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 NaV 1.8, and methods of treating a subject with those compounds for conditions such as pain, itch, and cough.

Description

[0001] Patent Application LTGO-019 / 01WO 36088 / 124 SODIUM CHANNEL BLOCKING COMPOUNDS, DERIVATIVES THEREOF, AND METHODS OF THEIR USE

[0002] Field of the Invention

[0003] The present disclosure relates generally to sodium channel blocking compounds, derivatives thereof, and the use of such compounds as pharmacological agents.

[0004] Background

[0005] 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 intolerable side effects. Therefore, existing treatments are inadequate for many patients who suffer from these conditions.

[0006] Summary

[0007] 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.

[0008] In one aspect, the invention provides a compound of Formula (XIII):

[0009]

[0010] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein:

[0011] Ring A

[0012]

[0013] is X2= CR12, N, or N+-O-;

[0014] X3or X3= CR13, N, or N+-O-;Patent Application LTGO-019 / 01WO 36088 / 124 X4= N, N -O’, or CRI4;

[0015] X5= CR15; N or N+-O-;

[0016] X6= CR16, N or N+-O-;

[0017] Zi is CR4b orN;

[0018] Z2is CR4cor N;

[0019] Z3is CR4dor N;

[0020] Z4is CR4eor N;

[0021] R1a, R1b, R2b, R3a, and R3bare independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl. CX-Ce cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated. Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C-Co alkoxy, Ci -Co deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C0 alkenyl, C2-C5 alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, cyano. -[CfReXRvXm-Ca-Cg cycloalkyl, -[C(R6)(R7)]m-C3-Cs cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and N;

[0022] wherein any of said alkyl or alkenyl moieties in R1a, R1b, R2b, R3a, R3bmay be further substituted with one, two, three or four R5substituents, where each R5is independently selected from halo, C1-C8alkyl, C3-C6cycloalkyl, deuterated C1-C8alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, Ci-Cs alkoxy, Ci-Cg deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, and m = 0 to 2:

[0023] R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Cg fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or folly fluorinated, branched alkyl, substituted or unsubstituted C2-Ca alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Cg haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, C1-C6-haloalkoxy wherein the C1-C6alkoxy may be fully or partially holgenated. cycloalkoxy, deuterated Ci-Cg alkyl wherein the Ci-Cg alkyl chain may be fully or partially deuterated, cyano, -S(O)qRc, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7. -NHS(O)2R6, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl - NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cs-Cs cycloalkyl, Ci-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein said Ci-Cg haloalkyl, C1-C6alkyl, Ci-Ce alkoxy, cycloalkoxy, Ci-CgPatent Application LTGO-019 / 01WO 36088 / 124 haloalkoxy are optionally further substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rg substituents; wherein Rs is H, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cg folly or partially fluorinated fluoroalkyl;

[0024] wherein each R, and Rio are independently selected from the group comprising H, Ci-Cg alkyl, Ci-Cg cycloalkyl, C2-Cs alkenyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, or Ci-Cs haloalkoxy;

[0025] R6and R6aare individually and independently selected from the group consisting of H, Ci-Cg alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs folly or partially fluorinated fluoroalkyl;

[0026] R7is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cg folly or partially fluorinated fluoroalkyl;

[0027] R12is selected from the group consisting of hydrogen, OH, -OC1-C6alkyl, -OC1-C6alkoxyl, C1-C6alkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[0028] R13, R14, R15, and R16are independently selected from hydrogen, deuterium, hydroxy, oxo, - CfOyNRgR?, -(CH2)nS(O)2NRgR7, -(CH2)nC(O)NR6R7, cyano, halo, Ci-Cgalkyl, deuterated Ci-Cg alkyl wherein the C1-C5 alkyl chain may be folly or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyny 1, haloCi-C* alkyl wherein the C1-C4 alkyl chain may be fully or partially halogenated, C1-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or folly fluorinated, Ci-Caalkoxy, C1-C4 deuteroalkoxy wherein the C1-C4 alkyoxy chain may be fully or partially deuterated, cycloalkoxy -S(O)qRg, -NR6NR7, -NHS(O)2R6, -C(=NR6a)NR6R7, -NHC(=O)-Ci-C4-alkyl, - NH(C=O)NR6R7, -SO(=NH)Rg, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cs-Cg cycloalkyl, C3-C8cycloalkenyl, substituted or unsubstituted Ce-Cio aryl, substituted or unsubstituted Cs-Cg heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalky 1 comprises at least one heteroatom independently selected from 0. S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13 substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[0029] R20 is selected from the group consisting of hydrogen, CI-CG alkyl, CI-CG deuteroalkyl wherein the alkyl may be folly or partially deuterated, haloalkyl wherein the alkyl may be fully or partially halogenated, fluoroalkyl wherein the alkyl may be folly or partially fluorinate, C3-C8 cycloalkyl, C3- Cg fluorocycloalkyl wherein the cycloalkyl may be folly or partially fluorinated, and substituted or unsubstituted -[C(R6)(R7)]m-C6-C10-aryl;Patent Application LTGO-019 / 01WO 36088 / 124 m is 1-5;

[0030] n is 0-3; and

[0031] q is 0-2.

[0032] In another aspect, the invention provides a compound of Formula (XIV):

[0033] R20O " / AR

[0034] ^3b

[0035] R...... ZZ,4

[0036] 4a \ 'L

[0037] 7 - -Z3

[0038]

[0039] 1”Z2 (XIV)

[0040] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R1a, R1b, R2b, R3b, R4a, R20, Z1, Z2, Z3, and Z4are defined above; and R2ais independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, Cs-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-C, alkoxy. Ci-Cb deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated. C2-C6 alkenyl, C2-Ce alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-C8 cycloalkyl. -[C(R6)(R7)]m-C3-Cs cycloalkenyl, -[C(R6)(R7)]m-N(Rs)(R7), or -[C(R6)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N..

[0041] In another aspect, the invention provides a compound of Formula (XV):

[0042] o

[0043] R2b J

[0044] / HHxrx5

[0045] H

[0046] R / / Z / Zz

[0047] 4a \ '4

[0048] 7 -

[0049]

[0050] r2 (XV)

[0051] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R1a, R1b, R2b, R3a, R3b, R4a, R20, Z1, Z2, Z3, Z4, X2, X3, X4, X5, and X6are defined above.

[0052] In another aspect, the invention provides a compound of Formula (XVI):Patent Application LTGO-019 / 01WO 36088 / 124 o

[0053]

[0054] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R1a, R1b, R3a, R3b, R4a, R20, Z1, Z2, Z3, Z4, X2, X3, X4, X5, and X6are defined above.

[0055] In certain embodiments, in compounds of Formula (XIII) and Formula (XIV), Ring A is selected from the group consisting of:

[0056]

[0057] Patent Application LTGO-019 / 01WO 36088 / 124

[0058]

[0059] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), wherein Z1is CR4b; Z2is CR4c; Z3is CR4d; and Z4is CR4e.

[0060] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), R4ais selected from the group consisting of -CF3, -OCH3, -OCH2-CH3, -OH. -OCD3, -CH3. -O-cyclopropyl, -CH2-OH, -CHF2, -CH-(CH3)2, -O-CHF2, -CH(CH3)-OH, -O-CH(CH3)2. and -O-CH2-CH2-O-CH3.Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, in compounds of Formula (XIII), Formula (XIV). Formula (XV), and

[0061]

[0062] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Fonnula (XV). and Formula (XVI), R o is selected from the group consisting of C1-C3 alkyl, partially or completely halogenated C1-C3 alkyl, partially or completely deuterated C1-C3 alkyl, 6-membered ary 1, and partially or completely halogenated 6-membered aryl.Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), R20is selected from the group consisting of -CH3, -CF3, -CHF2, -CDs, -CFF-phenyl, phenyl, fluoro-phenyl, and -CH2-CF3.

[0063] In another aspect, the instant invention provides a compound of Formula (I):

[0064]

[0065] or a tautomer thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: —represents a single or double bond;

[0066] X - C(Ria) (Rib)

[0067] X

[0068]

[0069] 2= CRi2, N, orN+-O\

[0070] X3or X3= CR13, N, or N+-O-;

[0071] X = N, N -O', or CRI4;

[0072] X5= CR15; N or N+-O-;

[0073] X6= CR16, N or N+-O-;

[0074] Ring B is Cs-Cm aryl, Cs-Cs heteroaryl, monocyclic, bicyclic, or spirocyclic cycloalkyl ring, or a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains one or more heteroatoms independently selected from N, 0, and S, and wherein the B ring is substituted with one or more R4 substituents;

[0075] R1a, R1b, R2a, R2b, R3a, R3bare independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, C?,-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, Ci- Ce alkoxy, Ci-Ce deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated. C2-C6 alkenyl, C -G, alkynyl, -[C(R6)(R?)]m-C3-Cs- cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-Cs cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R?)]m-N(Re)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0. S, and N:Patent Application LTGO-019 / 01WO 36088 / 124 wherein any of said alkyl or alkenyl moieties in R]a, Rib, R2a. R2b, Rsa, Rsb may be further substituted with one, two. three or four Rs substituents, where each Rs is independently selected from halo, Ci-Cg alkyl, Cs-Ce cycloalkyl. deuterated Ci-Cs alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, Ci-Cs alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be fully or partially- deuterated, and m:::0 to 2;

[0076] 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 ring;

[0077] R4is hydrogen, deuterium, halo, C1-C6alkyl, Ci-C6fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially7or folly fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Ci-Ce haloalkyl wherein the alkyl may be folly7or partially halogenated, C1-C6alkoxy, Ci-Cs deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Cs-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qR6, -NR6NR7, -(CH2)nS(O)2NRfiR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(==O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Ci-Cg cycloalkyl, Cs-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0. S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R4substituents maybe further optionally substituted with one or more hydroxy, alkoxy or C1-C4alkyl substituents;

[0078] R6and R6aare individually and independently selected from the group consisting of H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cg folly or partially fluorinated fluoroalkyl;

[0079] R7is H. Ci-Cg alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cg folly or partially fluorinated fluoroalkyl;

[0080] R12is selected from the group consisting of hydrogen, OH, -OC1-C6alkyl, -OC1-C6alkoxyl, C1-C6alkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[0081] Ri2a is selected from the group consisting of hydrogen, Ci-Csalkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;Patent Application LTGO-019 / 01WO 36088 / 124 R13, R14, R15, and R16are independently selected from hydrogen, deuterium, hydroxy, oxo, - C(O)NReR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NRfiR7, cyano, halo, Ci-Cealkyl, deuterated Ci-Cf alkyl wherein the Ci-Cg alkyl chain may be fully or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloCi-C4 alkyl wherein the C1-C4 alkyl chain may' be fully or partially halogenated, C1-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or fully fluorinated, Ci-C4alkoxy, ( -f: deuteroalkoxy' wherein the C1-C4 alky oxy' chain may be fully' or partially' deuterated, cycloalkoxy -S(O) Rd, -NR6NR7, -NHS(O)2R6, -C(=NR6a)NR6R7, -NHC(=O)-Ci-C4-alkyl, -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, Cs-Cs cycloalkenyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted Cs-Cg heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N. and further wherein the haloalkyl, alky l, alkoxy, cycloalkoxy, haloalkoxy fragments of R13substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[0082] m is 1-5;

[0083] n is 0-3;

[0084] q is 0-2.

[0085] In certain embodiments, X is -C(R1a) (R1b)

[0086] In some embodiments, the present disclosure provides a compound of Formula (1), wherein the compound is a compound of Formula (II):

[0087] V

[0088] Z ' - z ZQ *3

[0089] 1'7.

