H), 7.83 (d, J = 5.4 Hz, 1 H), 7.05 (q, J = 9.4 Hz, 1 H), 6.63-6.55 (m, 1 H), 4.78 (s, 1 H), 4.34 (s, 1 H), 3.80 (s, 1 H), 3.68 (s, 3 H), 3.48 (q, J = 7.9 Hz, 1 H), 3.39 (s, 3 H), 3.12 (s, 3 H), 2.65-2.56 (m, 1 H), 2.47-2.40 (m, 1 H). LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 509.13, found 509.30. Example 26, Third eluting isomer (37.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 10 δ 10.58 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.9 Hz, 1 H), 7.86 (dd, J = 5.5, 2.0 Hz, 1 H), 7.10-7.02 (m, 1 H), 6.71-6.64 (m, 1 H), 4.65 (dd, J = 9.1, 3.5 Hz, 1 H), 4.31 (s, 1 H), 3.97 (d, J = 11.2 Hz, 1 H), 3.74 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.36 (s, 3 H), 3.11 (s, 3 H), 2.76 (dd, J = 13.9, 9.3 Hz, 1 H), 2.40 (dd, J = 14.0, 3.2 Hz, 1 H). LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 509.13, found 508.85. 15 Example 27, Fourth eluting isomer (36.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.59 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.9 Hz, 1 H), 7.85 (dd, J = 5.5, 2.0 Hz, 1 H), 7.06 (dd, J = 18.5, 9.4 Hz, 1 H), 6.73-6.63 (m, 1 H), 4.65 (dd, J = 9.2, 3.5 Hz, 1 H), 4.31 (s, 1 H), 3.97 (d, J = 11.3 Hz, 1 H), 3.74 (s, 3 H), 3.57 (d, J = 11.4 Hz, 1 H), 3.36 (s, 3 H), 3.12 (s, 3 H), 2.76 (dd, J = 13.9, 9.3 Hz, 1 H), 2.40 (dd, J = 13.9, 3.4 Hz, 1 H). LCMS (ESI) calcd. for 20 C20H22F5N4O4S [M + H]+m / z 509.13, found 508.85. Example 28, Fifth eluting isomer (18.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.86 (s, 1 H), 8.54 (d, J = 5.4 Hz, 1 H), 8.24 (s, 1 H), 7.78-7.66 (m, 1 H), 7.04 (dd, J = 18.6, 9.2 Hz, 1 H), 6.65 (s, 1 H), 4.83 (t, J = 8.0 Hz, 1 H), 4.32 (s, 1 H), 3.98 (d, J = 11.3 Hz, 1 H), 3.80 (s, 3 H), 3.60 (d, J = 11.1 Hz, 1 H), 3.42 (s, 3 H), 3.10 (s, 3 H), 2.81 (dd, J = 13.9, 6.7 Hz, 1 H), 2.29 25 (dd, J = 13.7, 8.6 Hz, 1 H). LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 509.13, found 509.35. Example 29, Sixth eluting isomer (19.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.86 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.25 (s, 1 H), 7.70 (dd, J = 5.4, 2.1 Hz, 1 H), 7.04 (q, J = 8.8 Hz, 1 H), 6.67-6.60 (m, 1 H), 4.82 (t, J = 7.8 Hz, 1 H), 4.31 (s, 1 H), 3.98 (d, J = 11.5 Hz, 1 30 H), 3.80 (s, 3 H), 3.60 (d, J = 11.4 Hz, 1 H), 3.42 (s, 3 H), 3.10 (s, 3 H), 2.80 (dd, J = 13.6, 7.3 Hz, 138 LTGO-017 / 01WO 36088 / 98 Patent Application 1 H), 2.29 (dd, J = 13.5, 8.7 Hz, 1 H). LCMS (ESI) calcd. for C20H22F5N4O4S [M + H]+m / z 509.13, found 509.35 Examples 30, 31, 32, 33, 34 and 35 5 (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- methyl-N-(2-sulfamoylpyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R)-1-(3,4- difluoro-2-methoxyphenyl)-3-methyl-N-(2-sulfamoylpyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide, (2S)-1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-10 N-(2-sulfamoylpyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide, (2S,4S)-1-(3,4- difluoro-2-methoxyphenyl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide, and (2R,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4- methyl-N-(2-sulfamoylpyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide LTGO-017 / 01WO 36088 / 98 Patent Application Reagents & conditions: a) Cs2CO3, Xantphos-Pd-G2, dioxane, 100 ℃; b) TFA / DCM; c) SFC Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine-2-carboxamide mixture (400 mg, 1.18 mmol), 4-bromo-N,N-bis(2,4- 5 dimethoxybenzyl)pyridine-2-sulfonamide (633.6 mg, 1.18 mmol), Cs2CO3 (1.15 g, 3.54 mmol) and Xantphos-Pd-G2(104.8 mg, 0.12 mmol) in 1,4-dioxane (10 mL) was heated at 100 ℃ for 2 hours under N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 1 / 1) to provide a mixture of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-10 difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide and N-(2- (N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-3- methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide (700 mg, 71% yield) as a yellow solid. LCMS (ESI) calcd. for C37H40F5N4O8S [M + H]+m / z 795.25, found 795.25. Step 2: A solution of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-15 difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide and N-(2- (N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-3- methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide mixture (700 mg, 0.88 mmol) in DCM / TFA (3 / 1, 12 mL) was stirred at 25 ℃ for 4 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the 20 aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The crude product was purified by prep-HPLC (Xbridge 5 um C18column, 150*21.2 mm, eluting with 20% to 80% MeCN / H2O containing 0.05% NH3) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4- methyl-N-(2-sulfamoylpyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-25 difluoro-2-methoxyphenyl)-3-methyl-N-(2-sulfamoylpyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide (200 mg, 45% yield) as a white solid. LCMS (ESI) calcd. for C19H20F5N4O4S [M + H]+m / z 495.11, found 494.75. Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-sulfamoylpyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-N- 30 (2-sulfamoylpyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide mixture (200 mg) was further purified by prep-HPLC (Xbridge 5 um C18 column, 150*21.2 mm, eluting with 40% to 140 LTGO-017 / 01WO 36088 / 98 Patent Application 60% MeCN / H2O containing 0.05% NH3), then further purified by Chiral-Prep-SFC (DAICEL IH 20 mm I.D.*250 mm L 5µm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3), Chiral-Prep- SFC (DAICEL IC 20 mm I.D.*250 mm L 5µm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) and Chiral-Prep-SFC ((R,R)-Whelk-O120 mm I.D.*250 mm L 5µm, eluting with 80 / 20 5 CO2-MeOH containing 0.1% NH3) to provide 6 isomers. Example 30, First eluting isomer (5 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.77 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.14 (d, J = 1.8 Hz, 1 H), 7.67 (dd, J = 5.5, 2.0 Hz, 1 H), 7.40 (s, 2 H), 7.03 (d, J = 9.1 Hz, 1 H), 6.67-6.56 (m, 1 H), 4.84-3.81 (m, 1 H), 3.92 (d, J = 9.6 Hz, 1 H), 3.79 (s, 3 H), 3.20 (d, J = 9.5 Hz, 1 H), 2.41-2.33 (m, 1 H), 2.24 (d, J = 8.2 Hz, 1 H), 10 1.37 (s, 3 H). LCMS (ESI) calcd. for C19H20F5N4O4S [M + H]+m / z 495.11, found 494.80. Example 31, Second eluting isomer (20 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.76 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.23 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 5.4, 1.6 Hz, 1 H), 7.42 (s, 2 H), 7.09-7.02 (m, 1 H), 6.66-6.56 (m, 1 H), 4.63 (s, 1 H), 3.70 (s, 4 H), 3.45-3.38 (m, 1 H), 2.40-2.29 (m, 1 H), 2.09-2.01 (m, 1 H), 1.24 (s, 3 H). LCMS (ESI) calcd. for 15 C19H20F5N4O4S [M + H]+m / z 495.11, found 494.75. Example 32, Third eluting isomer (3 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 11.01-10.52 (m, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.14 (d, J = 1.9 Hz, 1 H), 7.67 (dd, J = 5.5, 2.0 Hz, 1 H), 7.39 (s, 2 H), 7.03 (d, J = 9.1 Hz, 1 H), 6.68-6.54 (m, 1 H), 4.85-4.81 (m, 1 H), 3.93 (d, J = 9.6 Hz, 1 H), 3.79 (s, 3 H), 3.20 (d, J = 9.5 Hz, 1 H), 2.40-2.35 (m, 1 H), 2.24 (d, J = 8.2 Hz, 20 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C19H20F5N4O4S [M + H]+m / z 495.11, found 494.90. Example 33, Fourth eluting isomer (16 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.75 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.23 (d, J = 1.9 Hz, 1 H), 7.86 (dd, J = 5.4, 1.8 Hz, 1 H), 7.41 (s, 2 H), 7.09-7.01 (m, 1 H), 6.65-6.55 (m, 1 H), 4.63 (s, 1 H), 3.70 (s, 4 H), 3.42 (d, J = 8.2 Hz, 1 H), 2.39-2.32 (m, 1 H), 2.08-2.03 (m, 1 H), 1.24 (s, 3 H). LCMS (ESI) calcd. for 25 C19H20F5N4O4S [M + H]+m / z 495.11, found 494.80. Example 34, Fifth eluting isomer (43 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.79 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.18 (d, J = 1.8 Hz, 1 H), 7.69 (dd, J = 5.5, 2.0 Hz, 1 H), 7.41 (s, 2 H), 7.07-6.99 (m, 1 H), 6.62-6.52 (m, 1 H), 4.83-4.70 (m, 1 H), 3.75 (s, 3 H), 3.67 (d, J = 10.7 Hz, 1 H), 3.57 (d, J = 10.6 Hz, 1 H), 2.77 (dd, J = 13.8, 8.7 Hz, 1 H), 2.07 (dd, J = 13.9, 6.1 30 Hz, 1 H), 1.39 (s, 3 H). LCMS (ESI) calcd. for C19H20F5N4O4S [M + H]+m / z 495.11, found 494.90. 141 LTGO-017 / 01WO 36088 / 98 Patent Application Example 35, Sixth eluting isomer (47 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.79 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.18 (d, J = 1.8 Hz, 1 H), 7.69 (dd, J = 5.5, 2.0 Hz, 1 H), 7.41 (s, 2 H), 7.07-6.99 (m, 1 H), 6.57 (ddd, J = 9.2, 5.0, 1.9 Hz, 1 H), 4.89-4.63 (m, 1 H), 3.74 (d, J = 10.6 Hz, 3 H), 3.71-3.64 (m, 1 H), 3.57 (d, J = 10.6 Hz, 1 H), 2.77 (dd, J = 13.8, 8.7 Hz, 1 H), 5 2.07 (dd, J = 14.0, 6.1 Hz, 1 H), 1.39 (s, 3 H). LCMS (ESI) calcd. for C19H20F5N4O4S [M + H]+m / z 495.11, found 494.70. Examples 36, 37, 38, 39, 40 and 41 (2R,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin- 4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2S,4S)-1-(3,4-difluoro-2-methoxyphenyl)-10 4-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide, (2S)-1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R)-1-(3,4- difluoro-2-methoxyphenyl)-3-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-15 methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide, and (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide 142 LTGO-017 / 01WO 36088 / 98 Patent Application R Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- 5 (trifluoromethyl)pyrrolidine-2-carboxamide mixture (400 mg, 1.18 mmol), tert-butyl (R)-((4- bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (396.4 mg, 1.18 mmol), Cs2CO3(1.15 g, 3.54 mmol) and Xantphos-Pd-G2 (104.8 mg, 0.12 mmol) in 1,4-dioxane (10 mL) was heated at 100 ℃ for 2 hours under N2. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography10 (eluting with PE / EtOAc = 1 / 1) to provide a mixture of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2- methoxyphenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2- yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(3,4-difluoro-2- methoxyphenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2- yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (500 mg, 71% yield) as a yellow solid. LCMS15(ESI) calcd. for C25H30F5N4O5S [M + H]+m / z 593.19, found 592.90. 143 LTGO-017 / 01WO 36088 / 98 Patent Application Step 2: tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4- (trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-3-methyl-3- (trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- 5 sulfaneylidene)carbamate mixture (500 mg, 84 mmol) in DCM / TFA (10 / 1, 11 mL) was stirred at 25 ℃ for 2 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (30 mL x 3). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. The crude product was purified by prep- 10 HPLC (Xbridge 5 um C18 column, 150*21.2 mm, eluting with 20% to 80% MeCN / H2O containing 0.05% NH3) to provide a mixture of 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4- difluoro-2-methoxyphenyl)-3-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide (140 mg) as a white solid. LCMS (ESI) calcd. for 15 C20H22F5N4O3S [M + H]+m / z 493.14, found 492.85. LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.85. Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4- difluoro-2-methoxyphenyl)-3-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3- 20 (trifluoromethyl)pyrrolidine-2-carboxamide mixture (140 mg) was further purified by prep-HPLC (Xbridge 5 um C18 column, 150*21.2 mm, eluting with 40% to 60% MeCN / H2O containing 0.05% NH3) and Chiral-Prep-SFC (DAICEL IH 20 mm I.D.*250 mm L 5µm, eluting with 80 / 20 CO2- MeOH containing 0.1% NH3) to provide 6 isomers. Example 36, First eluting isomer (6 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 25 10.80 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.32 (d, J = 1.6 Hz, 1 H), 7.88 (d, J = 4.1 Hz, 1 H), 7.05 (d, J = 9.2 Hz, 1 H), 6.68-6.55 (m, 1 H), 4.65 (s, 1 H), 4.34 (s, 1 H), 3.71 (s, 4 H), 3.48-3.39 (m, 1 H), 3.12 (s, 3 H), 2.39-2.30 (m, 1 H), 2.13-1.98 (m, 1 H), 1.24 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.75. Example 37, Second eluting isomer (16 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 30 δ 10.81 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 7.68 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07-6.99 (m, 1 H), 6.72-6.53 (m, 1 H), 4.84 (t, J = 8.0 Hz, 1 H), 4.32 (s, 1 H), 3.93 (d, J = 9.5 144 LTGO-017 / 01WO 36088 / 98 Patent Application Hz, 1 H), 3.80 (d, J = 6.7 Hz, 3 H), 3.20 (d, J = 9.5 Hz, 1 H), 3.11 (d, J = 6.8 Hz, 3 H), 2.38 (dd, J = 12.6, 7.8 Hz, 1 H), 2.22 (dd, J = 12.7, 8.3 Hz, 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.85. Example 38, Third eluting isomer (4 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 5 10.79 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.32 (d, J = 1.8 Hz, 1 H), 7.88 (d, J = 5.5 Hz, 1 H), 7.11- 6.98 (m, 1 H), 6.68-6.54 (m, 1 H), 4.65 (s, 1 H), 4.35 (s, 1 H), 3.75 (s, 4 H), 3.46-3.37 (m, 1 H), 3.12 (s, 3 H), 2.39-2.31 (m, 1 H), 2.04 (d, J = 13.2 Hz, 1 H), 1.24 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.90. Example 39, Fourth eluting isomer (16 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 10 δ 10.81 (s, 1 H), 8.53 (d, J = 5.4 Hz, 1 H), 8.24 (d, J = 1.7 Hz, 1 H), 7.69 (dd, J = 5.4, 1.9 Hz, 1 H), 7.03 (d, J = 9.2 Hz, 1 H), 6.67-6.55 (m, 1 H), 4.84 (t, J = 8.0 Hz, 1 H), 4.32 (s, 1 H), 3.93 (d, J = 9.5 Hz, 1 H), 3.81 (d, J = 7.8 Hz, 3 H), 3.20 (d, J = 9.5 Hz, 1 H), 3.11 (d, J = 7.6 Hz, 3 H), 2.41-2.35 (m, 1 H), 2.22 (dd, J = 12.7, 8.2 Hz, 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.90. 15 Example 40, Fifth eluting isomer (16 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.82 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 7.70 (dd, J = 5.5, 1.9 Hz, 1 H), 7.03 (q, J = 9.4 Hz, 1 H), 6.64-6.49 (m, 1 H), 4.84-4.70 (m, 1 H), 4.32 (s, 1 H), 3.75 (s, 3 H), 3.67- 3.55 (m, 2 H), 3.11 (s, 3 H), 2.80-2.74 (m, 1 H), 2.09-2.03 (m, 1 H), 1.39 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.85. 20 Example 41, Sixth eluting isomer (12 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.82 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.27 (d, J = 1.8 Hz, 1 H), 7.72 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07-6.99 (m, 1 H), 6.57 (ddd, J = 9.3, 5.0, 2.0 Hz, 1 H), 4.90-4.65 (m, 1 H), 4.32 (s, 1 H), 3.75 (s, 3 H), 3.66-3.55 (m, 2 H), 3.11 (d, J = 0.7 Hz, 3 H), 2.80-2.74 (m, 1 H), 2.15-1.96 (m, 1 H), 1.39 (s, 3 H). LCMS (ESI) calcd. for C20H22F5N4O3S [M + H]+m / z 493.14, found 492.80. 25 Examples 42, 43, 44, 45 and 46 (2S)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4S)-1-(2- (difluoromethoxy)-3,4-difluorophenyl)-4-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4R)-1-(2-(difluoromethoxy)-3,4-30 difluorophenyl)-4-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide, (2S)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)- 145 LTGO-017 / 01WO 36088 / 98 Patent Application 3-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2- carboxamide, and (2R)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide 5 ; d) SFC Step 1: A solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3- methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamide mixture (250 mg, 0.67 mmol), tert-butyl 10 (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (224 mg, 0.67 mmol), Cs2CO3(1.09 g, 3.33 mmol) and Xantphos-Pd-G2(59 mg, 0.07 mmol) in dioxane (10 mL) was heated to 100 °C and refluxed for 2 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue 146 LTGO-017 / 01WO 36088 / 98 Patent Application was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide tert-butyl ((1R)-(4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl-4-(trifluoromethyl)pyrrolidine- 2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and tert-butyl ((1R)-(4- (1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3-methyl-3-(trifluoromethyl)pyrrolidine-2- 5 carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (330 mg, 78.63% yield) as a yellow oil. LCMS (ESI) calcd. for C25H28F7N4O5S [M + H]+m / z 629.17, found 629.00. Step 2: A solution of tert-butyl ((1R)-(4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4-methyl- 4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-10 3-methyl-3-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate (330 mg, 0.52 mmol) in DCM (5 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL x 3). The combined 15 organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide 3 isomers where the first and third eluting isomers were further fractionated. Step 3: First eluting isomer from HPLC (50 mg, 0.09 mmol) was further purified by Chiral-Prep- 20 SFC (DAICEL IH, 20 mm I.D.* 250 mm L, 5 μm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) to provide two isomers. Example 42, First eluting isomer (13.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 11.01 (s, 1 H), 8.56 (d, J = 5.4 Hz, 1 H), 8.25 (d, J = 1.7 Hz, 1 H), 7.78 (dd, J = 5.4, 1.9 Hz, 1 H), 7.35-6.85 (m, 2 H), 6.81-6.72 (m, 1 H), 4.85 (s, 1 H), 4.35 (s, 1 H), 3.84-3.79 (m, 1 H), 3.42- 25 3.38 (m, 1 H), 3.11 (s, 3 H), 2.38-2.30 (m, 1 H), 2.08-1.97 (m, 1 H), 1.25 (s, 3 H). LCMS (ESI) calcd. for C20H20F7N4O3S [M + H]+m / z 529.12, found 529.25. Example 43, second eluting isomer (13.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 11.01 (s, 1 H), 8.56 (d, J = 5.4 Hz, 1 H), 8.26 (s, 1 H), 7.77 (dd, J = 5.4, 1.8 Hz, 1 H), 7.35- 6.87 (m, 2 H), 6.81-6.74 (m, 1 H), 4.85 (s, 1 H), 4.34 (s, 1 H), 3.84-3.81 (m, 1 H), 3.42-3.36 (m, 1 30 H), 3.11 (s, 3 H), 2.39-2.29 (m, 1 H), 2.09-1.96 (m, 1 H), 1.26 (s, 3 H). LCMS (ESI) calcd. for C20H20F7N4O3S [M + H]+m / z 529.12, found 529.25. 147 LTGO-017 / 01WO 36088 / 98 Patent Application Example 44, Second eluting isomer from HPLC (17.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.89 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.23 (dd, J = 5.6, 1.9 Hz, 1 H), 7.66 (td, J = 5.3, 2.0 Hz, 1 H), 7.36-6.95 (m, 2 H), 6.85 (dd, J = 8.7, 3.8 Hz, 1 H), 4.87 (t, J = 8.0 Hz, 1 H), 4.33 (s, 1 H), 3.93 (d, J = 9.5 Hz, 1 H), 3.16 (d, J = 9.5 Hz, 1 H), 3.10 (s, 3 H), 2.42-2.36 (m, 5 1 H), 2.23 (dd, J = 12.8, 8.4 Hz, 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C20H20F7N4O3S [M + H]+m / z 529.12, found 529.25. Step 4: Third eluting isomer from HPLC (50 mg, 0.09 mmol) was further purified by Chiral-Prep- SFC (DAICEL IC, 20 mm I.D.* 250 mm L, 5μm, eluting with 65 / 35 CO2-IPA containing 0.1% EDA) to provide two isomers. 10 Example 45, First eluting isomer (33.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.87 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.25 (d, J = 1.7 Hz, 1 H), 7.67 (dd, J = 5.5, 2.1 Hz, 1 H), 7.33-6.90 (m, 2 H), 6.84-6.76 (m, 1 H), 4.80 (t, J = 7.7 Hz, 1 H), 4.32 (s, 1 H), 3.68 (d, J = 10.8 Hz, 1 H), 3.52 (d, J = 10.6 Hz, 1 H), 3.10 (d, J = 0.9 Hz, 3 H), 2.79-2.69 (m, 1 H), 2.09-2.03 (m, 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C20H20F7N4O3S [M + H]+m / z 529.12, found 529.20. 15 Example 46, Second eluting isomer (29.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.88 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.26 (d, J = 1.9 Hz, 1 H), 7.66 (dd, J = 5.5, 2.0 Hz, 1 H), 7.35-6.91 (m, 2 H), 6.84-6.73 (m, 1 H), 4.80 (t, J = 7.7 Hz, 1 H), 4.32 (s, 1 H), 3.68 (d, J = 10.8 Hz, 1 H), 3.52 (d, J = 10.6 Hz, 1 H), 3.11 (s, 3 H), 2.83-2.76 (m, 1 H), 2.09-2.02 (m, 1 H), 1.37 (s, 3 H). LCMS (ESI) calcd. for C20H20F7N4O3S [M + H]+m / z 529.12, found 529.20. 20 Examples 47, 48, and 49 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)pyrrolidine-2-carboxamide, (S)-1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2-carboxamide, and (R)-1-(3,4-difluoro-2- methoxyphenyl)-3,3-dimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2- 25 carboxamide 148 LTGO-017 / 01WO 36088 / 98 Patent Application Step 1: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylpyrrolidine-2- carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine-2-carboxamide 5 mixture (170 mg, 0.59 mmol) in 1,4-dioxane (5 mL) was added tert-butyl (R)-((4-bromopyridin- 2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (241 mg, 0.71 mmol) and Cs2CO3(584 mg, 1.79 mmol) and Xantphos-Pd-G2(53 mg, 0.05 mmol) under N2. The mixture was stirred at 100 ℃ for 3 hours. Then the resulting mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and 10 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide a mixture of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2- methoxyphenyl)-4,4-dimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-3,3- dimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 15 (200 mg, 63% yield) as a yellow solid. LCMS (ESI) calcd. for C25H33F2N4O5S [M + H]+m / z 539.22, found 538.95. Step 2: A solution of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4,4- dimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethylpyrrolidine-2- 149 LTGO-017 / 01WO 36088 / 98 Patent Application carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate mixture (200 mg, 0.37 mmol) in DCM / TFA (10 / 1, 11 mL) was stirred at 25 ℃ for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL x 3). The combined 5 organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide two isomers. Example 47, Minor Isomer: ( (21 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.66 (s, 1 H), 8.52 (d, J = 5.4 Hz, 1 H), 8.26 (dd, J = 4.8, 1.9 Hz, 1 H), 7.72 (td, J = 5.3, 1.8 Hz, 10 1 H), 6.99-6.94 (m, 1 H), 6.50-6.37 (m, 1 H), 4.68 (t, J = 8.1 Hz, 1 H), 4.29 (s, 1 H), 3.72 (s, 3 H), 3.43 (d, J = 9.1 Hz, 1 H), 3.13-3.00 (m, 4 H), 2.22-2.16 (m, 1 H), 1.75-1.68(m, 1 H), 1.24-1.09(m, 6 H). LCMS (ESI) calcd. for C20H25F2N4O3S [M + H]+m / z 439.16, found 439.15. Major isomer: 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2-carboxamide (110 mg, white solid). 