[0090]

[0091] (II)

[0092] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0093] Z1is CR4bor N;

[0094] Z2is CR4cor N;

[0095] Z3is CR4dor N;

[0096] Z4 is CRie or N;

[0097] R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl. Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fiilly fluorinated, branched alkyl, substituted or unsubstituted Cg.-Cg alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy,Patent Application LTGO-019 / 01WO 36088 / 124 Ci-Cg deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be folly or partially deuterated, Ci-Cs- fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be folly or partially deuterated, cyano, -S(O)qRf,, -P(O)(Ci-C4alkyl). -NR6NR7, -(CHAnS / OhNRsRy, -(CH2)nC(O)NRsR7, -NHS(O)2R6, C(=NR6a)NR6R7, -CfOlNR O, -NHC(=O)-alkyl -NH(C=O)NR6Ry, -SO(=NH)R<5, -O-(CH2)mC(=O)NR6R7, -O-(CII2)m-O-Ci.4alkyI, - C(R<5)(R7)-cydoalkyl, substituted or unsubstituted C3-Cs cycloalkyl, Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or R8substituents: wherein Rs is H, Ci-Cs alkyl, deuterated Ci-C4alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyd, or Ci-Cs folly' or partially fluormated fluoroalkyl;

[0098] wherein each Rg and Rio are independently selected from the group comprising H, Ci-Cs alkyl, Ci-Cs cycloalkyl, C2-Ce alkenyl. Ci-Cg haloalkyl, Ci-Cs alkoxy, or Ci-Cg haloalkoxy.

[0099] In some embodiments, R^, Rdb. R4c. R4J, and.. are independently selected from halogen, F, -OCH3, -CII3, -OCFs, -CII(CH3)2, and -OCHF2.

[0100] In some embodiments. Ria, Rib, R4c, Rid, and R4e are independently selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[0101] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (III):

[0102]

[0103] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[0104] Zi is CR-ib orN;

[0105] Z2is CRdc or N;

[0106] Z? is CRw or Fl;

[0107] Z4is CRde or N;Patent Application LTGO-019 / 01WO 36088 / 124 Ra, TGb, Rc, R-4d, and R 4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted Cd-Ce alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherein the C -< alkyoxy chain may be fully or partially deuterated, Ci-Cs-fluoroalkoxy wherein the C1-C0 alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C.5 alkyl wherein the Ci-Ce alkyl chain may be folly or partially deuterated, cyano, -S(O)qR, -P(O)(Ci-C4alkyl), -NRNR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC =O)-alkyl -NH(C=O)NR6R7. -SO(=NH)Rf;, -O-(CH2)mC(=O)NRR7, -O-CCIfclm-O-Ct^alkyl, - C(Rf.)(R7)-cycloalkyl, substituted or unsubstituted C3-Cg cycloalkyl, C3-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy. -NR9R10. C1-C4 alkyl, or Rg substituents;

[0108] wherein each R« and Rio are independently selected from the group comprising H. Ci-Cs alkyl, Ci-Cg cycloalkyl, C2-Cs alkenyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, or Ci-Cg haloalkoxy.

[0109] In some embodiments, ia, Rib, Rc, Rd, and Reare independently selected from halogen, F, - OCRs, -CH3, -0CF3, -CH(CHJ)2, and -OCHF2.

[0110] In some embodiments, Ra, R4b, R-w R4d, and R; are independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[0111] In some embodiments, R4a, R b, Rc. Rd, and Rsare independently selected from those depicted in the compounds listed in Table I, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[0112] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (IV):

[0113]

[0114] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinPatent Application LTGO-019 / 01WO 36088 / 124 Zi is OR* orN;

[0115] Z2is C ic orN;

[0116] Z: is CRM or N:

[0117] Z: is CR.4e or N;

[0118] R4a. R&, RM, M, and Rieare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C -C alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, Cj-Cealkoxy, Ci-Cg deuteroalkoxy wherein the ( -C alkyoxy chain may be folly or partially deuterated, Ci-Cs- fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qR,, -P(O)(Ci- C4alk 1), -NRbNRv, -(CH2)nS(O)2NR6R- / , -(CH2)nC(O)NR6R7, -NHS(O)2R, C(=NR,a)NR> R7, -C(0)NRR7, -NHC(=O)-alkyl -NH(C=O)NRR7, -SO(=NH)R6, -0-(CH2)mC(=0)NRR7, -O-(CH2.)m-O-Cn4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cg-Cs cycloalkyl. Cg-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rs substituents;

[0119] wherein each R9 and Rio are independently selected from the group comprising H, Ci-Cs alkyl, Ci -Cs cycloalkyl, C2-Ce alkenyl, Ci-Cs haloalkyl, Ci-C alkoxy, or Ci-Cs haloalkoxy; p is 0-3;

[0120] Yi is C(Rga)(Rsb), O orN (Rd):

[0121] Y2= C(Rga)(Rgb), O or N (R);

[0122] each Y3is independently C(Rsa)(Rsb), O or N (Re); and with the proviso that only one of Yi, Y2, and Yj can be N;

[0123] each Rgaand Rgb are independently: hydrogen, -OH. deuterium, halo, cyano, Ci-Caalkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, Ci-Ce alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4 alkyl wherein the C1-C4 alkyl may be full x or partially deuterated, or Ci-Cg folly or partially fluorinated fluoroalkyl.

[0124] In some embodiments, Zi is CRib. Z? is CRdc Zg is CR4d,and 4 is CR.i,

[0125] In some embodiments, Ria, R-ib, u, Rdd, and Rte are independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Ccalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or folly fluorinated, branched alkyl, substituted or unsubstituted C2-Coalkenyl, substituted orPatent Application LTGO-019 / 01WO 36088 / 124 unsubstituted C2-C4alkynvl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Cs alkyoxy chain may be fully or partially deuterated, Ci -Cs-fluoroalkoxy wherein the Ci -Cr, alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qRs, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R5, C(=NR6a)NRR7, - C(O)MR5R7, -NHC(:=O)-alkyl -NH(C==O)NR6R7, -SO(-NH)R6, -O4CH2)I;'CA))NR. IR7. -O-(CH2)m-O-Cn 4alkyl, -C(Ro)(R7)-cycloalkyl, substituted or unsubstituted Cs-Cs cycloalkyl, Ch-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N.

[0126] In some embodiments. Ra, R4b, R4a, R4J, and R4eare independently selected from halogen, F, -OCR,, -CH3, -OCFs, -CH(CH3)2, and -OCHF2.

[0127] In some embodiments, u, Rib, R4c, id, and Rieare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[0128] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula ( V):

[0129]

[0130] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof is as defined above and described in embodiments herein, both singly and in combination.

[0131] In some embodiments, Zi is CR4b. Z2is CR4c, Z is CR4d, and Z4is C R

[0132] In some embodiments,a, Rib, R4c, Rid, and ieare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ct, fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-C4alkynvl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cgalkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Cg, alkyl chain may be fully or partially deuterated, cyano, -S(O)qRe,Patent Application LTGO-019 / 01WO 36088 / 124 -P(O)(Ci-C4alkyl), -NR6NR7, -(€H2)nS(O)2NRR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NRa)NR6R7, - C(O)NRR7, -NHC(=O)-alkyl -NH(O0)NRR7, -SO(===NH)R6, -O-(CH2)mC(===O)NRR7, -O-(CH2)m-O-Ci.! ky 1, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C3-Cg cycloalkyl. Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycJoalkyl composes at least one heteroatom independently selected from 0, S, and N.

[0133] In some embodiments, Ra, Rb,;. Rd, and Reare independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[0134] In some embodiments, Ra, Rib, Rc, Rd, and Rsare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB. Fable 2, Table 2A, or Table 2B.

[0135] In some embodiments, the present disclosure provides a compound of Formula (1), wherein the compound is a compound of Formula (VI):

[0136]

[0137] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R2b, R3a, b, Ra, Zi, Z2, Z3, and Z4is as defined above and described in embodiments herein, both singly and in combination.

[0138] In some embodiments, Zi is CR4b. Z2is CRc, Z is CR-w, and Z is C R..

[0139] In some embodiments,3, Rb, R4c. Rd, and Reare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl. Ci-Ct, fluoroalkyl wherein the Ci-Cf, fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Cg haloalky] wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-C4alkoxy, Ci- dcutcroalkoxy wherein the Ci-Cc alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Cg alkyl chain may be fully or partially deuterated, cyano, -S(O)qR, -P(O)(Ct-C4alkyl). -NR6NR7, -(CH2)„S(O)2NRR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NRa)NRR7, -C(0)NRR7, -NHC(=O)-alkyl -NH(C=0)NRR7, -S0(=NH)R, -O-(CH2)mC(=O)NRR7. -O-(CH2)m-O-Ci4alkyl, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C -Cg cycloalkyl, C3-Cg cycloalkenyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and M.

[0140] In some embodiments, R;a, R b, i=, Rw. and M are independently selected from halogen. F, - OCH3, -CH3, -OCR, -CH(CH3)3, and -OCHF3.

[0141] In some embodiments. Ria, Rib, u, R-w, and RM are independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[0142] In some embodiments, R^, R*, Ru, R«, and RM are independently selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[0143] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (VII):

[0144]

[0145] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R2b, Rja, Rsb, Ria, Zi, Z2, Z3, and Z4is as defined above and described in embodiments herein, both singly and in combination.

[0146] In some embodiments, Zi is C +b. Zz is CRMS 3is CR+d.and i is C R;.

[0147] In some embodiments, Ria, IGb, RM, M, and RM are independently selected from the group consisting of hydrogen, deuterium, halo, Ci -Coalkyl, Ci-Cs fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C0 alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cs baloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-C'ealkoxy, Ci-Ce deuteroalkoxy wherein tire Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Co-fluoroalkoxy wherein the Ci-Cs alkoxy maybe fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Cs alkyl chain may be fully or partially deuterated, cyano, -S(O)qRe, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)„C(O)NR; R7, -NHS(O)2Rs, C(=NR6a)NR6R7, - C(O)N 5R7, -NHC(:::O)-alkyl -NHfC-OJNReRr. -SO(-NH)R6, -O-(CH2)mC(==O)NR6R7, -O-(CH2)m-O-Ci.

[0148] 4alkyl, -C(Re)(R7)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, C3-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments. Ria, Rib, Re, Rd, and R. are independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[0149] In some embodiments, Ra, b. ic, Rd, and Reare independently selected from those depicted m the compounds listed in Table 1 or Table 2.

[0150] In some embodiments, Ra, b, Re, Ri, and Reare independently selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B,

[0151] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (VIII):

[0152]

[0153] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of X, Ra, R2b, a, Rb, Ra, Zi, Z2, Z3, Z4, X2. X7X3, X4, X5, and Xg is as defined above and described in embodiments herein, both singly and in combination.

[0154] In some embodiments, Zi is C b, Z2is CRc, Z3is CR d, and Z4is CRe

[0155] In some embodiments, Ra, Rb, Rc, Rd, and Reare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Cg fluoroalkyl wherein the Ci-C& fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Cg alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy. Ci-CTalkoxy, Ci-Cg deuteroalkoxy wherein the Ci-Cg alkyoxy chain may be fully or partially deuterated, Ci -Cg-fluoroalkoxy wherein the C 1 -Cg alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cg alkyl wherein the Ci-Ct, alkyl chain may be fully or partially deuterated, cyano, -S(O)qR, -P(O)(Ct-C4alkyl), -NR6NR7, -(CH2)nS(O)2NRR7, -(CH2)nC(O)NR6R7. -NHS(O)2Rf„ C(=NRa)NRR7, -C(O)NRR7. -NHC(=O)-alkyl -NH(C=O)NRR7, -SO(=NH)Rg, -O-(CH2)mC(=O)NRR7, -O-(CH2)m-O-Ci..jalkyl, -C(R)(R)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, C3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments. Ria, Rib, Re, Rd, and R, are independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[0156] In some embodiments, Ra, Rb, Rc. Rd, and Reare independently selected from those depicted in the compounds listed m Table 1 or Table 2.

[0157] In some embodiments, Ra, b, Rc, Rd, and R: are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[0158] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (IX):

[0159]

[0160] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ria, Rib, R2a, R2b, R3a, R3b, Ra, Zi, Z2, Z3, Z4, X2, X3, X.i, X5, and Xs is as defined above and described in embodiments herein, both singly and in combination.

[0161] In some embodiments, Zi is CRb. Z2is CRcZ3is CR4d,«nd 4 is CR4e

[0162] In some embodiments, Ra, b, Rc, Rd, andeare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl, C1-C5 fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or fiilly fluorinated, branched alkyl, substituted or unsubstituted C2-Coalkenyl, substituted or unsubstituted C -C. alkynyl, Ci-Cg haloalkyl wherein the alkyl may be fiilly or partially halogenated, hydroxy, Cj-Cealkoxy, Ci-Cg deuteroalkoxy wherein the Ci-Cb alkyoxy chain may be fully or partially deuterated, Ci -Cs-fluoroalkoxy wherein the Ci -Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cf, alkyl wherein the Ci-Ce alkyl chain may be fiilly or partially deuterated, cyano, -S(O)q., -P(O)(Ci-C4alkyl), -NRNR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R, CRNReONR^R?, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NRR7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-Ci.

[0163] 4alkyl, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C3-C§ cycloalkyl, C3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments. Ria, Rib, Re, Rd, and R. are independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[0164] In some embodiments, Ra, b. ic, Rd, and Reare independently selected from those depicted m the compounds listed in Table 1 or Table 2.

[0165] In some embodiments, Ra, Rb, Re, Ri, and Reare independently selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B,

[0166] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (X):

[0167]

[0168] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ra. Rb. Ra, Rb, Ra, Zi. Z2, Z3, Z4, X2, XAX4. X5, and Xr, is as defined above and described in embodiments herein, both singly and in combination.

[0169] In some embodiments, Zi is CRb, Z2is CRc. Zs is CR4d.aj.dZ4 is CRe

[0170] In some embodiments, Ra, Rb, Rc, Rd, and Rearc independently selected from tire group consisting of hydrogen, deuterium, halo, Ci-Csalkyl, Ci-Ct, fluoroalkyl wherein the Ci-Ct, fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C<5 alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Ce haloalky] wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cgalkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, C 1 -Co-fluoroalkoxy wherein the C 1 -Ct, alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C -C alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qR, -P(O)(Ct-C4alkyl), -NR6NR7, -(CH2)„S(O)2NRR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NRa)NRR7, -C(O)NRR7. -NHC(=O)-alkyl -NII(C=O)NRR7, -SO(=NH)R5, -O-(CH2) C(=O)NRR7, -O-(CH2)m-O-Ci.

[0171] 4alky 1, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C3-C« cycloalkyl, C3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments. Ria, Rib, Re, Rd, and R. are independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[0172] In some embodiments, Ra, Rb, Rc. Rd, and Reare independently selected from those depicted in Table 1 below.

[0173] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (XI):

[0174] o

[0175]

[0176] Z2 (XI)

[0177] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ria, Rib, R2a, Ra, R3a, Rb. Ra, Zi, Z2, Z3, Z4, X2, X3, X4, X5, and X6is as defined above and described in embodiments herein, both singly and in combination.

[0178] In some embodiments, Zi is CRb. Z? is CRc, Z3is C dand is C e

[0179] In some embodiments, Ra, Rdb, Rc, Rd, and R, are independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl, Ci-Cs fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fiilly fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-Cd alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fiilly or partially halogenated, hydroxy, Cj-Cealkoxy, Ci-Ce deuteroalkoxy wherein tire Ci-Cg alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-C& alkyl wherein the Ci-Cs alkyl chain may be fully or partially deuterated, cyano, -S(O)qR, -P(0)(Ci-C4alkyI), -NRNR?, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R. C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR«R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-Ci.

[0180] 4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, C3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.

[0181] In some embodiments, Ra. b, Rc, R4d, and Reare independently selected from halogen, F, -OCHs, -CH3, -OCF3, -CH(CH3)2, and -OCHF2.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, the present disclosure provides a compound of Formula (XII):

[0182]

[0183] or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R1a, R1b, R2a, R2b, R3a, R3bare defined above, or R1a, R1b, R2a, R2b, R3a, R3bare independently selected from the group consisting ofH, deuterium, halo, hydroxyl, Ci-Cg alkyl, C3-C5 cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Ce alkoxy, Ci-Ce deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, Ci-Ce alkenyl, C2-C6alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C1-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and N;

[0184] wherein any of said alkyl or alkenyl moieties above may be further substituted with one, two. three or four R substituents, where each Rs is independently selected from halo, Ci-Cs alkyl, Ci-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cg fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, C1-C0 alkoxy, C i -Ce deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, and m = 0 to 2;

[0185] R2aand R2bmay be independently selected from aryl or heteroaryl and may optionally together form a substituted or unsubstituted exocyclic alkene, wherein alkene substituents are selected from H, deuterium, fluoro, C1-C6alkyl, aryl or heteroaryl;

[0186] wherein at least one of R1a, R2aand R3aare selected from the group comprising hydroxyl, Ci-Cs alkoxy, Ci-Ce deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be folly or partially halogenated, Ci-Cg cycloalkoxy, C3-C8fluorocycloalkoxy wherein the cylcoalkoxy may be fully or partially fluorinated, and substituted or unsubstituted -O-[C(R6)(R7)]m-C6-C10-aryl,

[0187] represents a single or double bond;Patent Application LTGO-019 / 01WO 36088 / 124

[0188]

[0189] X2= CR12, N, or N+-O-;

[0190] X3= CR13, N, orN+-O’;

[0191] X4= N, N+-O-, or CR14;

[0192] X> = CRi.y N or N+-O’;

[0193] X6= CR16, N or N+-O-;

[0194] Ring B is selected from the group consisting of a C6-C10membered aryl ring, C5-C8membered heteroaryl ring: monocyclic, bicyclic, or spirocyclic cycloalkyl ring; or monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl ring or the C5-C8heteroaryl ring contain one or more heteroatoms independently selected from N, O, and S, and wherein Ring B is substituted with one or more R4 substituents;

[0195] R4is hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, C1-C.5 haloalkyl wherein the alkyl may be fully or partially halogenated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, S(O)qR6, -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N; and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R4 substituents maybe further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[0196] R6and R6aare individually and independently selected from the group consisting of H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl,

[0197] R7is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl,Patent Application LTGO-019 / 01WO 36088 / 124 R12is selected from the group consisting of hydrogen, OH, -OC1-C6alkyl, -OC1-C6alkoxyl, C1-C6alkyl, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[0198] R12ais selected from the group consisting of hydrogen, C1-C6alkyl, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[0199] Ris, RI4- P ■ and Ris are independently selected from the group consisting of hydrogen, deuterium, hydroxy, oxo. -C(O)NR6R7, -(CH SCO NR^R?, -(CftlnCfOjNRftR?. cyano, halo, Ci-Csalkyl, deuterated Ci-Cs alkyl wherein the Ci-Cs alkyl chain may be folly or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloCi-C4alkyl wherein the C1-C4 alkyl chain may be fully or partially halogenated, C1-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or fully- fluorinated, Ci-C4alkoxy, C1-C4 deuteroalkoxy wherein the C1-C4 alkyoxy chain may be folly or partially deuterated, cycloalkoxy -S(O)qR6, -NR6NR7, -NHSfOhRs, -C(=NR6a)NR6R7, -NHC(=O)-Ci - t-alkyl, -NH(C=O)NRSR7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-ICH^-O-GM alkyl.-C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cs-C cycloalkyl, C?,-Cs cycloalkenyl, substituted or unsubstituted Cs-Cio ary l, substituted or unsubstituted Cs-Cs heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13, R14, R15, and R16substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[0200] m is 1-5:

[0201] n is 0-3; and

[0202] q is 0-2.

[0203] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 2, or Table 2A.Patent Application LTGO-019 / 01WO 36088 / 124 O

[0204] In some embodiments, Ring

[0205]

[0206] A is In some embodiments, Ring A is

[0207]

[0208] In some embodiments, Ring A is

[0209]

[0210] In some embodiments. Ring A is O

[0211] . In some embodiments, Ring

[0212]

[0213] A is H. In some embodiments. Ring A is

[0214]

[0215] . In some embodiments, Ring

[0216]

[0217] A is. In some embodiments, Ring A is

[0218]

[0219] Patent Application LTGO-019 / 01WO 36088 / 124

[0220]

[0221] embodiments, Ring

[0222]

[0223] A is In some embodiments, Ring

[0224]

[0225] A is In some

[0226] embodiments, Ring

[0227]

[0228] A is In some embodiments, Ring

[0229]

[0230] A is

[0231] embodiments, Ring

[0232]

[0233] A is In some embodiments. Ring

[0234]

[0235] A is In some

[0236] embodiments, Ring A

[0237]

[0238] is O

[0239] some embodiments, Ring A

[0240]

[0241] is

[0242] embodiments, Ring

[0243]

[0244] A is In some embodiments, Ring

[0245]

[0246] A isPatent Application LTGO-019 / 01WO 36088 / 124

[0247]

[0248] In other embodiments. Ring

[0249]

[0250] A is In some embodiments, Ring A is

[0251]

[0252] In some embodiments.

[0253] N NH

[0254] Ring A

[0255]

[0256] is In some embodiments. Ring

[0257]

[0258] A is. In some embodiments, RingPatent Application LTGO-019 / 01WO 36088 / 124

[0259]

[0260] . In some embodiments, Ring A is. In some embodiments, Ring A

[0261] In some embodiments, Ring A

[0262] O

[0263]

[0264] In some embodiments,

[0265] Ring A is. In some embodiments. Ring A is In some embodiments.

[0266]

[0267] In some embodiments. Ring A is selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[0268] In some embodiments, Ring B is phenyl, a ring selected from a Cg-Cio membered and ring, a ( ’■-Cg membered heteroaryl ring; a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; or a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl ring or the C₅-C₈ heteroaryl ring contain one or more heteroatoms independently selected from N, 0, and S, and wherein Ring B is substituted with one or more R4 substituents.

[0269] In some embodiments, Ring B is a Cs-Cio membered aryl ring substituted with one or more R-i substituents. In some embodiments, Ring B is a Cs-Cs membered heteroaryl ring having one or more heteroatoms independently selected from N, 0, and S; and substituted with one or more R4 substituents. In some embodiments, Ring B is a monocyclic, bicyclic, or spirocyclic cycloalkyl ring substituted with onePatent Application LTGO-019 / 01WO 36088 / 124 or more substituents. In some embodiments, Ring B is a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring having one or more heteroatoms independently selected from N, 0. and S; and substituted with one or more R substituents.

[0270] In some embodiments, Ring

[0271]

[0272] B is wherein

[0273] Z1is CR4bor N;

[0274] Z2is CR4cor N;

[0275] Z3is CR4dor N;

[0276] Z4is CR4eor N;

[0277] R4a, R4b, R4c, R4d, and R4eare independently selected from the group consisting of hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C4alkynyl, C1-C6haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C6alkyl wherein the C1-C6alkyl chain may be fully or partially deuterated, cyano, -S(O)qR6, -P(O)(C1-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N; wherein the C1-C6alkyl, C1-C6fluoroalkyl, haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4alkyl, or R8substituents; wherein R8is independently selected from H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;

[0278] wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy.