15 Step 3: Major isomer, 1-(3,4-difluoro-2-methoxyphenyl)-3,3-dimethyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2-carboxamide (110 mg, 0.25 mmol), was further purified by Chiral-Prep-SFC ((R,R)-Whelk-O1 20 mmI.D.*250mmL 5µm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3) to provide two isomers. Example 48, First eluting isomer, (31 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 20 10.54 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.32 (d, J = 1.8 Hz, 1 H), 7.89 (dd, J = 5.4, 1.8 Hz, 1 H), 7.03-6.96 (m, 1 H), 6.58-6.42 (m, 1 H), 4.33 (s, 1 H), 4.02 (s, 1 H), 3.66 (s, 3 H), 3.57-3.38 (m, 2 H), 3.13 (s, 3 H), 1.88-1.79 (m, 1 H), 1.72 (dd, J = 7.5, 4.7 Hz, 1 H), 1.15-1.02 (m, 6 H). LCMS (ESI) calcd. for C20H25F2N4O3S [M + H]+m / z 439.16, found 439.45. Example 49, Second eluting isomer, (35 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 25 δ 10.53 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.33 (s, 1 H), 7.88 (d, J = 4.1 Hz, 1 H), 7.01 (d, J = 9.4 Hz, 1 H), 6.58-6.38 (m, 1 H), 4.34 (s, 1 H), 4.02 (s, 1 H), 3.66 (s, 3 H), 3.57-3.39 (m, 2 H), 3.13 (s, 3 H), 1.85 (t, J = 10.2 Hz, 1 H), 1.71 (dd, J = 9.6, 7.0 Hz, 1 H), 1.13-0.99 (m, 6 H). LCMS (ESI) calcd. for C20H25F2N4O3S [M + H]+m / z 439.16, found 439.15. 30 Examples 50, 51, 52 and 53 150 LTGO-017 / 01WO 36088 / 98 Patent Application (S)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethyl-N-(6-oxo-1,6-dihydropyridazin-4- yl)pyrrolidine-2-carboxamide, (R)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethyl-N- (6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-2-carboxamide & (S)-1-(2-(difluoromethoxy)-3,4- difluorophenyl)-3,3-dimethyl-N-(6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-2-carboxamide, 5 and (R)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethyl-N-(6-oxo-1,6- dihydropyridazin-4-yl)pyrrolidine-2-carboxamide R 20 ℃; c) SFC 10 Step 1: A solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2- carboxamide and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2- carboxamide mixture (500 mg, 1.73 mmol), 5-bromo-3-chloropyridazine (363 mg, 1.90 mmol) and Cs2CO3(1.70 g, 5.19 mmol) and Xantphos-Pd-G2(150 mg, 0.17 mmol) in 1,4-dioxane (10 mL) was heated at 100 ℃ for 3 hours under N2. After the reaction was completed, the mixture was 15 concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 1 / 1) to provide a mixture of N-(6-chloropyridazin-4-yl)-1-(2- (difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamide and N-(6- chloropyridazin-4-yl)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2- 151 LTGO-017 / 01WO 36088 / 98 Patent Application carboxamide (430 mg, 62% yield) as a yellow solid. LCMS (ESI) calcd. for C18H18ClF4N4O2 [M + H]+m / z 433.11, found 433.00. Step 2: A solution of N-(6-chloropyridazin-4-yl)-1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4- dimethylpyrrolidine-2-carboxamide and N-(6-chloropyridazin-4-yl)-1-(2-(difluoromethoxy)-3,4- 5 difluorophenyl)-3,3-dimethylpyrrolidine-2-carboxamide (400 mg, 1.00 mmol) and NaOAc (245 mg, 2.99 mmol) in AcOH (8 mL) was heated at 120 °C for 8 hours. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. 10 The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.05% NH3) to provide a mixture of 1-(2-(difluoromethoxy)- 3,4-difluorophenyl)-4,4-dimethyl-N-(6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-2- carboxamide and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethyl-N-(6-oxo-1,6- dihydropyridazin-4-yl)pyrrolidine-2-carboxamide (140 mg, 72% yield) as a white solid. LCMS 15 (ESI) calcd. for C18H19F4N4O3[M + H]+m / z 415.14, found 415.05. Step 3: 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethyl-N-(6-oxo-1,6- dihydropyridazin-4-yl)pyrrolidine-2-carboxamide and 1-(2-(difluoromethoxy)-3,4- difluorophenyl)-3,3-dimethyl-N-(6-oxo-1,6-dihydropyridazin-4-yl)pyrrolidine-2-carboxamide 7- mixture (140 mg, 0.37 mmol) was first purified by Chiral-Prep-SFC (DIACEL IH, 20 mm I.D.*250 20 mm L, 5 µm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3), then the mixture of peak 2 and peak 3 was further purified by Chiral-Prep-SFC (IB N-5, 20 mm I.D.*250 mm L, 5 µm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) to provide 4 isomers. Example 50, First eluting isomer, (11 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 12.74 (s, 1 H), 10.43 (s, 1 H), 7.82 (d, J = 2.2 Hz, 1 H), 7.26-6.62 (m, 4 H),, 4.74 (t, J = 8.4 Hz, 1 25 H), 3.42 (d, J = 9.0 Hz, 1 H), 3.00 (d, J = 9.1 Hz, 1 H), 2.20 (dd, J = 12.4, 7.4 Hz, 1 H), 1.79-1.68 (m, 1 H), 1.17-1.06 (m, 6 H). LCMS (ESI) calcd. for C18H19F4N4O3[M + H]+m / z 415.14, found 415.10. Example 51, Second eluting isomer, (11 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 12.76 (s, 1 H), 10.40 (s, 1 H), 7.88 (d, J = 2.0 Hz, 1 H), 7.35-6.47 (m, 4 H), 4.14 (s, 1 H), 3.74- 30 3.59 (m, 1 H), 3.41 (dd, J = 16.2, 7.8 Hz, 1 H), 1.88-1.74 (m, 2 H), 1.24-1.02 (m, 6 H). LCMS (ESI) calcd. for C18H19F4N4O3 [M + H]+m / z 415.14, found 415.14. 152 LTGO-017 / 01WO 36088 / 98 Patent Application Example 52, Third eluting isomer, (10 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 12.74 (s, 1 H), 10.43 (s, 1 H), 7.82 (d, J = 2.3 Hz, 1 H), 7.26-6.62 (m, 4 H), 4.79-4.66 (m, 1 H), 3.42 (d, J = 9.0 Hz, 1 H), 3.00 (d, J = 9.1 Hz, 1 H), 2.20 (dd, J = 12.1, 7.6 Hz, 1 H), 1.82-1.66 (m, 1H), 1.17-1.06 (m, 6 H). LCMS (ESI) calcd. for C18H19F4N4O3 [M + H]+m / z 415.14, found 415.05. 5 Example 53, Fourth eluting isomer, (10 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 12.76 (s, 1 H), 10.39 (s, 1 H), 7.88 (d, J = 2.0 Hz, 1 H), 7.35-6.47 (m, 4 H), 4.14 (s, 1 H), 3.74- 3.59 (m, 1 H), 3.51-3.41 (m, 1 H), 1.87-1.76 (m, 2 H), 1.24-1.02 (m, 6 H). LCMS (ESI) calcd. for C18H19F4N4O3[M + H]+m / z 415.14, found 415.05. Examples 54 and 55 10 4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinic acid and 4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2- carboxamido)picolinic acid , , , 15 LiOH / THF / MeOH / H2O Step 1: To a solution of 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2- carboxamide and 1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2- carboxamide mixture (300 mg, 0.93 mmol) in 1,4-dioxane (10 mL) was added methyl 4- bromopicolinate (242 mg, 1.12 mmol) and Xantphos-Pd-G2 (83 mg, 0.09 mmol) and Cs2CO3 (915 20 mg, 2.81 mmol) under N2. The mixture was stirred at 100 ℃ for 3 hours. After the reaction was completed, the organic layers were concentrated under vacuum. The residue was purified by silica 153 LTGO-017 / 01WO 36088 / 98 Patent Application gel column chromatography (eluting with PE / EtOAc =1 / 1) to provide methyl 4-(1-(2- (difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylpyrrolidine-2-carboxamido)picolinate and methyl 4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-3,3-dimethylpyrrolidine-2- carboxamido)picolinate (310 mg, 69.0% yield) as a clear oil. LCMS (ESI) calcd. for 5 C21H22F4N3O4[M + H]+m / z 456.16, found 455.75. Step 2: To a solution of methyl 4-(1-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4- dimethylpyrrolidine-2-carboxamido)picolinate and methyl 4-(1-(2-(difluoromethoxy)-3,4- difluorophenyl)-3,3-dimethylpyrrolidine-2-carboxamido)picolinate (310 mg, 0.68 mmol) in MeOH / THF / H2O = 1 / 1 / 1 (9 mL) was added LiOH (163 mg, 6.80 mmol). The mixture was stirred 10 at 25 ℃ for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (15 mL x 3). The organic layers were concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide two isomers. 15 Example 54, First eluting isomer, (21 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.56 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.26 (s, 1 H), 7.80-7.76 (m, 1 H), 7.28-6.91 (m, 2 H), 6.59-6.53 (m, 1 H), 4.17 (s, 1 H), 3.75-3.69 (m, 1 H), 3.49-3.36 (d, J = 8.1 Hz, 1 H), 1.90-1.74 (m, 2 H), 1.22 (s, 1 H), 1.03 (s, 3 H). LCMS (ESI) calcd. for C20H20F4N3O4[M + H]+m / z 442.14, found 442.05. 20 Example 55, Second eluting isomer, (68 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.60 (s, 1 H), 8.51 (d, J = 5.5 Hz, 1 H), 8.22 (d, J = 1.9 Hz, 1 H), 7.71 (dd, J = 5.5, 2.1 Hz, 1 H), 7.28-6.90 (m, 2 H), 6.66 (dd, J = 8.7, 3.8 Hz, 1 H), 4.80-4.71 (m, 1 H), 3.45 (d, J = 9.0 Hz, 1 H), 3.01 (d, J = 9.0 Hz, 1 H), 2.22 (dd, J = 11.8, 7.7 Hz, 1 H), 1.82-1.72 (m, 1 H), 1.16 (s, 1 H), 1.08 (s, 1 H). LCMS (ESI) calcd. for C20H20F4N3O4 [M + H]+m / z 442.14, found 442.05. 25 Examples 56, 57, 58, 59 and 60 (2S,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(2-sulfamoylpyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2S,4R)-1- (3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-sulfamoylpyridin-4-yl)-4-30 (trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(2-sulfamoylpyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, and 1- 154 LTGO-017 / 01WO 36088 / 98 Patent Application (3,4-difluoro-2-methoxyphenyl)-3-methoxy-N-(2-sulfamoylpyridin-4-yl)-3- (trifluoromethyl)pyrrolidine-2-carboxamide 5 Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide and 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- (trifluoromethyl)pyrrolidine-2-carboxamide mixture (700 mg, 1.98 mmol), 4-bromo-N,N-bis(2,4- dimethoxybenzyl)pyridine-2-sulfonamide (1.06 g, 1.98 mmol), Cs2CO3 (3.2 g, 9.76 mmol) and Xantphos-Pd-G2 (350 mg, 0.39 mmol) in dioxane (10 mL) was heated to 105 °C and refluxed for 10 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide N-(2-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-15 (trifluoromethyl)pyrrolidine-2-carboxamide and N-(2-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-3- 155 LTGO-017 / 01WO 36088 / 98 Patent Application (trifluoromethyl)pyrrolidine-2-carboxamide (740 mg, 46% yield) as a yellow solid. LCMS (ESI) calcd. for C37H40F5N4O9S [M + H]+m / z 811.25, found 810.95. Step 2: A solution of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4- difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxamide and N-(2- 5 (N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-3- methoxy-3-(trifluoromethyl)pyrrolidine-2-carboxamide (740 mg, 0.91 mmol) in DCM (10 mL) was added TFA (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted 10 with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide two isomers. Major isomer: 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-sulfamoylpyridin-4- 15 yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (150 mg) as a white solid, LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 511.11, found 510.85. Example 56, Minor isomer: 1-(3,4-difluoro-2-methoxyphenyl)-3-methoxy-N-(2- sulfamoylpyridin-4-yl)-3-(trifluoromethyl)pyrrolidine-2-carboxamide (15.00 mg, white solid).1H NMR (400 MHz, DMSO-d6, ppm) δ 10.68 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.22 (d, J = 1.8 Hz, 20 1 H), 7.79 (dd, J = 5.5, 2.0 Hz, 1 H), 7.40 (bs, 2 H), 7.05 (q, J = 9.6 Hz, 1 H), 6.62-6.56 (m, 1 H), 4.75 (s, 1 H), 3.83-3.74 (m, 1 H), 3.67 (s, 3 H), 3.48 (q, J = 7.9 Hz, 1 H), 3.39 (s, 3 H), 2.66-2.56 (m, 1 H), 2.48-2.41 (m, 1 H). LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 511.11, found 510.80. Step 3: The major isomer, 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(2-sulfamoylpyridin- 25 4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (150 mg, 0.29 mmol), was further purified by Chiral-Prep-SFC (DAICEL (R,R)-Whelk-O1, 20 mm I.D.