[0279] In some embodiments, Z1is CR4b, Z2is CR4c, Z3is CR4d, and Z4is CR4e

[0280] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from the group consisting of hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl isPatent Application LTGO-019 / 01WO 36088 / 124 partially or fully fluorinated, branched alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₄ alkynyl, C₁-C₆ haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C₁-C₆alkoxy, C₁-C₆ deuteroalkoxy wherein the C₁-C₆ alkoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C₁-C₆ alkyl wherein the C₁-C₆ alkyl chain may be fully or partially deuterated, cyano, -S(O)qRe. -P(O)(Ci-C4alkyl), -NR6NR7, -(CH^S / O^NRdG, -(CH2)riC(O)NR6R7, -NHS(O)2R5, CO R^NRJG, - C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NReR7, -SO(=NH)R6, -O-(CH2)mC(=O)NRR / , -O-(CH2)m-O-Ci...alkyl. -C(Rd)(R7)-cycloalkyl, substituted or unsubstituted C2,-Cg cycloalkyl. C3-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N

[0281] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from hydrogen, halogen, F, Cl, -OCH3, -O-CH2CH3, -CH3, -OCF3, -OCD3, -CH(CH3)2, -CF3, and -OCHF2.

[0282] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B,

[0283] In some embodiments, Ring B is substituted phenyl. In some embodiments. Ring B is phenyl with

[0284] one ormore R4substituents. In some embodiments. Ring

[0285]

[0286] B is F. In some embodiments, Ring

[0287] In some embodiments. Ring B

[0288]

[0289]

[0290] In some embodiments, Ring B is F. In some embodiments, Ring B isPatent Application LTGO-019 / 01WO 36088 / 124

[0291] F F

[0292]

[0293] . In some embodiments, Ring B is F. In some embodiments. Ring B is

[0294] F

[0295]

[0296] . In some embodiments, Ring B is. In some embodiments. Ring B

[0297] HO

[0298] F

[0299]

[0300] , In some embodiments, Ring B is F In some embodiments. Ring B is

[0301] F F

[0302] F

[0303] . Tn some embodiments. Ring

[0304]

[0305] B is F. In some embodiments. Ring B is

[0306] . In some embodiments, Ring B is

[0307]

[0308] . In some embodiments. Ring B is

[0309] In some embodiments, Ring B is

[0310]

[0311] . In some embodiments, Ring B is

[0312] In some embodiments, Ring

[0313]

[0314] B is In some embodiments, Ring B is

[0315] In some embodiments. Ring

[0316]

[0317] B is. In some embodiments. Ring B is

[0318] HO F F

[0319] . In some embodiments, Ring

[0320]

[0321] B is. In some embodiments, Ring B

[0322]

[0323] . In some embodiments, Ring B is

[0324]

[0325] . In some embodiments, Ring B isPatent Application LTGO-019 / 01WO 36088 / 124

[0326] F F

[0327]

[0328] F. In some embodiments. Ring B is F. In some embodiments, Ring B is

[0329]

[0330] In some embodiments. Ring B is substituted cyclohexyl. In some embodiments, Ring B is

[0331]

[0332] In some embodiments, Ring A is selected from those depicted in the compounds listed in Table 1 or Table 2.

[0333] In some embodiments. Ring A is selected from those depicted in the compounds listed in Table 1 A or Table 2A.

[0334] In some embodiments, Ring A is selected from those depicted in the compounds listed in Table IB or Table 2B.

[0335] In some embodiment, X is O. In some embodiments, X is or -C(R1a)(R1b). In some embodiments, X is CH2.

[0336] In some embodiments, X is selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2. Table 2A, or Table 2B.

[0337] In some embodiments, Riaand Rib are independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, Ci-Cs alkyl, Cs-Ce cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, Cj-Ce alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6alkenyl, C2-C6alkynyl, -|C(R6)(R7)]m-C3-C8-cycloalkoxy, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N.

[0338] In some embodiments, R-iaand Rib are both hydrogen.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, R2a and R3b are independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, Ci-Cs alkyl, C3-C5 cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Cs alkoxy, Ci -Cg 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(R6)(R7)]m-C3-C8-cycloalkoxy, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and N,

[0339] In some embodiments, R2aand R2bare both -CH3. In some embodiments, R2aand R2bare independently -CF3and -CH3. In some embodiments, R2aand R2bare independently -CF3and -OCH3. In some embodiments, R2aand R2bare independently hydrogen and -OCHF2. In some embodiments, R?ais H and R-b is alkoxy or fluoroalkoxy. In some embodiments, R3ais H and R?b is alkyl, aryl or fluoroalkyl. In some embodiments, R3ais ary I or heteroaryl and a is alkoxy. In some embodiments, R?.ais -OH and R?.b is alkyl or fluoroalkyl. In some embodiments. R3ais -OH and R3b is -CF3. In some embodiments, R?, is II and R?i, is benzyloxy. In some embodiments, R3ais II and R3b is trifluoroethoxy. In some embodiments, R3ais H and R?b is -OCF3. In some embodiments, R2ais H and R2b is phenoxy or substituted phenoxy. In some embodiments, ia is H and R?b is 4-fluorophenoxy. In some embodiments, R3ais H and R3b is isopropoxy.

[0340] In some embodiments, R2aand R2btogether with the carbon they attach from form an optionally substituted 3-6 membered cycloalkyl spirocyclic ring. In some embodiments, R2aand R2btogether with the carbon they attach from form an optionally substituted 3-6 membered heterocycloalkyl spirocyclic ring having heteroatoms selected from N or O. In some embodiments, R2aand R2btogether with the carbon they attach from form an optionally substituted cyclopropyl, cyclobutyl, or cyclopentyl spirocyclic ring. In some embodiments, R2aand R2btogether with the carbon they attach from form an optionally substituted heterocyclopropyl, hetero cyclobutyl, or heterocyclopentyl spirocyclic ring having heteroatoms selected from N or O. In some embodiments, R2aand R2btogether with the carbon they attach from form an

[0341] optionally substituted spirocyclic ring

[0342]

[0343] . In some embodiments, R2aand R2btogether with the

[0344] carbon they attach from form an optionally substituted spirocyclic ring

[0345]

[0346] .

[0347] In some embodiments, R2aand R2bare selected from those depicted in Table 1 below.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, R2aand R2b are selected from those depicted in Table 1A below.

[0348] In some embodiments, R2aand R2bare selected from those depicted in Table 1B below.

[0349] In some embodiments, R3aand R3bare independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, 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-C8alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6alkenyl, C2-C6alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N.

[0350] In some embodiments, R3aand R3bare both hydrogen.

[0351] In some embodiments, R3aand R3bare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B

[0352] In some embodiments, R4is hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, C1-C6haloalkyl wherein the alkyl may be fully or partially halogenated, C1-C6alkoxy, C1-C8deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C8alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C6alkyl wherein the C1-C6alkyl chain may be fully or partially deuterated, cyano, S(O)qR6, -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O) NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N

[0353] In some embodiments, R4is halogen. In some embodiments, R4is F. In some embodiments, R4is -OCH3. In some embodiments, R4is -CH3. In some embodiments, R4is -OCF3. In some embodiments, R4is -CH(CH3)2. In some embodiments, R4is -OCHF2. In some embodiments, R4is -OCH2CH3. In some embodiments, R4is -OCD3. In some embodiments, R4is cyclopyloxy. In some embodiments, R4is hydroxymethyl. In some embodiments, R4is -CF2H. In some embodiments, R4is -CF3. In some embodiments, R4is -OCH2CH2OCH3. In some embodiments, R4is Cl.

[0354] In some embodiments, R4is selected from those depicted in Table 1 below.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, R4is selected from those depicted in Table 1A below.

[0355] In some embodiments, R4is selected from those depicted in Table 1B below.

[0356] In some embodiments, R5is H, C1-C6alkyl, C1-C6cycloalkyl, C(O)NR6R7, C1-C6alkoxy or C1-C6cycloalkoxy; wherein the forgoing alkyl, cycloalkyl, alkoxy and cylcoalkoxy fragments of R5maybe further substituted with one or more substituents selected from halogen, OH, C1-C4alkoxy.

[0357] In some embodiments, X2is CR12. In some embodiments, X2isN. In some embodiments, X2is N+-O-. In some embodiments, X2is CR12 and R12 is H.

[0358] In some embodiments, X2is selected from those depicted in the compounds listed in Table 1, Table I A, Table IB, Table 2, Table 2A, or Table 2B.

[0359] In some embodiments, X3is CR13. In some embodiments X3is, N. In some embodiments, X3is N+-O-.

[0360] In some embodiments, X3is CR13and R13is H. In some embodiments, X3 is CR13 and R13 is -CN. In some embodiments, X3is CR13and R13is -C(O)NH2. In some embodiments, X3is CR13and R13is -C(O)N(CH3)2. In some embodiments, X3is CR13 and R13is -OH. In some embodiments, X3is CR13 and R13

[0361]

[0362] is the depicted structure. In some embodiments, X3is CR13and R13is -Cl. In some embodiments, X3is CR13and R13is -NH2. In some embodiments, X3is CR13 and R13 is -S(O)2NH2. In some embodiments, X3is CR13 and R13 is -S(O)(NH)CH3. In some embodiments, X3is CR13 and R13 is -C(O)NHCH3.

[0363] In some embodiments, X3is selected from those depicted in the compounds listed in Table I, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[0364] In some embodiments, X4is N. In some embodiments, X4is N+-O-. In some embodiments, X4is CR14. In some embodiments, X4is NH.

[0365] In some embodiments, X4is selected from those depicted in the compounds listed in Table I. Table 1 A, Table IB, Table 2, Tabic 2A, or Table 2B.

[0366] In some embodiments, X5 is N. In some embodiments, X5is N+-O-. In some embodiments, X5is CR15. In some embodiments, X5is C=O.

[0367] In some embodiments, X5is selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, Xg is N. In some embodiments, Xg is N’-O'. In some embodiments, Xg is CRig.

[0368] In some embodiments, X6is selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B.

[0369] In some embodiments. R is hydrogen In some embodiments R’.3is -ON. In some embodiments, RB is -C(O)NH2. In some embodiments, R13 is -OMe. In some embodiments, is -OH. In some N^N-^

[0370]

[0371] embodiments R13is the depicted structure. In some embodiments, R13is -Cl. In some embodiments, R13is -NH2. In some embodiments, R13is -C(O)N(CH3)2. In some embodiments, R13is -C(O)N(CH3)2. In some embodiments, R13is -S(O)2NH2. In some embodiments, R13 is -S(O)(NH)CH3. In some embodiments, R13 is -C(O)NHCH3.

[0372] In some embodiments, R13 is selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[0373] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B,

[0374] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table I.

[0375] Table 1

[0376]

[0377] Patent Application LTGO-019 / 01WO 36088 / 124 0 NC O^NH2o o O 1

[0378] N

[0379] H ilN

[0380] \ /

[0381] C J jXr

[0382] F3X X jL FgC X-A^A^ H. XJlbhb" ''G' Y 'F Xr 'Y ^F X'^ Y^F F F / / u. p F

[0383] \ z—

[0384] 0 yo=u. / zi / - o

[0385] Q /

[0386] / / / \ \

[0387] ( o \=

[0388] 2 / " VAA'''^ / ( A \ / V /

[0389] \ '

[0390] HF CO— 1 H p W Y\ | H

[0391] o o (

[0392] r / /

[0393] LL.

[0394] X

[0395] ^O'^X^'F

[0396] F F TM C m

[0397] *“ Tl w

[0398] H 7 Z \ -~ w O /

[0399] O-. Y o / OL u-- O 1 0 NC ( \= _ O < p H) z /

[0400] 11 1 y( 0= / LL (z: E— f / /

[0401] o VZ / o=

[0402] / sp

[0403] A / o1°N1 ( o —

[0404] o— \ / 'zJL AJ11JO iz X, Z^V ^N / ^ / JX / \ 0>

[0405] s I H Z \ \O= " H TZ— X\ 1HFXX 1 - ea o /

[0406] ■ a IL / X ntZ--:

[0407] O Y F ^O'^ Y^F ^^ACFJ

[0408] F!F

[0409] \ z-- Q MeO o O

[0410] II

[0411] p 11 Z3Z $ — / XiN(f ]]Nj! 1<AXNH23C / "- / X yo / _x

[0412] Xyj[H 0X\ JH(\ /

[0413] o / M Y'^p 'F MeO' y T LL F

[0414] F

[0415] , NH2O CN

[0416] q V X / Y LX

[0417] j6i 1 u

[0418] X H

[0419] gC XU

[0420] ■i XK:: / .

[0421] MeO y F

[0422] F F F

[0423]

[0424] Patent Application T1 LI CN o LTGO-019 / 01 WO 36088 / 124 o

[0425] Ok-Z0 p U_ - O / YJ ° HO ) o — X. K / o^

[0426] o>= / 12 z ) ( o — / x o J. V / \ /

[0427] \ / " Y 'N

[0428] S H o /

[0429] " M3en ■ X

[0430] F CH

[0431] i F LL3C A-VYYX'O'x" Y^'F CJ ^o'^ y^F F _ H

[0432] \ \> ZXK- F yO- Z 7 Li- '

[0433] ZOH o 9 0 / °

[0434] lo2

[0435] l A / u. / ZI 0- / _ / r / =U- ZX k~ “J

[0436] / Sr 'N YYS'N

[0437] VS o ) ( O —

[0438] l b J1,S J

[0439] ~ N \ Z / \ / / / ^ \

[0440] x / ^Y x N

[0441] o / AH

[0442] LL LL co co o /

[0443] MeO^^S^F L 0 X Yi FFiCn.

[0444] "o Y >

[0445] F F F NZZN— 0 0

[0446] 01

[0447] SSj N i'. Ji / J FgCO — 6 _] H \J 1HFJC^CX^A

[0448] S'^ Y#^F s 0 o Y. F S'Y^F F F

[0449] / LL F J1« Q NH2° O

[0450] o Qi\!; fl — \ Y - O^NH20 o

[0451] o Y

[0452] / \ z / - n A ( / / / } O — )oA / — SN kk A

[0453] ) / / 1 kj 1 kJ

[0454] L /

[0455] N kk " V N ~

[0456] Z\ / " V > J H0^ TZ I# \JX o / ! H S

[0457] F3"

[0458] C y / y^S F3CV\ / O.

[0459] IL. o < Az- •C o.. J / F

[0460] F F F

[0461] O^NH2o

[0462] O

[0463] 11 Y *X.® o®

[0464] Nf / Q

[0465] •x.

[0466] X H X H

[0467] 3X I

[0468] F3F CH

[0469] C F3c

[0470] ''^■'kCF3S'^xps'FYY^FF 1 F

[0471]

[0472] T) 13 Patent Application W w O / z— O / LTGO-019 / 01 WO 360 \ / 8 o u-—8 / 124 \ z g

[0473] \ / ® >\ ( _= z= ) / o — O^NH2J Qj LL / - -—

[0474] 9 J

[0475] 4 J 4 yo IZ^ a iz 9 11 ~ m ® n J JU ) X '^X f

[0476] x A / 'N Z Xo o- 'I 'NX / / o

[0477] X I " < z n— w > f* o / ■

[0478] Z\H

[0479] FaLLc

[0480] I X O YFTl CM '■'■'X^^OCFs X F w

[0481] F F O / O

[0482] j y \ / —f °u-- ( / / O / f X Xi O

[0483] I ) O — ^ y Q jj_ <z n ZX ——— / . / NH, O

[0484] \ / \ o "j

[0485] / \ ( \Uo 4^ '71iz— U'j ) ( o— — < Xf^

[0486] JiNu y J V \ > < Ti — 4 Ji, / L, NH? / z2\ / ~- _ x / ^u^N n(vX o Uy J.H 0o / L X 1H / 2■"~ v r> LL 0> ZXHS F3C

[0487] Q-^XxsXp

[0488] - / <X\CF3FM C n 1 F w

[0489] \ f X

[0490] o u Z ku1-\ / O — — A u

[0491] 0oX“- “- ° N' 1, > K / ■"\==

[0492] is 1 4 Yo= f TZ{ y° "'x\ / --jQ

[0493] F CX J.HPjU V-'-'X. / --X, 4) ° / H C o / co X wZ.-. LL NJ

[0494] ^o'' y^x'F

[0495] F

[0496] n Tl w O / a /

[0497] 0

[0498] / ) O — - ) ( o — —

[0499] / \ X

[0500] 0 >^04 J°= "r| / iz— ■H “Y ~ / Jv O_ AH / U > x o_ H / A / / ~ FSC Z X0 £0= m— (M ■" V v z \L 2®£ - < _ O'^ y^F X N} / •k F

[0501] F F

[0502] 0

[0503] ? SpN

[0504] x, / UNl

[0505] X J.H

[0506] F3C ''^''X^O M e

[0507]

[0508] Patent Application LTGO-019 / 01WO 36088 / 124

[0509] > Z-~

[0510] u_ A A

[0511]

[0512] pX © zr? u- — > / / <<- Z\ \ '

[0513] ) ( o —

[0514] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 1A.

[0515] o

[0516] u.

[0517] Table 1A:

[0518] 0 O^NHO°YNHS2A A A J A Y / " V T N O HF2CO AA^ Ji HF2CO-< H F3COAA H.

[0519] YA

[0520] MeO'" A^''T MeO' Y ' F MeO'^Y^'F F F F

[0521] 0 O^NH2O.;;ZNH2

[0522] II O-,, O XNH2 o x o A A^A-N

[0523] AAYNA"-A' N MeCt MeO D J i D3

[0524] X I3CO N CO

[0525] H

[0526] F3C XHXHXH

[0527] F3C F3C F3C

[0528] ^'O''’ ‘AXF 'AVS '^O'^A^F

[0529] F F F F

[0530] O^ / NH2o o O^, NH2

[0531] 0 X 0 X0O.VNH2A / X AAAH2

[0532] I I J AAiN

[0533] M TAN

[0534] aet>

[0535] D COZ'V 'N MeC\

[0536] H ph~v / 'Y' XHXN'i^JF3F3C X

[0537] C F3H

[0538] C °AAA^ ^O'^A^F AAYFMeO" A- A 1 VFX

[0539] F 1 F F „ O. X. NH, o OyNH

[0540] O Vi2„ O.. NH

[0541] 2, « OO^NH, o X o Y [f ilN„ ZW'^'N'^'A 70\ 1HF^ O — (, H

[0542] -I b

[0543] F3C-7^AfA A°YAAL MeO^ y r \ yx— - j■, M.eO Y F J.... / MeO^A^F F'T ' MeoYoAp F F F F F F 1 r

[0544]

[0545] | T1« Patent Application © U)

[0546] o n LTGO-019 / 01 WO 36088 / 124 71 / \

[0547] / \ / -n — —

[0548] O^, NH2OX ZNH2

[0549] 0 Y )° 4 Yz x /

[0550] 7# \ o Y_

[0551] [i llNIl JjN47 MeO.

[0552] Y4 z -__

[0553] T X KJ F3C A-Y^H

[0554] F 2 n- to W HO. 1 Xx.

[0555] | F 0 0 F

[0556] Q. XNH2 O. NH2

[0557] o 00OVNH2OX^NH 'Y " Y2

[0558] 0 Y 4 \ \O^= y Jj' \ 01 _ 3 (i llNMeO. EtO. / wXl ''’7

[0559] 3HO

[0560] XHXHM C ’ F CO-< | H

[0561] 3X

[0562] F C F3C X- YY KJ F3CHZY ’FZ^Y^F

[0563] F F s -n» ro w F F

[0564] O O

[0565] o.x NI 0 VHsOX^NH20 Y 0 Y Jx l

[0566] N0^ <0

[0567] ~ \ / v \ 0N-~__z

[0568] MeOvZx / 'N HF2CO~< H JL X MeO. Z> AN

[0569] O 6 X3X I

[0570] F CHX Z £ " H:—~ J CP-) S X 1H

[0571] F3C ^-^YY xxa Y F

[0572] FOC'^^ 'F F

[0573] 0., O^NH2NHO., NH, NH OX / 2 0 Y O Y20 Y 0 Y

[0574] fl Yj

[0575] JL AJNz. A X 3 F3C Z-^X?'MI / X^■ F

[0576] Me3coYY H ""

[0577] MeO / >zs'N^xZO, X X N

[0578] H HMeOX-Y X X

[0579] F3C FgC rx J

[0580] EtO-'X^X

[0581] ci'^XMF1 F I yX

[0582] F MeO J r F Ox, NH2O.x „NH O YOOVNH2 7

[0583] 0 °YNH20 yzAA IT IINxA

[0584] FoC. XL XL X MeO XL Xl. X ZAXX y r l \ / y- N

[0585] F3CT \__ F3C0--X T N MeO VJ.Fxx a t.H

[0586] FI 7 F-\XJX\=^X, 'O-X-^Y ux

[0587] ' F / F / F1FO„ 0x

[0588] °YNHZ0 °yNH*. NH2p

[0589] 0 Y

[0590] ■j^Y^ Fac fl H |

[0591] x jfxb YZY^N'''^<X )Ci B ■^ vJ O

[0592] HO ''"HF3C \ J ' \ _ (.H

[0593] X-'-x

[0594] jQ MeO7JT”% Med JI X F^Xp " X^X

[0595] / I F F

[0596]

[0597] F F FPatent Application LTGO-019 / 01WO 36088 / 124

[0598]

[0599] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table IB.

[0600] Table 1B:

[0601]

[0602] Patent Application LTGO-019 / 01WO 36088 / 124 (

[0603] )

[0604] O^, NH20 o

[0605] j / ' O «X H

[0606] FaC-AJk - F F

[0607] O^, NH20

[0608] o II0H

[0609] \ / >r " N / ^'

[0610] F fX H

[0611] X IHF3CX>k ^. -X JlH'^O'X^F YyXX'-p / Q_xo / y 'F

[0612] F F F

[0613] 0 O „ O..., NH o 'Y2fX Xi FaCx Z-X'N^X A 1 H

[0614] F3C -X 1H%X A > 8 X CJH°\r2^x X'xy^F / rX

[0615] F F

[0616] F

[0617] (

[0618] 0 O NC 0 MeO if 11NF<> C-. / " X'N XFX X X\ IH

[0619] -X J.H

[0620] '" O^ X 'F \0J\^XFMeO'^X^'F F F F

[0621] O^NH20 o O A T II 11 ~ ®, 0

[0622] 5 1 '" A'N

[0623] j / l X J. / ixzNH! JOO f J vnfs^ “ x Z'~Y

[0624] j ] ' N X Lh° H

[0625] F3C

[0626] J

[0627] juX X 0 Yl F F F

[0628] F

[0629]

[0630] Patent Applicati M C 2\ x W / LL _ Xon LTGO-019 / 01 WO 36088 / 124

[0631] Q XY / Zi i3Z $. --- HJ' \ / \ LA ) □H=

[0632] 0 CN O^NH2) ( O — o V o Y / \ / A co o / co o X /

[0633] O

[0634] / V *N AX LL LL

[0635] F3C “\ 1HX 1 H

[0636] 'AyX m iij A " ~

[0637] x XL / A

[0638] V MeO^Xp ^F 'O Y" F

[0639] F F F

[0640] Q' o

[0641] A n

[0642] 0 0 HO OH XXIZo

[0643] J^1 / r.NYA^< YNXX Z T

[0644] / YXNA F3A yy jM 'AX A H ^

[0645] F3C V-A.3A

[0646] F CH

[0647] \o>ysA.FMeO'^X^'F F F F

[0648] 0 O p O^NH20 / 1' A / o Y

[0649] Y N / -AY^N

[0650] 1 u Y AN1 J / I. ■'X' N'. A-Y N AO / \ YAN7F rX T H

[0651] _ w X i H

[0652] _ X F3C X

[0653] F3CH

[0654] . 0I YX X i

[0655] / y Ji- F "'O' \o-Ay<. F 0 Y Fo= / ZI F ° F F F; o ( —

[0656] ( \ /

[0657] 0 o o 0., NH2o A 0 I! 1 ® O A T

[0658] . / ^A'NZA''X

[0659] AHX X

[0660] F3c X jHFjC X'-Ayy F3c '-'AX ■x0JyX.FXAXCF3"'O' -'^>"FF F

[0661] o 0 O^NH2

[0662] X-% o Y

[0663] A A juO AXN

[0664] \ / 'Y N

[0665] AH HA IM

[0666] F3C A

[0667] F3CX'' y^ A 1H

[0668] v yS Xy\jYAF

[0669] F 1FO' Y^'F

[0670] A. F

[0671] F F

[0672]

[0673] Tl Patent Application US LTGO-019 / 01 WO 36088 / 124 X

[0674] 2o< —~-^ _

[0675] o o NH2)yX° ■" ^\,p. o W ' V <o

[0676] J. D

[0677] x f — < N T fT

[0678] M

[0679] F3C Y.