* 250 mm L, 5μm, eluting with 60 / 40 CO2-MeOH containing 0.1% NH3) and Chiral-Prep-SFC (DAICEL IC, 20 mm I.D.* 250 mm L, 5μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to provide 4 isomers. Example 57, First eluting isomer, (25.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 30 δ 8.53 (d, J = 5.5 Hz, 1 H), 8.13 (d, J = 1.8 Hz, 1 H), 7.68 (dd, J = 5.4, 2.0 Hz, 1 H), 7.04 (dd, J = 18.6, 9.4 Hz, 1 H), 6.72- 6.56 (m, 1 H), 4.81 (t, J = 7.9 Hz, 1 H), 3.98 (d, J = 11.4 Hz, 1 H), 3.80 156 LTGO-017 / 01WO 36088 / 98 Patent Application (s, 3 H), 3.60 (d, J = 11.4 Hz, 1 H), 3.42 (s, 3 H), 2.81 (dd, J = 13.7, 7.6 Hz, 1 H), 2.30 (dd, J = 13.7, 8.5 Hz, 1 H). LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 511.11, found 511.00. Example 58, Second eluting isomer, (22.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.81 (s, 1 H), 8.54 (d, J = 5.4 Hz, 1 H), 8.14 (d, J = 1.7 Hz, 1 H), 7.68 (dd, J = 5.5, 1.9 5 Hz, 1 H), 7.41 (s, 2 H), 7.04 (dd, J = 18.5, 9.4 Hz, 1 H), 6.68-6.59 (m, 1 H), 4.81 (t, J = 7.9 Hz, 1 H), 3.98 (d, J = 11.4 Hz, 1 H), 3.80 (s, 3 H), 3.60 (d, J = 11.5 Hz, 1 H), 3.42 (s, 3 H), 2.81 (dd, J = 13.5, 7.3 Hz, 1 H), 2.30 (dd, J = 13.8, 8.6 Hz, 1 H). LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 511.11, found 511.00. Example 59, Third eluting isomer, (36.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) 10 δ 10.55 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.26 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 5.5, 2.0 Hz, 1 H), 7.41 (s, 2 H), 7.07 (dd, J = 18.5, 9.4 Hz, 1 H), 6.73-6.64 (m, 1 H), 4.64 (dd, J = 9.2, 3.4 Hz, 1 H), 3.96 (d, J = 11.3 Hz, 1 H), 3.73 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.36 (s, 3 H), 2.76 (dd, J = 13.9, 9.4 Hz, 1 H), 2.41 (dd, J = 13.8, 2.9 Hz, 1 H). LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 511.11, found 511.00. 15 Example 60, Fourth eluting isomer, (37.00 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.53 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.26 (s, 1 H), 7.85 (dd, J = 5.5, 1.8 Hz, 1 H), 7.41 (s, 2 H), 7.07 (dd, J = 18.5, 9.4 Hz, 1 H), 6.74-6.63 (m, 1 H), 4.64 (dd, J = 9.2, 3.3 Hz, 1 H), 3.96 (d, J = 11.2 Hz, 1 H), 3.73 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.36 (s, 3 H), 2.76 (dd, J = 13.9, 9.3 Hz, 1 H), 2.41 (dd, J = 13.9, 2.9 Hz, 1 H). LCMS (ESI) calcd. for C19H20F5N4O5S [M + H]+m / z 20 511.11, found 511.00. Examples 61, 62, 63, and 64 (S)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)-2-azaspiro[4.4]nonane-3-carboxamide, (R)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2- ((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3-carboxamide, (S)-2-(2-25 (difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2- azaspiro[4.4]nonane-1-carboxamide, and (R)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2- ((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-1-carboxamide 157 LTGO-017 / 01WO 36088 / 98 Patent Application C Step 1: To a solution of 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane-3- 5 carboxamide and 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane-1- carboxamide mixture (240 mg, 0.69 mmol) in 1,4-dioxane (10 mL) was added tert-butyl (R)-((4- bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (279. mg, 0.83 mmol), Cs2CO3(677 mg, 2.07 mmol) and Xantphos-Pd-G2 (61 mg, 0.06 mmol) under N2. The mixture was heated at 100 ℃ for 3 hours. After the reaction was completed, the organic layers were concentrated under 10 vacuum. The residue was directly purified by silica gel column chromatography (eluting with PE / EtOAc = 1 / 1) to provide a mixture of tert-butyl ((1R)-(4-(2-(2-(difluoromethoxy)-3,4- difluorophenyl)-2-azaspiro[4.4]nonane-3-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6- sulfaneylidene)carbamate and tert-butyl ((1R)-(4-(2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-1-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 15 (360 mg, 87% yield) as a white solid. LCMS (ESI) calcd. for C27H33F4N4O5S [M + H]+m / z 601.21, found 600.85. Step 2: To a solution of tert-butyl ((1R)-(4-(2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2- azaspiro[4.4]nonane-3-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate 158 LTGO-017 / 01WO 36088 / 98 Patent Application and tert-butyl ((1R)-(4-(2-(2-(difluoromethoxy)-3,4-difluorophenyl)-2-azaspiro[4.4]nonane-1- carboxamido)pyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate mixture (360 mg, 0.59 mmol) in DCM / TFA (10 / 1, 11 mL). The mixture was stirred at 25 ℃ for 1 hour. After the reaction was completed, the residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3.The organic 5 layers were concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 95% MeCN / H2O containing 0.05% NH3.H2O) to give a mixture of 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3-carboxamide and 2-(2- (difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2- 10 azaspiro[4.4]nonane-1-carboxamide (140 mg, 47% yield) as a white solid. LCMS (ESI) calcd. for C22H25F4N4O3S [M + H]+m / z 501.16, found 501.50. Step 3: 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)-2-azaspiro[4.4]nonane-3-carboxamide and 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2- ((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-1-carboxamide mixture was 15 further purified by Chiral-Prep-SFC (DAICEL AD-H, 20 mm I.D.*250 mm L, 5 μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to give 4 isomers. Example 61, First eluting isomer, (40 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.77 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.28 (d, J = 1.9 Hz, 1 H), 7.80 (dd, J = 5.5, 2.0 Hz, 1 H), 7.38-6.78 (m, 2 H), 6.66-6.50 (m, 1 H), 4.35 (s, 1 H), 4.26 (s, 1 H), 3.69 (td, J = 8.9, 3.8 Hz, 1 H), 20 3.46 (q, J = 7.5 Hz, 1 H), 3.12 (s, 3 H), 2.00-1.90 (m, 1 H), 1.87-1.78 (m, 1 H), 1.75-1.52 (m, 7 H), 1.43-1.31 (m, 1 H). LCMS (ESI) calcd. for C22H25F4N4O3S [M + H]+m / z 501.16, found 501.10. Example 62, Second eluting isomer, (32 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.75 (s, 1 H), 8.53 (d, J = 5.5 Hz, 1 H), 8.24 (d, J = 1.9 Hz, 1 H), 7.69 (dd, J = 5.5, 2.1 Hz, 1 H), 7.28-6.88 (m, 2 H), 6.70-6.60 (m, 1 H), 4.75-4.64 (m, 1 H), 4.32 (s, 1 H), 3.54 (d, J = 9.0 Hz, 25 1 H), 3.20-3.01 (m, 4 H), 2.36-2.28 (m, 1 H), 1.93-1.85 (m, 1 H), 1.72-1.48 (m, 8 H). LCMS (ESI) calcd. for C22H25F4N4O3S [M + H]+m / z 501.16, found 501.15. Example 63, Third eluting isomer, (39 mg, white solid):1H NMR (400 MHz, DMSO-d6, ppm) δ 10.77 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 7.79 (dd, J = 5.5, 2.0 Hz, 1 H), 7.36-6.79 (m, 2 H), 6.66-6.51 (m, 1 H), 4.36 (s, 1 H), 4.26 (s, 1 H), 3.69 (td, J = 8.7, 3.7 Hz, 1 H), 30 3.47 (q, J = 7.7 Hz, 1 H), 3.12 (s, 3 H), 2.01-1.91 (m, 1 H), 1.89-1.77 (m, 1 H), 1.75-1.53 (m, 7 H), 1.44-1.30 (m, 1 H). LCMS (ESI) calcd. for C22H25F4N4O3S [M + H]+m / z 501.16, found 501.15. 159 LTGO-017 / 01WO 36088 / 98 Patent Application Example 64, Fourth eluting isomer, (29 mg, white solid): (S)-2-(2-(difluoromethoxy)-3,4- difluorophenyl)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3- carboxamide or (R)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-2-azaspiro[4.4]nonane-3-carboxamide.1H NMR (400 MHz, 5 DMSO-d6, ppm) δ 10.75 (s, 1 H), 8.52 (d, J = 5.5 Hz, 1 H), 8.26 (d, J = 1.9 Hz, 1 H), 7.68 (dd, J = 5.5, 2.1 Hz, 1 H), 7.27-6.89 (m, 2 H), 6.71-6.60 (m, 1 H), 4.70 (dd, J = 9.0, 7.5 Hz, 1 H), 4.32 (s, 1 H), 3.53 (t, J = 8.4 Hz, 1 H), 3.20-3.00 (m, 4 H), 2.36-2.28 (m, 1 H), 1.93-1.85 (m, 1 H), 1.71- 1.50 (m, 8 H). LCMS (ESI) calcd. for C22H25F4N4O3S [M + H]+m / z 501.16, found 501.10. The following compounds were prepared using the techniques for preparation of the 10 intermediates and examples described above. MS (m / z d, 0 ), 86 3 ), 160 LTGO-017 / 01WO 36088 / 98 Patent Application 66 second 501.151H NMR (400 MHz, eluting DMSO-d6, ppm) δ d, 9 ), 7 3 ), , = 3 - , 2 m, 161 LTGO-017 / 01WO 36088 / 98 Patent Application 68 second 501.151H NMR (400 MHz, eluting DMSO-d6, ppm) δ d, m, , 1 ), z, , = 1 z, ), , = 1 1 162 LTGO-017 / 01WO 36088 / 98 Patent Application (m, 5 H), 2.14-2.00 (m, 2 H). , , ), 1 z, ), 1 z, , ), 3 163 LTGO-017 / 01WO 36088 / 98 Patent Application 73 first eluting 378.71H NMR (400 MHz, isomer from DMSO-d6, ppm) δ 1 z, , ), 3 1 z, , z, ), 3 , m, ), 9 ), 164 LTGO-017 / 01WO 36088 / 98 Patent Application 76 third eluting 443.01H NMR (400 MHz, isomer from DMSO-d6, ppm) δ d, m, ), 0 ), , J , 3 ), , , 1 z, ), 3 165 LTGO-017 / 01WO 36088 / 98 Patent Application 79 second 475.11H NMR (400 MHz, eluting DMSO-d6, ppm) δ d, 9 ), 1 ), 4 ), , m, 5 m, 3 , 9 ), - 166 LTGO-017 / 01WO 36088 / 98 Patent Application 82 fourth 475.451H NMR (400 MHz, eluting DMSO-d6, ppm) δ d, = 8 J s, = 3 4 m, m, 7 m, m, 167 LTGO-017 / 01WO 36088 / 98 Patent Application 85 first eluting 383.051H NMR (400 MHz, isomer from DMSO-d6, ppm) δ 2 m, z, m, 9 m, z, m, , ), 7 ), 6 ), 168 LTGO-017 / 01WO 36088 / 98 Patent Application 88 second 405.051H NMR (400 MHz, eluting DMSO-d6, ppm) δ d, 5 ), 8 ), 7 ), , = 9 3 z, 3 , = 8 3 z, 169 LTGO-017 / 01WO 36088 / 98 Patent Application 1.19 (s, 3 H), 1.08 (s, 3 H). , ), ), , m, ), 6 m, , m, , 1 , 170 LTGO-017 / 01WO 36088 / 98 Patent Application 0.72-0.57 (m, 3 H), 0.49 (d, J = 9.8 Hz, 1 , , J s, ), 3 , J , ), 171 LTGO-017 / 01WO 36088 / 98 Patent Application 96 408.11H NMR (400 MHz, DMSO-d6, ppm) δ d, - , ), 3 Examples 97 and 98 (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide & (2S,4R,5R)-5 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide 172 LTGO-017 / 01WO 36088 / 98 Patent Application Ac; e) tBuONa, Pd(dba)2, BINAP, toluene, 110 ℃; f) FeCl2, TMSCN, TBHP, MeOH, 35 ℃; g) K2CO3, H2O2, DMSO; h) Cs2CO3, Xantphos-Pd-G2, dioxane, 100 ℃; i) TFA, DCM 5 Step 1: To a solution of tert-butyl (2R,3R)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (4.3 g, 0.021 mol) in DCM (40 mL) was added PCC (9.18 g, 0.043 mol) in one portion. The resulting mixture was stirred at 25 °C for 4 hours and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 5 / 1) to provide tert-butyl (R)-2-methyl-3-oxopyrrolidine-1-carboxylate (3.3 g, 90% purity, 70% yield) as