[0680] Y o 7 o- XYZY0CF3 A \ y o=ZT

[0681] O^NH2o 0 0 H2N O W V JL _ci

[0682] AA

[0683] fl ^^NJ Ju W W / 1 Cqo / n

[0684] Y\ ]Ho -x rvX’N

[0685] „X

[0686] xH3X 1 c X F CHlF3CX"\^'X

[0687] ^o'xXjXx O A Y A FF

[0688] F

[0689] 1F F F

[0690] 0 0 0

[0691] f| X^N^AX / ^N Jx H ■x ZYz^N',zU^?^ F F3C X

[0692] 3XX / H

[0693] CV X|X X z \ JHz\- / MeO / Ass|’ / '> X'F O'^ Y^F

[0694] QX LL- QA^Y^QP <,= _ \ / z F Jx, F

[0695] / \, T- F F 1

[0696] o NH2OX. NH2OJx O

[0697] 0 £ 1! Z 1 9 T z V YAA N ro Q /

[0698] ibo [i I!<> Ni

[0699] LL B IN•x l x X YXN^ x Z" / '

[0700] XHz\ _1HFXix^ F3C x XX iH

[0701] Y-- > YXj

[0702] F3Cv'Ay'^ Il I FgQ-^xjS^Q^g YVS Q-'XY^F 1 F F A F F

[0703] H O NC

[0704] O °YUNHOxX"

[0705] o X / A / YNil A 1 l| £ x. ZYA'N'ZJ N fi llN^ / ^ X / ^~Z ^ ' JX H

[0706] X^ ZX^N^5^ F3C ^AY%X X iH

[0707] F3e3Z\

[0708] F CHJl J MeO'zY'''F O' X^'F QX^'X.- F 11F F 1 F

[0709]

[0710] *TI Patent Applicat TiM Co CM Wzn x O / LTGO-019 / 01 WO 36088 FXX / 124 ( / / A >

[0711] x Axro XA X> Y< d r- y oXu.-- H °v O <“-”

[0712] °\V~33A / o #1,- VVzo ■n b) 2

[0713] VZ! CO 0 4“

[0714] Z X / / T—

[0715] L LL O M L M C ZZ-» X - % \ f

[0716] 4 M X J

[0717] A

[0718] / )C) - - Ao=u. / \ \ ZI--- A / rk _0 O

[0719] / ( X \ \r ——

[0720] 9 0 / \ O - 0 p

[0721] IS b b

[0722] A

[0723] / yAN 7

[0724] 51 U JM5 •Z_ eo

[0725] LL jXo

[0726] X IH

[0727] F3C Cl\ FgC

[0728] F,cAl

[0729] "xy zM C X

[0730] o yA / zz- I "71

[0731] O y Y7\ / coZ. ■ " C>t A

[0732] F O /

[0733] X A AC 0

[0734] o=AA ) < 0

[0735] yu.y zz #- AW Lq q

[0736] / AA

[0737] A A > A=

[0738] OXXNH2) 7o\ / —\ ' \ X< LO -n. -r— OXXNH O-.XNH 0 J2 2X / \ / 0 / A / \ox 0 1

[0739] 11X » L Ah

[0740] coKo A AA ft } / J Qh

[0741] LL JuO

[0742] \ Z-A'NNto

[0743] X H3X iHb / A

[0744] 1 F C

[0745] AA.F,cA

[0746] zAb O F Ho^y X F3C OMe

[0747] F F

[0748] O NC AAN A A

[0749] F. XU

[0750] ■ A h

[0751] F

[0752] 0. NH2? 1 0 X 51. X / Y ^Q-ASpN Ji J! J \ / ''A N '' F F3CCK / CX XH

[0753] F3C ^-Ayy A^' y#'i"'F F F

[0754]

[0755] JT’ Patent Application LTGO-019 / 01WO 36088 / 124? (f / A / °

[0756] ) J<\==:==

[0757] O.. NH2 OX^NH2J \°= y a ZZ / y= 0 y 0 T y p\=

[0758] YY-’N I ( if ]!N

[0759] 1 " Xx F3C-X 1 H \ / " Y ^N

[0760] r)s

[0761] -n z,0. sz JyL Y'-FF3CY

[0762] y )X HO. Xn

[0763] y Xx o ZFF

[0764] / XXA O F ( / / y Q u.. X ZX~” - ( ) o —

[0765] ) ( 0 —

[0766] XO <= ZZ —X. / \ X OX, NH2

[0767] 0 V K / YX Y / v L m 0

[0768] L 4 ® J F3X w C < A zyHX

[0769] Z ** w

[0770] \o= O Tl z W \ X 'X

[0771] O ' 0 'F \ / ) / \ F

[0772] )0( — / \

[0773] oxz3=- ' /

[0774] ° \ y - / \o‘= ■n —

[0775] ) ( O — Ck _NH2y(y v P_

[0776] O; 0.,u0^ _NH2O3NH* / \ / o yZA0TZ. L, NH2

[0777] 0 S 0 V Q X Y^N « A J- fi 1! ', LL xSf C 4mzV \n--2. IZ_ n ilN\ ■xX

[0778] LL X

[0779] 3X

[0780] F CHX 1HKIYH

[0781] _ _ x \ F3CVv n } \\ 1 ZF3C %

[0782] I X X A.

[0783] G ''X ) / <. / '=F O X F

[0784] 1 J ( O< V ^=“- 1

[0785] / (

[0786] N-N O o ° H 0 'N'W

[0787] O z4JI zwX

[0788] LL0

[0789] f INyy H

[0790] 3X

[0791] F CH

[0792] F,cY 1

[0793] O v F

[0794] F

[0795] F

[0796] 0 N' lf l y Xf iA JLA X i H

[0797] F3C X-Y XHF3C vy F

[0798] F

[0799]

[0800] Tl Patent Applicatio Tn w Z O / LTGO-019 / 01 WO 36088 / 124 Y

[0801] /

[0802] ) o — \ y U. —

[0803] 0 O. NH2

[0804] X° Z IZ 0 Cl o v

[0805] A / A \ °-__ / \ P o — / AANl \ \ /

[0806] A jX0N li t Z \ "7- jj JI J VJ H M \ Z'A

[0807] 3Z

[0808] C ro \ / A X ' LL ZJ F ' X ' ^ X

[0809] x A. <#'- ) — \ XHF3CH4,

[0810] O J F I -n

[0811] F w;

[0812] o ■ Yr' yAp Y'AA'Y F F

[0813] i ) \ / \ / ) o | O _

[0814] O 0

[0815] JI d \O= I "" IZ —,.^., NH2

[0816] )f^ i —rr r'^

[0817] Y A * A 3A

[0818] X ] H 0 \ / " X X 4XmA °

[0819] F3C A ) — \ XHM |

[0820] 'Y'YF ^gX^xAp i “n Tt “n

[0821] F w W

[0822] F a O! z ✓ n

[0823] i I z

[0824] O / -fi\ Z I

[0825] \ / d \ / o \ / O

[0826] / / — —

[0827] o H / Y ° - / \

[0828] _ N-N 4 \o 0= ■^“ VN> o A A-N N — \

[0829] " / ) ° IE2:I / # “x \ X N— - AO=X X Y 55^ if "

[0830] / A 0 X Q>M: EZA / O0

[0831] / ) T T! /

[0832] Ji,x AA( o\= o=

[0833] F3C X JHX Z i z z

[0834] A 4 F3Hi z M X

[0835] z F3CHc ro Ki

[0836] XOx^'y 'Fvjr 'if

[0837] FF CF F

[0838] 8t 0 X yX F

[0839] F

[0840] Ov, NHZ(X NH2o Y o Y 1! J J

[0841] AX

[0842] Z'" X''M' '' VTH ' FsC-J I H / F,c: xi

[0843] O Y F HF2CO'' YA'F F OMe ox, NH2

[0844] o Y

[0845] A X

[0846] 1 J! J

[0847] X\H

[0848] F3c Y" Y-A.

[0849] O X YA F

[0850] F

[0851]

[0852] Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2.

[0853] Table 2

[0854] o? O^NH ll a. X o NC2® O o X / " XN

[0855] 1 L J

[0856] \ / X o t| XjN'X VN

[0857] XXHXJlHJ] H X^X^F yX X’^X^'F

[0858] F X-^ y^F F F F

[0859] 0 O NC Q.JZNH20

[0860] o I!N< N A x 4 i "~X~NJI x> \ / '" X N

[0861] F3C X \A H

[0862] 3JX H

[0863] F C X-A F3C X VA / H;. F3CAJ,„

[0864] x. A X

[0865] XA X^X^F x-'x’x \_, Xx.

[0866] O y F F F F F X Z~

[0867] / o A u-—

[0868] X ( \ _= z O-^NH2 0 Oou_ / zi #— o " V

[0869] ) o —

[0870] ( \ / x Z>r^N'z^'

[0871] XX H

[0872] FjcXjs. Jt F3C'

[0873] o o ' F3C

[0874] c

[0875] LU X^' y^F \-XAFxo'AyxFF F F

[0876] 0 0 O0u liNtZXf X xX

[0877] (5CJ J11 / J x.

[0878] X> H XX H HF2CO-!' J H >sjlHF3C' F3c'

[0879] X’^^X' X-XX'-p •C XA F x xFF F F F

[0880]

[0881] Patent Application LTGO-019 / 01WO 36088 / 124

[0882]

[0883] T1 Patent Application M

[0884] o, LTGO-019 / 01 WO 36088 / 124 ( / /

[0885] O \ / O /

[0886] } Z o — ^A CAO=HLJ'ZT' \O= " H22— # 0 0

[0887] 4 Y© / "nft IZ y \— o Y— a / \ ° — A CH " - 11 1 Q / Z

[0888] 2z X. ' / NJ €0

[0889] XfS) H LL.

[0890] F3C'

[0891] - 0 X YX F ^O'AV? A'F

[0892] F F

[0893] O,>, NH, 0

[0894] AHO o HO O A M

[0895] F3C,, / "> ■' "~N J j\fs; 1 M ZxAH>4^’ * O-f^F I A

[0896] F F F OH o 9 0 9

[0897] Njl"> NA h J z JZ A AA A X 1 H

[0898] AA J H A / S) i H F3C'

[0899] CM- MeOX^ / ^ ft X oXF ■. Cl.

[0900] FF,cA 0 l F \=Z / == \ °IF F F rt o— '

[0901] x. A / < K,. NH2Q NH2O OyNH2 o / ' o y o X

[0902] LU> <* 9 1

[0903] M N'S^

[0904] Is 11 J 1 X->

[0905] Z''~r 'NF. C, N HF2CO—< J H HF2CO— JLU?< / sj H < X

[0906] jfX

[0907] xo yFMeO^Y^FXO'^ 'X^'FF F F

[0908] O 0 ^

[0909] O A

[0910] F3CO— 1 [ H <f Y J H

[0911] \ / \ i.H

[0912] F F F

[0913]

[0914] Patent Applicati Xon LTGO-019 / 01 WO 36088 / 124

[0915] \ / 7 0 = you.x zi y- H

[0916] cxX-- O y { S b —

[0917] Xz

[0918] F3L Fio / " c L

[0919] X I H

[0920] oXxX

[0921] 1 F

[0922] 0 0 0 O^NH y. / x Jk / ^N2

[0923] X^N

[0924] M / X*^ I N / U AX eCk

[0925] z\ 1 Fl X iH

[0926] F3C F, C X\ / \.

[0927] 01 TlXU

[0928] j F3XC' X

[0929] I fSj l w J "

[0930] 30? I (

[0931] XFR)), " CF3X'^ X^F F X) / F

[0932] )0— ■■

[0933] O^NH20 0 £XX Q OH2 O I U L ® n 1 A

[0934] OM? ^0 X C A X / 1

[0935] Z'~X ~X -u n ilN / ftHX 1 H X I H / X^N'^^5^ rj«

[0936] F3C F3CV\O F3C z\ JH

[0937] , X\ zZ

[0938] Xxy^'-'F

[0939] F ^ 6 rK zr~ 1F o^-C L yOXu. zi- F A FFF F

[0940] \ ) o —

[0941] / \ / O^N O- 0 A H20 O y-S-NH2. NH2O

[0942] 0 y A^xx Ax^X JAA-N

[0943] 1 XX^N"^^ x. / X ^N'^'^ ■V-X ^ X 1H

[0944] X H X H

[0945] Z\ JuHF, C F3C \-A w, IX| 'S F3C X-'-'Y^

[0946] J (K)), '^X'OOF3I (Si CFg o^y r -X^CF:3A F

[0947] F F

[0948] O^NH2O NC CXZNH2O Q

[0949] n <$ 0 0 y

[0950] 01 Xjf 'N

[0951] / XNJX X I H X IH / X- N / X^N-^^ F3C F3C X^HX<s; I H FaC, VV% F3C A--- ■X^^<'OCF3 ^^ <)CF3

[0952] ■^^^OCFg

[0953]

[0954] Patent Application LTGO-019 / 01WO 36088 / 124

[0955] o X

[0956] 1 X JHxlA "

[0957] O' Y^' T F, A -3

[0958] i F

[0959] / \ fr o /

[0960] 2Y Q^ C SJ- —

[0961] O o H2N O<^. NH211 Ci / \ °“~~ q X N

[0962] Ji JL if iJN

[0963] U <0 (J'' '

[0964] L A >' X TVS)! H

[0965] F3C^\IX, 2! F3C' ^'’yAMe%YH H

[0966] OJ Ci- ■ " H F3c' X" -v / Y, _ _ X

[0967] \ A- o? ii | \ J i

[0968] n \ / i “■ / — / Ax

[0969] n / O-YY Y F \u_—

[0970] F

[0971] y / / fi i ° S) ( /

[0972] Y y Q1F

[0973] LLu. i 2Z23Z & X—" zi 4’--Z q /

[0974] ) ° — ■■

[0975] O-Yfy \ r O”~ O NC C0 0°^mj ^ ~~ 0

[0976] q y § I 40 ' X / / ’''• N->

[0977] / ) z “H— /

[0978] ; U. co • C>'' '

[0979] j

[0980] 1 X4

[0981] Xffi H X iHX I H

[0982] )

[0983] 1M C F3C X><„, F3C MeO' ''' yY _! ~ X

[0984] izY / \ ]oxYyYFy 3 iXLL- YyYXf.

[0985] Q-^Y ^F MeO'^y ^F \ ( d —

[0986] 1 p

[0987] i J FFJ^ x-- U. i ZTF I

[0988] 4 ^“ #

[0989] 2j> 4? i / ' 0 oO <

[0990] o;;3--- i coo / " O y O\= LL 1

[0991] A, C z zN1 IJ N> Y i H \ / ^Y N Yys; H " X!H

[0992] ' Q

[0993] O 'CF3

[0994] - Y FgC'^^^'OMe

[0995] oO^NH2

[0996] o Y XY / XNFsC^ / '■'Y'' h3G Y / ^NYXIHO^ Y^F G'^Y 'Y Jx F F J\

[0997] F F F

[0998] F

[0999]

[1000] Patent Application LTGO-019 / 01WO 36088 / 124

[1001]

[1002] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2A.

[1003] Table 2A

[1004]

[1005] Patent Application O O, LTGO-019 / 01 WO 36088 / 124 ( ) O —

[1006] O^NH2 O^NH2^\° ■n IZ—Qo y

[1007] 0I (f j!N

[1008] 3?i3zjL D CO,ND CO_

[1009] X(S) H

[1010] 3y<

[1011] F T « Fs> C3CHTl z

[1012] P O MeO ^ y^'F yQ / x

[1013] Fo= / /

[1014] u >xA oo LL - “

[1015] §\ X / _ / ZX A F

[1016] y 0LLV ff zi-_

[1017] / \ <0

[1018] ) ( O - O^NH2) ( b \ 7 O — —

[1019] 0 / \ ® „ O^NH2o o Y \X \> sSo T

[1020] AAXNH2X^X^OOo=T= iz~ o N yk X--"0

[1021] 3o oo r "A

[1022] D C / i MeO, I N 1 O, / ^XN-XA ^ Dx co3o «CO / ■'-X N'X'-x>

[1023] QA ’ sXX “■- > / s) H

[1024] M VR; H

[1025] F3C F3C' F3C

[1026] S >x* — - T j

[1027] □

[1028] X^ X> F / yy “■? o < 'YY'F

[1029] o o. 1 F F yu-~

[1030] ) / O —

[1031] O O O^NH27 i O — ' / \ ®

[1032] xX01 A> NH2£ Xo 'T|< ZZ— AX^N A Z Ph-A Z-XNXA MeO. r°

[1033] o H O' -\ H m vz—

[1034] <sK>- JN F3C' W-JV^.

[1035] x A 4 XI MeO y F z 'O' f' 'F

[1036] C 7 LL \ - F F

[1037] HJxo rx oz

[1038] “HyQ (=LL / -■^O''^- x> £ x s>

[1039] \ / ® ) ( o — \ / o — ) O - / \ ®

[1040] 2

[1041] tb°xo iT r O ° £ Cx ■"* 2: w z— \ ZZL_ CL X

[1042] „ O^NH=

[1043] A A

[1044] MeO'^Y^’F

[1045] F

[1046]

[1047] V I Patent Applicatio Xn LTGO-019 / 01 ) \ / > — \ J>^ WO 36088 / 124 _ / ,, c FI— Y ® X s <

[1048] \ / ® \ O ( — o., NH2 / \ ® / \ O —

[1049] F 0 Y

[1050] 1 §

[1051] / \ AX rY-0’

[1052] XXX vXF1 Ax XX-lJL'

[1053] LU

[1054] _ X OJ

[1055] MeO'^Y^'F 7^0Z

[1056] F y / CLL

[1057] f / / X O

[1058] y y \ y Q=U-Z: C-n°^NH= Q.. NH2G.,, NH2O^NH2o Y / \ 0) / \ O — ' o Y o Y \z s

[1059] XX*NXojN

[1060] FA if jjN° \ AHO

[1061] o J H 'Y 1 H MeO'^^'F MeoXyXp MeO'^Y^'F MeO'^'Y^'F F F F F

[1062] Q., NH2O^NH2O^NH2

[1063] o f o Y o Y o Y YYYN OXX YY^NMeO, A 'N Ax JL AP

[1064] MeO. z^Y^N

[1065] °' \ JHZs) H MeO,

[1066] H

[1067] F3C3SyVSJ H

[1068] F C F3C

[1069] MMeOOIX / F OXY'F

[1070] F -^^'OCFg F F

[1071] O-, NHZO^NH2 O^. NH2

[1072] o y o Y o Y o Y ZYS XX MeO vyjNft AX ft ft j JY XY

[1073] MeO. / '>z 'f< ''-zMeO, •''<'N‘Z^~XMeO. Z--Y'NX^ / MeO, Z^zC^zCs^? VR) I H l»s; H I H Zs; 1 H F3C' F3C FaC F3C WAyY AAOCF.. HO. JI X, HO. JL X,

[1074] Y" F AXY^F F F F

[1075] O^XNH2„ O^NH2„ o^

[1076] oNH* O..^NH2o Y Y o Y ZYYN

[1077] MeO.Fy COFv I iU XRJ H YX ^N

[1078] F30AQi HY p

[1079] C' \H\ X

[1080] x^x XyXFXY^-F

[1081]

[1082] F F F FPatent Application LTGO-019 / 01WO 36088 / 124

[1083]

[1084] Patent Application LTGO-019 / 01WO 36088 / 124

[1085] O °Y ~ O-^NH o VNH2,

[1086] 0 < / ' / 'N rf A X*

[1087] fi H 1 Ao F3CO^27' ^^ F3co^f yxN'K / H

[1088] F3C' V?

[1089] Eto M C

[1090] x m ' " Y- X

[1091] / F ^ z z- EtO" XcA 'Y\X 'F F f F F AC X / F

[1092] z\^ X -;Y A \\ o0

[1093] p %-NH2 „ o,. NH2O>., MH,

[1094] / ) 0 "r, NH 0 X"22 / o 32= YXA '

[1095] AA^PV== / m / /

[1096] X X“\ \ ClT i CO X2 z •—F C / ...66 F3C,41 XL AF ft,unx mb^ FScots0- r X w m-* ’ SS7 N ' M LL 2:3J H

[1097] MeO MeO V-\ u.oXXB

[1098] CM / / A A Ars r X ao" V<^ ^ z z— <"\A r< X FA’AA, \ # \ MeO 2 F MeO / F1F F r r

[1099] / zV \- 0LL

[1100] ( OZ zrZ=

[1101] „ 0^X. NH, „ O>., NH,OO^-NHJ 0 Y

[1102] nA.KJL X X X jz / ° [j^ Y [ \ 9!j X A [f llNMeOz^. JL 1 J MeO A Y A

[1103] 0

[1104] F3C^ Jh0X / A' o c Y< X J LL

[1105] A 3 'oXXN tFy^ T rf!F ZA Z““

[1106] A / v /

[1107] { 6 \=0O^NH2

[1108] 0 °YNH2f zx O<"

[1109] yC F3C Jl^Xy cy / ° ~ FjCO-fE^ y 'H ■"! A

[1110] HO V-*..t <> Q;c CO n LL 22 JY \ Fy °"\=A

[1111] 1Fr>0OyNH20 °yNH20OVNH2cA

[1112] > Ac? ^v^-CX^.73; 1 AFsVr O

[1113] HO' \ HO ' - JQ T y MeO< R>jAj Y> rXF

[1114] F

[1115]

[1116] Patent Application 71 i ®,

[1117] £ i LTGO-019 / 01 WO 36088 / 124

[1118] AL O^NH2„ CK, NH

[1119] o Y2

[1120] zOOVNH2L L l° —

[1121] S A. Sf A A - N ( iH I V 2 —......66

[1122] A \ JA n i ZEMi F3CCX? F3C^€CH

[1123] MeO J J Med YA M C

[1124] X Med Y S

[1125] Z AA / XF F F F S A

[1126] ( O ZI,7 ft -----0% / NH2p A A^- / \ 0 n ANH2

[1127] AAb > A! A L v cLit A ' N, z..66YLL C’ -CoF3Q / \, A AS F3c O" AL-JN o' AL HMJ LL

[1128] MeO J %FC / LM. O-A

[1129] AHM CF^F Y 6

[1130] X

[1131] / X Fxz z X~ / F M S

[1132] F F F F

[1133] / L—A \- / XS 0M a=0OYNH2O °VNH2

[1134] , / AA “■ '

[1135] YM \ LL- A 1

[1136] JL 6 <6

[1137] g u_r t ° ( I A" A HO z. A St ^L o^ If

[1138] ^L O / O1A i 8

[1139] FA 2 oV-" LA

[1140] FvAS LL.