a yellow oil. 10 LCMS (ESI) calcd. for C6H10NO3[M – tBu + H]+m / z 144.07, found 143.60. Step 2: To a bottle of tert-butyl (R)-2-methyl-3-oxopyrrolidine-1-carboxylate (2.67 g, 0.013 mol) in THF (25 mL) was added TMSCF3 (3.78 g, 0.027 mol) at 0 °C under N2. Then TBAF in THF (5.22 g, 0.020 mol) was added dropwise into the solution. The mixture was stirred at 25 ℃ for 8 hours under N2and quenched with saturated aqueous NH4Cl solution and extracted with 15 EtOAc (30 mL x 3). The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with PE / EtOAc = 5 / 1) to provide tert-butyl (2R)-3-hydroxy-2-methyl-3-(trifluoromethyl)pyrrolidine-1- 173 LTGO-017 / 01WO 36088 / 98 Patent Application carboxylate (3.26 g, 88% yield, 95% purity) as a white solid. LCMS (ESI) calcd. for C7H11F3NO3 [M – tBu + H]+m / z 214.07, found 213.65. Step 3: To a solution of tert-butyl (2R)-3-hydroxy-2-methyl-3- (trifluoromethyl)pyrrolidine-1-carboxylate (3.3 g, 0.012 mol) in DMF (25 mL) was added 60% 5 NaH (0.88 g) portion wise at 0 ℃. The mixture was stirred at 0 ℃ for 0.5 hour. Then MeI (5.2 g, 0.037 mol) was added to the mixture and stirred at 25 ℃ for 3 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide tert-butyl (2R)-3- 10 methoxy-2-methyl-3-(trifluoromethyl)pyrrolidine-1-carboxylate (3.2 g, 88% yield, 95% purity) as a colorless oil. LCMS (ESI) calcd. for C8H13F3NO3 [M – tBu + H]+m / z 228.08, found 227.65. Step 4: A solution of tert-butyl (2R)-3-methoxy-2-methyl-3-(trifluoromethyl)pyrrolidine- 1-carboxylate (3.2 g, 0.011 mol) in EtOAc (25 mL) was added 4M HCl EtOAc (50 mL). The reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. 15 The mixture was concentrated under vacuum to provide crude (2R)-3-methoxy-2-methyl-3- (trifluoromethyl)pyrrolidine hydrochloride (1.99 g) as a white solid. LCMS (ESI) calcd. for C7H13F3NO [M + H]+m / z 184.09, found 183.60. Step 5: A solution of crude (2R)-3-methoxy-2-methyl-3-(trifluoromethyl)pyrrolidine hydrochloride (1 g, 4.5 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (1.2 g, 0.0054 mol), t- 20 BuONa (1.30 g, 0.0135 mol), Pd(dba)2 (0.26 g, 0.00045 mol) and BINAP (0.42 g, 0.00068 mol) in toluene (20 mL) was heated at 110 °C for 16 hours under N2 atmosphere. LCMS showed the reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide (2R)-1-(3,4-difluoro- 2-methoxyphenyl)-3-methoxy-2-methyl-3-(trifluoromethyl)pyrrolidine (0.93 g, 60% yield, 95% 25 purity) as a yellow oil. LCMS (ESI) calcd. for C14H17F5NO2[M + H]+m / z 326.12, found 325.75. Step 6: To a flask containing FeCl2(180.6 mg, 1.43 mmol) was added (2R)-1-(3,4- difluoro-2-methoxyphenyl)-3-methoxy-2-methyl-3-(trifluoromethyl)pyrrolidine (930 mg, 2.85 mmol) and TMSCN (565.6 mg, 5.70 mmol) in MeOH (10 mL) under N2. Then TBHP (642.2 mg, 7.13 mmol) was added dropwise into the mixture. The mixture was stirred at 35 ℃ for 16 hours 30 then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4- 174 LTGO-017 / 01WO 36088 / 98 Patent Application methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2-carbonitrile (400 mg, 38.0%) and (2S,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-4- (trifluoromethyl)pyrrolidine-2-carbonitrile (240 mg, 22.8% yield) as light yellow oil. LCMS (ESI) calcd. for C15H16F5N2O2 [M + H]+m / z 351.11, found 350.70. 5 Step 7: To a solution of (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5- methyl-4-(trifluoromethyl)pyrrolidine-2-carbonitrile (390 mg, 1.11 mmol) in DMSO / H2O2 = 3 / 1 (4 mL) was added K2CO3 (460.3 mg, 3.33 mmol). The mixture was stirred at 25 ℃ for 3 hours. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under 10 vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-4- (trifluoromethyl)pyrrolidine-2-carboxamide (324 mg, 75.1% yield) as a colorless oil. Following the same procedure, (2S,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy- 5-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamide (178 mg, 95% purity) was obtained from15 (2S,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-4- (trifluoromethyl)pyrrolidine-2-carbonitrile. LCMS (ESI) calcd. for C15H18F5N2O3[M + H]+m / z 369.12, found 368.65. Step 8: A solution of (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl- 4-(trifluoromethyl)pyrrolidine-2-carboxamide (290 mg, 0.79 mmol), tert-butyl (R)-((4- 20 bromopyridin-2-yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (290.4 mg, 0.86 mmol), Cs2CO3 (767.6 mg, 2.36 mmol) and Xantphos-Pd-G2 (69.8 mg, 0.079 mmol) in dioxane (10 mL) was heated to 100 °C and stirred for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide tert-butyl ((R)-(4-((2R,4R,5R)-1-(3,4-difluoro-2-25 methoxyphenyl)-4-methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2- yl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (260 mg, 50.4% yield) as a white solid. Following the same procedure, tert-butyl ((R)-(4-((2S,4R,5R)-1-(3,4-difluoro-2- methoxyphenyl)-4-methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2- yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (180 mg) was obtained from (2S,4R,5R)-1-(3,4- 30 difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2-carbonitrile. LCMS (ESI) calcd. for C21H24F5N4O4S [M - Boc + H]+m / z 523.14, found 522.85. 175 LTGO-017 / 01WO 36088 / 98 Patent Application Step 9: To a solution of tert-butyl ((R)-(4-((2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)- 4-methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)- l6-sulfaneylidene)carbamate (250 mg, 0.40 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise. The mixture was stirred at 25 ℃ for 2 hours. The mixture was quenched with saturated 5 aqueous NaHCO3and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 85% MeCN / H2O containing 0.05% NH3.H2O) to provide (2R,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-5-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4- 10 (trifluoromethyl)pyrrolidine-2-carboxamide (40 mg) as a white solid. Following the same procedure, (2S,4R,5R)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy- 5-methyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide (40 mg) as a white solid was obtained from tert-butyl ((R)-(4-((2S,4R,5R)-1-(3,4- difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-4-(trifluoromethyl)pyrrolidine-2- 15 carboxamido)pyridin-2-yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate. Example 97:1H NMR (400 MHz, DMSO-d6, ppm) δ 10.40 (s, 1 H), 8.57 (d, J = 5.5 Hz, 1 H), 8.39 (d, J = 1.9 Hz, 1 H), 7.91 (dd, J = 5.5, 1.8 Hz, 1 H), 7.08 (q, J = 9.4 Hz, 1 H), 6.99-6.90 (m, 1 H), 4.39-4.25 (m, 2 H), 4.03 (q, J = 6.1 Hz, 1 H), 3.80 (d, J = 1.5 Hz, 3 H), 3.28 (s, 3 H), 3.14 (s, 3 H), 2.73-2.64 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H). LCMS (ESI) calcd. for C21H24F5N4O4S 20 [M + H]+m / z 523.14, found 522.85. Example 98:1H NMR (400 MHz, DMSO-d6, ppm) δ 10.84 (s, 1 H), 8.52 (d, J = 5.4 Hz, 1 H), 8.21 (d, J = 1.9 Hz, 1 H), 7.63 (dd, J = 5.5, 2.0 Hz, 1 H), 7.03 (q, J = 9.2 Hz, 1 H), 6.83-6.74 (m, 1 H), 4.82-4.72 (m, 1 H), 4.54-4.12 (m, 2 H), 3.82 (s, 3 H), 3.57 (s, 3 H), 3.10 (s, 3 H), 2.99 (dd, J = 14.3, 6.9 Hz, 1 H), 2.20 (dd, J = 14.2, 9.1 Hz, 1 H), 0.99 (d, J = 6.1 Hz, 3 H). LCMS (ESI) 25 calcd. for C21H24F5N4O4S [M + H]+m / z 523.14, found 522.85. Examples 99, 100, 101 and 102 (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4S)-1-30 (3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide , (2S,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4- 176 LTGO-017 / 01WO 36088 / 98 Patent Application (methoxy-d3)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide and (2R,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide 5 BINAP, toluene, 110 ℃; d) FeCl2, TMSCN, TBHP, MeOH, 35 ℃; e) K2CO3, H2O2, DMSO; f) Cs2CO3, Xantphos-Pd-G2, dioxane, 100 ℃; g) TFA, DCM; h) SFC Step 1: To a mixture of NaH (5.4 g, 60% dispersion in mineral oil) in DMF (200 mL) was added tert-butyl 3-hydroxy-3-(trifluoromethyl)pyrrolidine-1-carboxylate (19 g, 74 mmol) at 0 ℃ 10 under N2. The mixture was stirred at 0 ℃ for 45 min. Then the mixture was added CD3I (32 g, 222 mmol) at 0 ℃ under N2. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched and diluted with brine (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with15 PE / EtOAc = 10 / 1) to provide tert-butyl 3-(methoxy-d3)-3-(trifluoromethyl)pyrrolidine-1- carboxylate (13 g, 64% yield) as a yellow oil. LCMS (ESI) calcd. for C7H8D3F3NO3[M + H - t- Bu]+m / z 217.13, found 216.6. 177 LTGO-017 / 01WO 36088 / 98 Patent Application Step 2: A solution of tert-butyl 3-(methoxy-d3)-3-(trifluoromethyl)pyrrolidine-1- carboxylate (13 g, 47 mmol) in EtOAc (50 mL) was added 4M HCl-EtOAc (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated to provide crude 3-(methoxy-d3)-3- 5 (trifluoromethyl)pyrrolidine hydrochloride (8 g) which was used directly in next step without purification. Step 3: A solution of crude 3-(methoxy-d3)-3-(trifluoromethyl)pyrrolidine hydrochloride (10 g), 1-bromo-3,4-difluoro-2-methoxybenzene (11.75 g, 52.69 mmol), t-BuONa (11.51 g, 119.75 mmol), Pd(dba)2(2.75 g, 4.79 mmol) and BINAP (4.47 g, 7.18 mmol) in Toluene (100 mL) was 10 heated to 110 °C and refluxed for 16 hours under N2 atmosphere. LCMS showed the reaction was completed. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-3-(methoxy-d3)-3- 15 (trifluoromethyl)pyrrolidine (12 g) as yellow oil. LCMS (ESI) calcd. for C13H12D3F5NO2[M + H]+m / z 315.12, found 314.65. Step 4: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-3-(methoxy-d3)-3- (trifluoromethyl)pyrrolidine (12 g, 38.20 mmol), TMSCN (15.12 g, 119.29 mmol), FeCl2(0.48 g, 3.81 mmol) and TBHP (5-6 M in decane, 80 mL) in MeOH (100 mL) was stirred at 35 °C for 16 20 hours. LCMS showed the reaction was completed. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4- (methoxy-d3)-4-(trifluoromethyl)pyrrolidine-2-carbonitrile (7 g, 54.26% yield) as yellow oil. 25 LCMS (ESI) calcd. for C14H11D3F5N2O2[M + H]+m / z 340.12, found 339.60. Step 5: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-4- (trifluoromethyl)pyrrolidine-2-carbonitrile (7 g, 20.64 mmol), K2CO3 (14.21 g, 102.97 mmol) and 30% H2O2 (10 mL) in DMSO (30 mL) was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The mixture was diluted with water (100 mL) and extracted with 30 EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on 178 LTGO-017 / 01WO 36088 / 98 Patent Application silica gel (PE / EtOAc = 3 / 2) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-4- (trifluoromethyl)pyrrolidine-2-carboxamide (3 g, 40.71% yield) as yellow oil. LCMS (ESI) calcd. for C14H13D3F5N2O3 [M + H]+m / z 358.13, found 357.65. Step 6: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-4- 5 (trifluoromethyl)pyrrolidine-2-carboxamide (1.5 g, 4.19 mmol), tert-butyl (R)-((4-bromopyridin- 2-yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (1.41 g, 4.19 mmol), Cs2CO3 (3.42 g, 10.43 mmol) and Xantphos-Pd-G2 (370 mg, 0.42 mmol) in dioxane (20 mL) was heated to 100 °C and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed 10 with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide tert-butyl ((1R)-(4-(1- (3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-4-(trifluoromethyl)pyrrolidine-2- carboxamido)pyridin-2-yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (1.8 g, 70.59% yield) as yellow oil. LCMS (ESI) calcd. for C25H27D3F5N4O6S [M + H]+m / z 612.20, found 611.90. 15 Step 7: A solution of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy- d3)-4-(trifluoromethyl)pyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-l6- sulfaneylidene)carbamate (1.8 g, 2.95 mmol) in DCM (10 mL) was added TFA (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated. The residue was adjusted to pH = 8-9 with saturated 20 aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18column, 150*21.2 mm, eluting with 40% to 90% MeCN / H2O containing 0.05% NH3.H2O) to provide 1-(3,4-difluoro-2- methoxyphenyl)-4-(methoxy-d3)-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4-yl)-4- 25 (trifluoromethyl)pyrrolidine-2-carboxamide (720 mg, 48% yield) as a white solid. LCMS (ESI) calcd. for C20H19D3F5N4O4S [M + H]+m / z 512.15, found 512.10. Step 8: 1-(3,4-difluoro-2-methoxyphenyl)-4-(methoxy-d3)-N-(2-((R)-S- methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (720 mg, 1.41 mmol) was further purified by Chiral-Prep-SFC (DAICEL IH, 20 mm I.D.* 250 mm L, 5μm, 30 eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) and Chiral-Prep-SFC (DAICEL IC, 20 mm 179 LTGO-017 / 01WO 36088 / 98 Patent Application I.D.* 250 mm L, 5μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to provide four isomers. Example 99 (113.00 mg, white solid) as the fourth eluting isomer:1H NMR (400 MHz, DMSO- d6, ppm) δ 10.84 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.25 (d, J = 1.9 Hz, 1 H), 7.70 (dd, J = 5.5, 2.0 5 Hz, 1 H), 7.04 (dd, J = 18.5, 9.4 Hz, 1 H), 6.68-6.60 (m, 1 H), 4.82 (t, J = 8.0 Hz, 1 H), 4.32 (s, 1 H), 3.98 (d, J = 11.4 Hz, 1 H), 3.80 (s, 3 H), 3.60 (d, J = 11.3 Hz, 1 H), 3.11 (s, 3 H), 2.80 (dd, J = 13.7, 7.2 Hz, 1 H), 2.29 (dd, J = 13.8, 8.6 Hz, 1 H). LCMS (ESI) calcd. for C20H19D3F5N4O4S [M + H]+m / z 512.15, found 512.25. Example 100 (119.00 mg, white solid) as the third eluting isomer:1H NMR (400 MHz, DMSO- 10 d6, ppm) δ 10.84 (s, 1 H), 8.54 (d, J = 5.5 Hz, 1 H), 8.23 (d, J = 1.8 Hz, 1 H), 7.71 (dd, J = 5.5, 2.0 Hz, 1 H), 7.04 (dd, J = 18.4, 9.5 Hz, 1 H), 6.69-6.60 (m, 1 H), 4.82 (t, J = 8.0 Hz, 1 H), 4.32 (s, 1 H), 3.98 (d, J = 11.4 Hz, 1 H), 3.80 (s, 3 H), 3.60 (d, J = 11.3 Hz, 1 H), 3.10 (s, 3 H), 2.80 (dd, J = 13.8, 7.6 Hz, 1 H), 2.29 (dd, J = 13.8, 8.6 Hz, 1 H). LCMS (ESI) calcd. for C20H19D3F5N4O4S [M + H]+m / z 512.15, found 512.20. 15 Example 101 (102.00 mg, white solid) as the first eluting isomer:1H NMR (400 MHz, DMSO-d6, ppm) δ 10.58 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.9 Hz, 1 H), 7.85 (dd, J = 5.5, 2.0 Hz, 1 H), 7.06 (dd, J = 18.5, 9.4 Hz, 1 H), 6.68 (dd, J = 7.4, 5.1 Hz, 1 H), 4.65 (dd, J = 9.2, 3.6 Hz, 1 H), 4.31 (s, 1 H), 3.96 (d, J = 11.2 Hz, 1 H), 3.74 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.12 (s, 3 H), 2.76 (dd, J = 14.0, 9.3 Hz, 1 H), 2.40 (dd, J = 14.1, 3.2 Hz, 1 H). LCMS (ESI) calcd. for 20 C20H19D3F5N4O4S [M + H]+m / z 512.15, found 512.10. Example 102 (87.00 mg, white solid) as the second eluting isomer:1H NMR (400 MHz, DMSO- d6, ppm) δ 10.58 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07 (dd, J = 18.5, 9.4 Hz, 1 H), 6.74-6.63 (m, 1 H), 4.65 (dd, J = 9.2, 3.4 Hz, 1 H), 4.31 (s, 1 H), 3.96 (d, J = 11.3 Hz, 1 H), 3.74 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.12 (s, 3 H), 2.76 25 (dd, J = 13.9, 9.3 Hz, 1 H), 2.40 (dd, J = 13.9, 3.3 Hz, 1 H). LCMS (ESI) calcd. for C20H19D3F5N4O4S [M + H]+m / z 512.15, found 512.20. Example 103 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethyl-N-(2-((R)-S-methylsulfonimidoyl)pyridin-4- 30 yl)pyrrolidine-2-carboxamide 180 LTGO-017 / 01WO 36088 / 98 Patent Application Step : sout on o -(3, -d uoro- -met oxyp eny )- , , -tr met y pyrro idine-2- carboxamide (60 mg, 0.20 mmol), tert-butyl (R)-((4-bromopyridin-2-yl)(methyl)(oxo)-l6- 5 sulfaneylidene)carbamate (74 mg, 0.22 mmol), Cs2CO3(196 mg, 0.60 mmol) and Xantphos-Pd- G2 (18 mg, 0.020 mmol) in dioxane (5 mL) was heated to 100 °C and stirred for 16 hours. LCMS showed the reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethylpyrrolidine-2-carboxamido)pyridin- 10 2-yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (86 mg, 77% yield) as a yellow solid. LCMS (ESI) calcd. for C26H35F2N4O5S [M + H]+m / z 553.23, found 553.10. Step 2: To a solution of tert-butyl ((1R)-(4-(1-(3,4-difluoro-2-methoxyphenyl)-2,4,4- trimethylpyrrolidine-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (86 mg, 0.16 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred at 25 ℃ for 2 15 hours. The mixture was adjusted to PH = 8-9 with saturated aqueous NaHCO3and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 85% MeCN / H2O containing 0.05% NH3.H2O) to provide 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethyl-N-(2-((R)-S- 20 methylsulfonimidoyl)pyridin-4-yl)pyrrolidine-2-carboxamide (17 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.36 (d, J = 2.4 Hz, 1 H), 8.60-8.48 (m, 2 H), 8.11-7.99 (m, 1 H), 7.11-7.00 (m, 1 H), 6.87-6.74 (m, 1 H), 4.28 (s, 1 H), 3.64 (d, J = 1.2 Hz, 3 H), 3.36-3.32 (m, 1 H), 3.30-3.27 (m, 1 H), 3.13 (s, 3 H), 2.16 (d, J = 13.5 Hz, 1 H), 1.95 (d, J = 13.6 Hz, 1 H), 1.26 (s, 3 H), 1.18 (d, J = 12.0 Hz, 6 H). LCMS (ESI) calcd. for C21H27F2N4O3S [M + H]+m / z 453.17, 25 found 453.10. 181 LTGO-017 / 01WO 36088 / 98 Patent Application Example 104 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethyl-N-(2-sulfamoylpyridin-4-yl)pyrrolidine-2- carboxamide 5 LiHMDS, MeI, THF, -78 ℃; d) i. LiEt3BH, THF, -78 ℃; Na2CO3, H2O2, 0 ℃; ii. Et3SiH, BF3∙Et2O, DCM, -78 ℃; e) HCl, dioxane, 60 ℃; f) Cs2CO3, CuI, DMSO, 120 ℃; g) HATU, NH3-MeOH; h) Cs2CO3, Xantphos-Pd-G2, dioxane, 100 ℃; i) TFA, DCM Step 1: To a solution of di-tert-butyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (30.0 g, 0.105 10 mol) in THF (400 mL) was added LiHMDS (115 mL, 0.115 mol, 1M in THF) at -78 °C. The mixture was stirred at -78 °C for 0.5 hour. Then CH3I (22.3 g, 0.157 mol) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 2.5 hours. After the reaction was completed, the resulting mixture was quenched with NH4Cl solution (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with water and brine, dried with sodium 15 sulfate, concentrated, and purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to provide di-tert-butyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (25 g, 80% yield) as a yellow oil. LCMS (ESI) calcd. for C30H50N2O10Na [2M + Na]+m / z 621.34, found 621.25. 182 LTGO-017 / 01WO 36088 / 98 Patent Application Step 2: To a solution of di-tert-butyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (25 g, 0.0832 mol) in THF (400 mL) was added LiHMDS (91 mL, 0.0915 mol, 1M in THF) at - 78 °C. The mixture was stirred at -78 °C for 0.5 hour. Then CH3I (23.6 g, 0.166 mol) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 2.5 hours. After the reaction was 5 completed, the resulting mixture was quenched with NH4Cl solution (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated, and purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to provide di-tert-butyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (16 g, 61% yield) as a yellow oil. LCMS (ESI) calcd. for C32H54N2O10Na [2M + Na]+m / z 649.38, 10 found 649.25. Step 3: To a solution of di-tert-butyl (S)-4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (16 g, 0.0509 mol) in THF (300 mL) was added LiHMDS (56 mL, 0.0560 mol, 1M in THF) at - 78 °C. The mixture was stirred at -78 °C for 0.5 hour. Then CH3I (10.84 g, 0.0764 mol) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 2.5 hours. After the reaction was 15 completed, the resulting mixture was quenched with NH4Cl solution (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with water and brine, dried with sodium sulfate, concentrated. The residue was first purified by silica gel column chromatography (eluting with PE / EtOAc = 2 / 1) to provide di-tert-butyl 2,4,4-trimethyl-5-oxopyrrolidine-1,2- dicarboxylate (14 g, 84% yield) as a yellow oil. LCMS (ESI) calcd. for C34H58N2O10Na [2M + 20 Na]+m / z 677.40, found 677.20. Step 4: To a solution of di-tert-butyl 2,4,4-trimethyl-5-oxopyrrolidine-1,2-dicarboxylate (4 g, 0.012 mol) in THF (100 mL) was added Lithium triethylborohydride (1.55 g, 0.0146 mol) at - 78 °C. Then the mixture was stirred at -78 °C for 1 hour. Then saturated aqueous Na2CO3 (50 mL) was added to the mixture. After that, 30% H2O2 (5 mL) was added to the mixture dropwise at 0 25 °C. Then the mixture was concentrated in vacuum. The residue was diluted with DCM (100 mL). Then triethylsilane (2.84 g, 0.0244 mol) and Boron trifluoride etherate (3.46 g, 0.0244 mol) was added to the mixture at -78 °C. The mixture was stirred at -78 °C for 2 hours. After the reaction was completed., the mixture was diluted with water and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under 30 vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc 183 LTGO-017 / 01WO 36088 / 98 Patent Application = 4 / 1) to provide di-tert-butyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate (1.6 g, 42% yield) as a yellow oil. LCMS (ESI) calcd. for C34H62N2O8[2M + Na]+m / z 649.46, found 649.25. Step 5: A solution of di-tert-butyl 2,4,4-trimethylpyrrolidine-1,2-dicarboxylate (3.3 g, 0.0105 mol) in HCl-dioxane (40 mL) was heated at 60 °C for 4 hours. Then the mixture was 5 concentrated in vacuum to give crude 2,4,4-trimethylpyrrolidine-2-carboxylic acid hydrochloride (2 g) which was used directly in next step without further purification.1H NMR (400 MHz, DMSO-d6, ppm) δ 14.19 (s, 1 H), 10.49 (s, 1 H), 9.06 (s, 1 H), 3.18-2.97 (m, 2 H), 2.23 (d, J = 13.6 Hz, 1 H), 1.86 (d, J = 13.6 Hz, 1 H), 1.62 (s, 3 H), 1.17 (s, 3 H), 1.02 (s, 3 H). Step 6: A solution of 2,4,4-trimethylpyrrolidine-2-carboxylic acid hydrochloride (1.2 g, 10 6.22 mmol), 1-bromo-3,4-difluoro-2-methoxybenzene (1.66 g, 7.46 mmol), Cs2CO3 (6.06 g, 18.66 mmol), CuI (118 mg, 0.62 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (177 mg, 1.24 mmol) in DMSO (20 mL) was heated at 100 °C for 16 hours under N2atmosphere. LCMS showed the reaction was completed. The mixture was adjusted to PH = 2-3 with 2 N HCl and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried 15 over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide 1-(3,4-difluoro-2-methoxyphenyl)- 2,4,4-trimethylpyrrolidine-2-carboxylic acid (310 mg, 6% yield, 40% purity) as a yellow oil. LCMS (ESI) calcd. for C15H20F2NO3[M + H]+m / z 300.14, found 299.70. Step 7: To a solution of 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethylpyrrolidine-2- 20 carboxylic acid (300 mg, 1.00 mmol), HATU (760 mg, 2.00 mmol) and DIEA (384 mg, 3.00 mmol) in DMF (10 mL) was added 7M NH3-MeOH (4 mL). The mixture was stirred at room temperature for 2 hours. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc 25 = 1 / 2) to provide 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethylpyrrolidine-2-carboxamide (125 mg, 42% yield) as a yellow oil. LCMS (ESI) calcd. for C15H21F2N2O2[M + H]+m / z 299.16, found 299.20. Step 8: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethylpyrrolidine-2- carboxamide (65 mg, 0.22 mmol), 4-bromo-N,N-bis(2,4-dimethoxybenzyl)pyridine-2- 30 sulfonamide (128 mg, 0.24 mmol), Cs2CO3 (212 mg, 0.65 mmol) and Xantphos-Pd-G2 (19 mg, 0.022 mmol) in dioxane (5 mL) was heated to 100 °C and stirred for 16 hours. LCMS showed the 184 LTGO-017 / 01WO 36088 / 98 Patent Application reaction was completed. The mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 2) to provide N-(2-(N,N-bis(2,4- dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1-(3,4-difluoro-2-methoxyphenyl)-2,4,4- trimethylpyrrolidine-2-carboxamide (95 mg, 58% yield) as a yellow solid. LCMS (ESI) calcd. for 5 C38H45F2N4O8S [M + H]+m / z 755.29, found 755.05. Step 9: To a solution of N-(2-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)pyridin-4-yl)-1- (3,4-difluoro-2-methoxyphenyl)-2,4,4-trimethylpyrrolidine-2-carboxamide (95 mg, 0.13 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 ℃ for 2 hours. The mixture was adjusted to PH = 8-9 with saturated aqueous NaHCO3and extracted with DCM (20 mL x 3). 10 The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 45% to 85% MeCN / H2O containing 0.05% NH3.H2O) to provide 1-(3,4-difluoro-2- methoxyphenyl)-2,4,4-trimethyl-N-(2-sulfamoylpyridin-4-yl)pyrrolidine-2-carboxamide (17 mg) as a white solid.1H NMR (400 MHz, DMSO-d6, ppm) δ 10.35 (s, 1 H), 8.72-8.35 (m, 2 H), 8.07 15 (s, 1 H), 7.36 (s, 2 H), 7.12-6.68 (m, 2 H), 3.62 (s, 3 H), 3.32-3.23 (m, 2 H), 2.23-2.08 (m, 1 H), 2.02-1.84 (m, 1 H), 1.37-0.98 (m, 9 H).1H NMR (400 MHz, CD3OD, ppm) δ 8.54 (s, 1 H), 8.42 (s, 1 H), 7.93 (s, 1 H), 6.96 (s, 2 H), 3.86 (s, 3 H), 3.29-3.15 (m, 2 H), 2.35 (d, J = 13.1 Hz, 1 H), 2.00 (d, J = 13.2 Hz, 1 H), 1.37-1.16 (m, 9 H). LCMS (ESI) calcd. for C20H25F2N4O4S [M + H]+m / z 455.16, found 455.05. 20 Examples 105, 106, 107 and 108 (2S,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(3-((R)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide, (2R,4R)-1-(3,4- difluoro-2-methoxyphenyl)-4-methoxy-N-(3-((R)-S-methylsulfonimidoyl)phenyl)-4-25 (trifluoromethyl)pyrrolidine-2-carboxamide, (2S,4R)-1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(3-((R)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide, and (2R,4S)-1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(3-((R)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide 185 LTGO-017 / 01WO 36088 / 98 Patent Application sulfaneylidene)carbamate, Cs2CO3, Xantphos-Pd-G2, dioxane, 100 ℃; b) TFA, DCM; c) SFC 5 Step 1: A solution of 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamide (450 mg, 1.2 mmol), tert-butyl (R)-((3- bromophenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (600 mg, 1.8 mmol), Cs2CO3 (1.2 g, 3.6 mmol) and Xantphos-Pd-G2 (106 mg, 0.1 mmol) in dioxane (5 mL) were heated to 100 °C and refluxed for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with 10 water (20 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 2) to provide tert-butyl ((1R)-(3-(1- (3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2- carboxamido)phenyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (340 mg, 47% yield) as yellow 15 oil. LCMS (ESI) calcd. for C26H30F5N3O6SNa [M + Na]+m / z 630.18, found 630.15. Step 2: tert-butyl ((1R)-(3-(1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4- (trifluoromethyl)pyrrolidine-2-carboxamido)phenyl)(methyl)(oxo)-λ6-sulfaneylidene)carbamate (340 mg, 0.56 mmol) in DCM (4 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture 20 was concentrated. The residue was adjusted to pH = 8-9 with saturated aqueous NaHCO3. Then the aqueous solution was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by prep-HPLC (Gemini 5 um C18 column, 150*21.2 mm, eluting with 40% to 90% 186 LTGO-017 / 01WO 36088 / 98 Patent Application MeCN / H2O containing 0.05% NH3.H2O) to provide 1-(3,4-difluoro-2-methoxyphenyl)-4- methoxy-N-(3-((R)-S-methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)pyrrolidine-2- carboxamide (160 mg, 56% yield) as a white solid. LCMS (ESI) calcd. for C21H23F5N3O4S [M + H]+m / z 507.13, found 507.9. 5 Step 3: 1-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-N-(3-((R)-S- methylsulfonimidoyl)phenyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide (160 mg, 0.31 mmol) was further purified by Chiral-Prep-SFC (DAICEL OD, 20 mm I.D.* 250 mm L, 5μm, eluting with 80 / 20 CO2-MeOH containing 0.1% NH3) and Chiral-Prep-SFC (DAICEL IC, 20 mm I.D.* 250 mm L, 5μm, eluting with 70 / 30 CO2-MeOH containing 0.1% NH3) to provide four 10 products. Example 105 (38.00 mg, white solid) as the fourth eluting isomer:1H NMR (400 MHz, DMSO- d6, ppm) δ 10.24 (s, 1 H), 8.20 (t, J = 1.8 Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.55 (dt, J = 15.8, 8.0 Hz, 2 H), 7.06 (dd, J = 18.5, 9.5 Hz, 1 H), 6.71-6.62 (m, 1 H), 4.63 (dd, J = 8.9, 4.4 Hz, 1 H), 4.17 (s, 1 H), 4.01 (d, J = 11.2 Hz, 1 H), 3.77 (s, 3 H), 3.54 (d, J = 11.3 Hz, 1 H), 3.40 (s, 3 H), 3.02 (s, 15 3 H), 2.75 (dd, J = 13.9, 9.0 Hz, 1 H), 2.40 (dd, J = 13.9, 4.3 Hz, 1 H). LCMS (ESI) calcd. for C21H23F5N3O4S [M + H]+m / z 507.13, found 507.9. Example 106 (35.00 mg, white solid) as the third eluting isomer:1H NMR (400 MHz, DMSO-d6, ppm) δ 10.24 (s, 1 H), 8.22 (t, J = 1.8 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.55 (dt, J = 15.8, 8.0 Hz, 2 H), 7.06 (dd, J = 18.5, 9.5 Hz, 1 H), 6.71-6.62 (m, 1 H), 4.64 (dd, J = 8.9, 4.4 Hz, 1 H), 4.17 20 (s, 1 H), 4.01 (d, J = 11.3 Hz, 1 H), 3.77 (s, 3 H), 3.54 (d, J = 11.3 Hz, 1 H), 3.39 (s, 3 H), 3.02 (s, 3 H), 2.75 (dd, J = 14.0, 9.0 Hz, 1 H), 2.40 (dd, J = 14.0, 4.2 Hz, 1 H). LCMS (ESI) calcd. for C21H23F5N3O4S [M + H]+m / z 507.13, found 507.9. Example 107 (18.00 mg, white solid) as the first eluting isomer:1H NMR (400 MHz, DMSO-d6, ppm) δ 10.46 (s, 1 H), 8.15 (t, J = 1.8 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.55 (dt, J = 15.8, 8.0 25 Hz, 2 H), 7.04 (dd, J = 18.5, 9.4 Hz, 1 H), 6.70-6.57 (m, 1 H), 4.77 (t, J = 8.0 Hz, 1 H), 4.17 (s, 1 H), 4.01 (d, J = 11.4 Hz, 1 H), 3.81 (s, 3 H), 3.56 (d, J = 11.5 Hz, 1 H), 3.42 (s, 3 H), 3.01 (d, J = 0.7 Hz, 3 H), 2.79 (dd, J = 13.3, 7.7 Hz, 1 H), 2.27 (dd, J = 13.7, 8.7 Hz, 1 H). LCMS (ESI) calcd. for C21H23F5N3O4S [M + H]+m / z 507.13, found 507.9. Example 108 (15 mg, white solid) as the second eluting isomer:1H NMR (400 MHz, DMSO-d6, 30 ppm) δ 10.58 (s, 1 H), 8.55 (d, J = 5.5 Hz, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 7.86 (dd, J = 5.5, 2.0 Hz, 1 H), 7.07 (dd, J = 18.5, 9.4 Hz, 1 H), 6.74-6.63 (m, 1 H), 4.65 (dd, J = 9.2, 3.4 Hz, 1 H), 4.31 187 LTGO-017 / 01WO 36088 / 98 Patent Application (s, 1 H), 3.96 (d, J = 11.3 Hz, 1 H), 3.74 (s, 3 H), 3.57 (d, J = 11.3 Hz, 1 H), 3.12 (s, 3 H), 2.76 (dd, J = 13.9, 9.3 Hz, 1 H), 2.40 (dd, J = 13.9, 3.3 Hz, 1 H). LCMS (ESI) calcd. for C21H23F5N3O4S [M + H]+m / z 507.13, found 507.9. 5 Examples 109 and 110 (S)-2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-N-(2-sulfamoylpyridin-4-yl)-6,10-dioxa-2- azaspiro[4.5]decane-3-carboxamide & (R)-2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-N-(2- sulfamoylpyridin-4-yl)-6,10-dioxa-2-azaspiro[4.5]decane-3-carboxamide 10 , MeOH; c) 1-bromo-3,4-difluoro-2-methoxybenzene, t-BuONa, Pd(dba)2, BINAP, toluene, 110 ℃; d) TMSCN, FeCl2, TBHP, MeOH; e) K2CO3, H2O2, DMSO, f) tert-butyl ((4-bromopyridin-2- yl)sulfonyl)(tert-butoxycarbonyl)carbamate, Cs2CO3, Xantphos-Pd-G2, dioxane, 80 ℃; g) silica gel, toluene; h) SFC 15 Step 1: To a solution of benzyl 3-oxopyrrolidine-1-carboxylate (5 g, 22.8 mmol) in toluene (50 mL) was added 2,2-difluoropropane-1,3-diol (7.67 g, 68.4 mmol) and TsOH (780 mg, 4.56 mmol). The mixture was heated at 130 ℃ for 16 hours. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide benzyl 8,8-difluoro-6,10-dioxa-2- 20 azaspiro[4.5]decane-2-carboxylate (3.5 g, 49% yield) as a clear oil. LCMS (ESI) calcd. for C15H18F2NO4 [M + H]+m / z 314.12, found 313.65. 188 LTGO-017 / 01WO 36088 / 98 Patent Application Step 2: To a solution of benzyl 8,8-difluoro-6,10-dioxa-2-azaspiro[4.5]decane-2- carboxylate (3.5 g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd / C (1 g). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. Then the mixture was filtered through celite 5 and the filtrate was concentrated under vacuum to give crude 8,8-difluoro-6,10-dioxa-2- azaspiro[4.5]decane (2 g) which was used directly in next step without further purification. Step 3: To a solution of crude 8,8-difluoro-6,10-dioxa-2-azaspiro[4.5]decane (2 g, 11.2 mmol) in toluene (20 mL) was added 1-bromo-3,4-difluoro-2-methoxybenzene (2.5 g, 11.2 mmol), Pd(dba)2(640 mg, 1.12 mmol), BINAP (1.05 g, 16.8 mmol) and t-BuONa (3.23 g, 33.6 mmol) 10 under N2. The mixture was stirred at 110 ℃ for 16 hours. Then the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 5 / 1) to provide 2-(3,4- difluoro-2-methoxyphenyl)-8,8-difluoro-6,10-dioxa-2-azaspiro[4.5]decane (2 g, 52% yield) as a 15 yellow solid. LCMS (ESI) calcd. for C14H16F4NO3[M + H]+m / z 322.11, found 321.65. Step 4: A solution of 2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-6,10-dioxa-2- azaspiro[4.5]decane (2 g, 6.2 mmol), TMSCN (1.85 g, 18.6 mmol), FeCl2 (790 mg, 6.2 mmol) and TBHP (5-6 M in decane, 6.4 mL) in MeOH (20 mL) was stirred at 35 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (60 mL) and extracted 20 with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide 2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-6,10- dioxa-2-azaspiro[4.5]decane-3-carbonitrile (1.1 mg, 48% yield) as yellow oil. LCMS (ESI) calcd. for C15H15F4N2O3 [M + H]+m / z 347.10, found 347.05. 25 Step 5: To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-6,10-dioxa-2- azaspiro[4.5]decane-3-carbonitrile (1.1 g, 3.2 mmol) in DMSO / 30% H2O2= 1 / 1 (20 mL) was added K2CO3 (2.2 g, 16 mmol). The mixture was stirred at 25 ℃ for 16 hours. Then the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. 30 The residue was purified by silica gel column chromatography (eluting with EtOAc / PE, 0% to 40%) to give 2-(3,4-difluoro-2-methoxyphenyl)-8,8-difluoro-6,10-dioxa-2-azaspiro[4.5]d...

Claims

1. LTGO-017 / 01WO 36088 / 98 Patent Application Claims:

1. A compound of Formula (I): (I) or a tautomer thereof, or a p , hydrate and solvate thereof, wherein: R1a, R1b, R2a, R2bR3a, R3bare independently H, D, halo, hydroxyl, C1-C8alkyl, C3-C6cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially halogenated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, unsubstituted or substituted heteroaryloxy, unsubstituted or substituted aryloxy,C2-C6 alkenyl, C2-C6 alkynyl, -[C(R8)(R9)]m-C3-C8- cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8cycloalkyl, -[C(R8)(R9)]m-C3-C8cycloalkenyl, - [C(R8)(R9)]m- C6-C10aryl,-[C(R8)(R9)]m-N(R8)(R9), or -[C(R8)(R9)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and with the proviso that at least one of R1a, R1b, R2a, R2bR3a, R3bis not H or D; wherein any of said alkyl, alkenyl, or alkoxy moieties above may be further substituted with one, two, three or four R5 substituents, where R5 is individually and independently selected from halo, C1-C8 alkyl, C3-C6 cycloalkyl, deuterated C1-C8 alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6 alkoxy, C1-C6 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated; wherein any of R1a, R1b, R2a, R2b, R3a, or R3bmay be optionally connected to another of R1a, R1b, R2a, R2b, R3a, or R3bthrough individual alkyl, fluoroalkyl, or alkoxy moieties to form a spirocyclic, fused bicyclic, or bridged bicyclic ring; 355 LTGO-017 / 01WO 36088 / 98 Patent Application R2a and R2b may optionally together form a substituted or unsubstituted exocyclic alkene, wherein alkene substituents are H, fluoro, C1-C6alkyl, aryl or C3-C6heteroaryl; R4a is H, -OH, halo, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl wherein the alkyl may be fully or partially halogenated, C1-C8 alkoxy, C1-C8 cycloalkoxy, C1-C8 haloalkoxy wherein the alkoxy may be fully or partially halogenated, -L1-(C1-C8alkyl), -L1-(C1- C8 cycloalkyl), -L1- (C1-C8 haloalkyl), -L1-(C1-C8 cyclohaloalkyl), -L1-(C1-C8 alkoxy), L1-(C1- C8 cycloalkoxy), -L1-L2-(C2-C6 alkyl)-OR4b, -L1-(C1-C6 alkenyl)-OR4b, -L1-(C1-C6 alkyl)- NR4cR4d, or -L1-L2-R4e; R4b, R4c, and R4dare independently H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1- C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy; and R4e is C3-C6 cycloalkyl, 3-8 membered heterocycloalkyl, 5- or 6-membered heteroaryl, - C(O)O(C1-C8alkyl), -COOH, or C(O)NR4cR4d, wherein said C3-C8cycloalkyl, 3-8 membered heterocycloalkyl or 5- or 6-membered heteroaryl is optionally substituted by one or more halo, - OH, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 haloalkoxy; and L1 is a bond or O; L2 is a bond, C1-C6alkyl or C1-C6alkenyl; X2a, X2b, X2c, and X2dare independently N or C-R4f; wherein each R4f on X2a, X2b, X2c, and X2d is independently H, -OH, halo, C1-C8 alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, C1-C8cycloalkoxy, C1-C8haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, -NR4cC(O)C1-C8 alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8 alkyl, -S(O)2NR4cR4d, -S(O)C1-C8 alkyl, or —P(O)(C1-C8 alkyl)2, wherein said C1-C8 alkyl, C1-C8 alkoxy, 3-7 membered heterocycloalkyl, 5 or 6-membered heteroaryl, or -NR4cC(O)C1-C8alkyl is optionally substituted by one or more R4c, C3-C8 cycloalkyl, -NR4cR4d, -OR4b, -CN, or 3-7 membered heterocycloalkyl optionally substituted by one or more R4c. R5ais -[C(R6)(R7)]n-R5c; R5bis H, C1-C4alkyl, or R5aand R5btogether with the nitrogen to which they are attached form a 3-7 membered heterocycloalkyl, wherein said 3-7 membered heterocycloalkyl is optionally substituted by one or more R5d; R5cis 5-10 membered heteroaryl, pyridinyl, pyridazinyl, pyrimidinyl, phenyl, 6-10 membered aryl, 3-7 membered heterocycloalkyl, wherein the R5c substituent is further optionally substituted by one or more R5d; 356 LTGO-017 / 01WO 36088 / 98 Patent Application R5d is hydrogen, deuterium, oxo, halo, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8 fluoroalkyl wherein the C1-C8 fluoroalkyl is partially or fully deuterated, nitro, cyano, SR8, S(O)R8, S(O)2R8, NR8NR9, -(CH2)nS(O)2NR8R9 (n is 0, 1, or 2), -(CH2)nCO NR8R9, -NHS(O)2R8, -C(O)OR8, C(O)NR8R9, -NHC(=O)-alkyl - NH(C=O)NR8R9, -SO(=NH)R4, -SO(=NR7)R4, -O-(CH2)1-5C(=O)NR8R9, -C(R8)(R9)-cycloalkyl, substituted or unsubstituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; R4 is C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated or C3-C7 cycloalkyl; R6is H, D, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R7 is H, C1-C8 alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R8is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; R9is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated, hydroxyalkyl, or alkoxyl alkyl; and m and n are independently 0, 1, or 2.

2. The compound of claim 1, wherein the compound is a compound of Formula (II): II) or a tautomer thereof, or a p , hydrate and solvate thereof, wherein: R1a, R1b, R2a, R2bR3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2dare defined above. 357 LTGO-017 / 01WO 36088 / 98 Patent Application 3. The compound of claim 1, wherein the compound is a compound of Formula (III): II) or a tautomer thereof, or a hydrate and solvate thereof, wherein: R2a, R2b R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above.

4. The compound of claim 1, wherein the compound is a compound of Formula (IV): V) or a tautomer thereof, or a p armaceu ca y accep a e sa , hydrate and solvate thereof, wherein: R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above; p is 0, 1, or 2; R6aand R6bare independently: hydrogen, -OH, deuterium, halo, cyano, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4alkyl wherein the C1-C4 alkyl may be fully or partially deuterated, or C1-C8 fully or partially fluorinated fluoroalkyl; Y1is C(R6a)(R6b) or N(R6); Y2 = CH2, O or N(R6); and each Y3 is independently CH2 or OCH2. 358 LTGO-017 / 01WO 36088 / 98 Patent Application 5. The compound of claim 1, wherein the compound is a compound of Formula (V): V) or a tautomer thereof, or a hydrate and solvate thereof, wherein R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2dare defined above.

6. The compound of claim 1, wherein the compound is a compound of Formula (VI): I) or a tautomer thereof, or a p y p , hydrate and solvate thereof, wherein R2b, R3a, R3b, R4a, R5a, R5b, X2a, X2b, X2c, and X2d are defined above.

7. The compound of claim 4, wherein when Y1 is C(R6a)(R6b), R6a or R6b are independently H or CH3.

8. The compound of any of claims 1-6, wherein R5a is selected from the group consisting of: 359 LTGO-017 / 01WO 36088 / 98 Patent Application 9. The compound of any of claims 1-6, wherein R2a and R2b are independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, fluorinated cyclopropyl, cyclopentyl, 360 LTGO-017 / 01WO 36088 / 98 Patent Application -OCH3, -CF3, -OCD3, -OCH2-CH3, -CHF2, -CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, - 10. The compound of any of claims 1-6, wherein R2aand R2bare independently -CF3and - CH3.

11. The compound of any of claims 1-6, wherein R2aand R2bare both -CH3.

12. The compound of any of claims 1-6, wherein R2a is CF3 and R2b is alkoxy.

13. The compound of any of claims 1-6, wherein R2ais CF3and R2bis -OCH3< / sub>.

14. The compound of any of claims 1-6, wherein R2a is CF3 and R2b is alkyl.

15. The compound of any of claims 1-6, wherein R2aand R2bcombine to form 3-6 membered substituted or unsubstituted cycloalkyl or heterocycloalkyl spiro ring, wherein one or more hetero atoms in the spiro ring are O or N.

16. The compound of claim 15, wherein the spiro ring is substituted or unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl.

17. The compound of any of claims 15, wherein R2aand R2bcombine to form the spirocyclic .<img src='' class="img-anchor img-center" img-id="IMGF000362_0002" / > 18. The compound of any of claims 1-6, wherein R1a and R1b are independently selected from the group consisting of H, -OH, -CH3, -cyclopropyl, cyclopentyl, -OCH3, -CF3, -OCD3, - OCH2-CH3, -CHF2, -CH(CH3)2, -OCF3, -OCHF2, -OCH(CH3)2, -OCH2-CF3, -CH2-CF3, - CH2-CF3, phenyl, or fluorinated phenyl. 361 LTGO-017 / 01WO 36088 / 98 Patent Application 19. The compound of any of claims 1-6, wherein R1aand R1bcombine to form spirocyclic substituted or unsubstituted cycloalkyl.

20. The compound of claim 19, wherein cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.

21. The compound of any of claims 1-6, wherein R1a and R1b are independently -CF3 and - CH3.

22. The compound of any of claims 1-6, wherein X2a, X2b, X2c, and X2dare independently C- R4f; wherein each R4fis independently selected from the group consisting of: H, -OH, halo, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C6 alkenyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 cycloalkoxy, C1-C8haloalkoxy, 3-7 membered heterocycloalkyl, 5- or 6-membered heteroaryl, -CN, -OR11, -COOH, -NR4cC(O)C1-C8alkyl, -S(O)2R7, -S(O)(NR4c) C1-C8alkyl, -S(O)2NR4cR4d, -S(O)C1-C8 alkyl, or —P(O)(C1-C8 alkyl)2, wherein said C1-C8 alkyl, C1-C8 alkoxy, 3-7 membered heterocycloalkyl, 5 or 6-membered heteroaryl, or - NR4cC(O)C1-C8alkyl is optionally substituted by one or more R4c, C3-C8cycloalkyl, - NR4cR4d, -OR4b, -CN, and 3-7 membered heterocycloalkyl optionally substituted by one or more R4c, wherein R4c, R4d, and R7 are defined above.

23. The compound of claims 1 or 22, wherein each R4fis selected from the group consisting of hydrogen, fluoro, chloro, -COOH, -OCF2H, -OCH3, -O-CH2-CH3, -OCD3, - OCH(CH3)2, cyclopropyl, and -CF3.

24. The compound of claims 1-6, wherein R5bis hydrogen.

25. The compound of claims 1-6 or 18, wherein R5a is selected from the group consisting of: .<img src='' class="img-anchor img-center" img-id="IMGF000363_0001" / > 26. The compound of claims 1-6 or 16, wherein R5ais: 362 LTGO-017 / 01WO 36088 / 98 Patent Application 27. y , wherein R3a and R3b are both hydrogen.

28. The compound of claims 1-6, wherein R3aand R3bare not halogen, hydroxy, or alkoxy.

29. The compound of claims 1-6, wherein R1a, R1b , R2a, R2b R3a, R3b are independently H, halo, hydroxyl, C1-C8alkyl, C3-C6cycloalkyl, deuterated C1-C8alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C6 alkoxy, C1-C6 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6alkenyl, C2-C6alkynyl, -[C(R8)(R9)]m-C3-C8-cycloalkoxy, cyano, -[C(R8)(R9)]m-C3-C8 cycloalkyl, -[C(R8)(R9)]m-C3-C8 cycloalkenyl, -[C(R8)(R9)]m- N(R8)(R9), or -[C(R8)(R9)]m-C3-C8 heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N; and when m is 0, R1a, R1b, R2a, R2b R3a, R3b are independently -C3-C8-cycloalkoxy, -C3-C8 cycloalkyl, -N(R8)(R9), or -C3-C8 heterocycloalkyl, wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N.

30. A compound selected from the group consisting of: 363 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 366 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 377 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 380 LTGO-017 / 01WO 36088 / 98 Patent Application 381 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 385 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 387 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application 389 LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application LTGO-017 / 01WO 36088 / 98 Patent Application<img src='' class="img-anchor img-center" img-id="IMGF000395_0001" / > 32. A method of treating a condition in a subject, the method comprising providing to a subject having a condition a compound in any of claims 1-31. 394 LTGO-017 / 01WO 36088 / 98 Patent Application 33. The method of claim 32, wherein the compound is selected from any one of the compounds recited in claims 1-31. 395

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