[1141] \p

[1142] " sn

[1143] FAL / F T1 F F X F O \ Zz—

[1144] o

[1145] p>

[1146] / 4 _ A < / ~ o A Ox S V£

[1147] K AC L < >o)ZI= / xHO^LO A A A ■"\ O C \\4 >o iz >js i ' > <? /

[1148] X LL 6Q!iS o / F

[1149] F

[1150] „ 0< X, NH20 °yNH2

[1151] o 'V

[1152] ^66

[1153] F JA?

[1154] °AA

[1155] F 'Cl M t F

[1156]

[1157] Patent Application A "p LTGO-019 / 01 WO 36088 / 124; x

[1158] \ z o

[1159] 0 \ \ \\ z

[1160] o / > / IZ' '=

[1161] ”Af < -. AAxz z—

[1162] Z M P'^€O XF J A

[1163] C' \x-''„ / r F F

[1164] ~ o., NH „ O^NH 020 °yNH2O 'T?

[1165] ^-W / 'ANXU AA F3CO^ J P" < 1 H pn / ^r H

[1166] F-{ vJ,HAVA " -A^ X )FHO jnFHOXA ' o V\

[1167] / F CiN «- T)

[1168] X T Ti a 1 r i<s>YS F;x\ Z Z Z Z—— \ F F

[1169] yt \ o- ^ AO■ ■^O- L I T

[1170] 0°<yNH2 ^ O( \ zx z0

[1171] :OyNH

[1172] "2° 0nCK Y, NH2i j. \ J ^ '2—

[1173] I fiI ° °r LN

[1174] A X J h J^ \ VOZ T^

[1175] iz\. A? / / 70= PY T

[1176] \ & < A° " M 'F- / °< V F~^ \-J,H\ -n

[1177] o O o F-A \— X

[1178] m 9 0

[1179] F HO^Z z

[1180] A LL Li_ n \ V / F HQ. J-!

[1181] / (T?7) pA \ “ rj

[1182] / p 8 / (AA i v F F N I X F F

[1183] T

[1184] ( / o —Zy ®.

[1185] A < 0

[1186] 0 Oes -NH,

[1187] n A(L) A P2„ CK.,wX zc'? <= NH2O X 0 °yNH2 / / \A \V 07ZI= ° ' p Y Y, o44==

[1188] / \^N AA A

[1189] ) k)' A / X"- -; ■ A N A A. \(5u Ao A\^

[1190] •A

[1191] K AJ HF2CO-<< iHF CO(R\^LHd.?5 * 2

[1192] o OFHOAA ^VA”'mxz LL O < N

[1193] £J* \A^-ACz^| z X Ll_ a 1 r M F

[1194] n kJ0< V X 'NH2o°YNH2

[1195] H2° A ^vW

[1196] F C ^J H. M«e AO J H

[1197] Ac,HO\^4 /

[1198] A c AA / A r

[1199]

[1200] FPatent Application LTGO-019 / 01WO 36088 / 124

[1201]

[1202] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2B.

[1203] Table 2B

[1204]

[1205] Patent Application LTGO-019 / 01WO 36088 / 124

[1206] O 0 p 0Hz^xf^N

[1207] Z jjNx jjz^NX / ^■■''^N / ^ /

[1208] JX JI H >4s)

[1209] F3H

[1210] C" F3C JX(SJ 1H

[1211] " F

[1212] F F F

[1213] 0 0

[1214] o OXX, NH20 OX y. NH22Z^Af^N

[1215] / J H T^P1H l ' 1^ F3C. / '-x.>'

[1216] H \ / " '< ' N x.yxX F3C X. I H

[1217] X22

[1218] 'OA / '> XF HO<|_F J no, Y J V'M! 'r

[1219] F C / J

[1220] F Y / j 1 -L\ ~—~ — \ / \AXXy\ XY\

[1221] 0 LL — F F

[1222] o— Xx

[1223] o (A70 NO 0 MeO y " u 1

[1224] o r) / o' '

[1225] LL, C '

[1226] LL Z jjNX / C " p / J H F3CV^'ANXq

[1227] S ©KZ- Z-A CJ / “■QCF. MeO’^^^^'F ^^O=> u. ZT— ^~~ F F;o / —x

[1228] A / OXA O O

[1229] o V zXz^ tno / "'01 Z ^f^NNA / XNJL XAC, Jl

[1230] x Z JLZ^XZ Z-xZ ^NU'X 'M' ''' IINH2I AZ JX Jj H X, IH0 x / X N

[1231] Z\ JlHz\ JH

[1232] '

[1233] XxoJx'p ^xF ' y^F

[1234] -X^XX^-0CF3,xX^X0CF^ F

[1235] F

[1236] O 0O nOx -NH, 11 ^®,o’JOVNH29 1 X'''Z ' N

[1237] AZL

[1238] AfSJ H Faq. ^xXL-AJFse. J U F3c' H Xs-’ 1 ” Xr ^^F HQ. J J

[1239] F Y^'-cHVQ

[1240] F > F AF F

[1241]

[1242] Patent Application LTGO-019 / 01 WO 36088 / 124 zA / K;=--- V r, n. (, ZX---■'' Az W= ° 0 CN 0^XNH2

[1243] o ’V o >

[1244] A

[1245] oz

[1246] LL X J, H

[1247] z\ JH

[1248] MeO'^^'F ^oXP^F

[1249] F / ' /

[1250] O ) — ■■ F

[1251] Y (O)= "nzz —\ /

[1252] 0 y / # o V o_- O^NH2O-^-NUg o 'Y O Y T N>

[1253] ?4s; H 7\fs; H F3C,, / Y '"kB

[1254] jy

[1255] F3C' F3C' s; H

[1256] F3C' ^ -yY

[1257] ^O'^ y^F ^Q-^Y^F

[1258] F F F F

[1259] O HO O HO 0 O 0 HN'Yjx^N

[1260] 60 ^1 11n / / ~'' -' "'N' '~xF3C YY^N XX

[1261] Tysj H OX iH

[1262] F3C' F3C"X- V^s. F F3cCX V— J %,H

[1263] ' X U X j r X MeO X y F

[1264] F F F F

[1265] 0 0 O^NH2O~^. NH2

[1266] Ij O Y

[1267] ,>w / '>No 1 AoNX> Y JXAM Il JlX. N I' A X N' Y o. ''N / >■■'' " N' A A O

[1268] Ap H ><(s; H A XX F3C,, / >•■ N F3C" - F3C TVs; H

[1269] F3C' JA J.H'" O' O' 'AF 'X. Q'^Y^F ^0X xXFF F F F

[1270] O O^NH2O^NH2o o o

[1271] ° 1

[1272] AfANNHi kJ [f j]N

[1273] / \ / ^r N Xo

[1274] \ X J H Xw H < X 1Hx / \ JHF3Y ^JQ^F 'X‘Ox^P''F

[1275] F F F F

[1276]

[1277] Patent Application LTGO-019 / 01WO 36088 / 124

[1278]

[1279] Patent Application LTGO-019 / 01WO 36088 / 124

[1280] / / O\ f w~X / k~ "■ 2 Q^r / - 0 0 H2N

[1281] oO NC 11 _CI ___ - / ■ ' N A'X N

[1282] J

[1283] \ N ' f t x

[1284] 3nA IHXw 1 H LL

[1285] F C X I H

[1286] F3C F3C

[1287] 2_CM

[1288] ^o'^ y^F t:o r _\ X

[1289] F F ' i!\ \

[1290] \u- \ z / OOT- u- °—Z’ F

[1291] \ / _ \ 1 y oO=< (u. -*-Z zi - A.f- - / f / / / A '0~

[1292] 0 0

[1293] ) f 0— — '

[1294] y xy

[1295] / X 1HAHU CO ex A

[1296] .

[1297] F3CVV^ F3C ^'"ps

[1298] MeO‘ / yx^‘F

[1299] A, F { 7z- F F F X

[1300] ,, J—. X

[1301] f

[1302] LL.

[1303] V

[1304] ) ( 0 O-^NH2O^ / NH2

[1305] 0 0 X o ~f

[1306] f jj N F3C*

[1307] \ c A / S; 1 H TVS) H XMH

[1308] F3C' V'A,^, F3C'

[1309] j w?

[1310] O^ Y

[1311] ZI4 F3C XX OMe V y 'F \O= u- ' F

[1312] ! F ° 1 F f \XLLA

[1313] y { O —

[1314] 2 ^ LL 4

[1315] OXNH20 'S

[1316] ] H

[1317] F3C

[1318] O'XjjA'F1F

[1319]

[1320] Patent Application LTGO-019 / 01WO 36088 / 124

[1321] OXNH 0 Q OigsN

[1322] n ° (VA sNHH

[1323] ANH

[1324] Jl jjNon, Z,

[1325] TVS) H TVS) H "i x N

[1326] Xw>t, / ''''f1' N F3C' F3C' Xw

[1327] F3C ]H H

[1328] F3(f

[1329] 'FO'XTxF O'A^F o'' yZ<F1 F 1 F

[1330] F 1F

[1331] H H O NO O<_. NH2O~.. xN-- O;. xN~- 0 y 0 Y 0 y

[1332] AAN

[1333] [f jlNH liNF3C / AN^

[1334] YA H F3C A A- t,.H

[1335] FaC" \ J

[1336] XfXH H

[1337] F3°v,yjy

[1338] x x'-0-s. XLA

[1339] 0 -X' F

[1340] !F 1 F F F

[1341] O^NHs CV / NH2OX XNH20 ° 1 0 Y

[1342] XY^NHX ZALN>^AO x, X Y JI

[1343] XH F®c\ XH H

[1344] F3F3C' A

[1345] C xH

[1346] A-y.

[1347] ,0. JL X, X x-V, XX^XYX' ''.F, ^X° \x^ZX\^< AXF

[1348] F F F F

[1349] O^ XNH2

[1350] NXA NXN-^. O Y O^XNH2

[1351] O 1 0 Y Q Y IL X ^ xQX

[1352] (A FsOt / '■'-> X'N F3C. / ~^. -''^'N TVS) H YR; 1 H

[1353] TVS) H pvf?) 1 H F3C- V-S x-y

[1354] F3C' ^'"yX

[1355] OA XXFQXA^P O'A’^F

[1356] 1 J i X\F1F

[1357] i

[1358] O~ «NH2

[1359] 00

[1360] 0 X n

[1361] A^N^ANH

[1362] N^ Zxx £ XX

[1363] >fa) 1 H z^-r ’N \ / ^VA'N'AS^ TVS) H A I

[1364] TVS) H F3C'H

[1365] FgC Y-A. / y F3c'V>-,.xy X*X

[1366] 1 F 1 J EtO' y^'F F

[1367] 11F r

[1368]

[1369] Patent Application LTGO-019 / 01WO 36088 / 124

[1370]

[1371] Patent Application LTGO-019 / 01WO 36088 / 124 \ JAzo — 1xz / ) \ \’ O — ■ —

[1372] C°^ ‘T17' — / / -ny=:u- / W X zr— > °" VX xy o O_ 0 o o Ox > NH2fA VCZ / \ °°=:x°O1=Wi:o ’L n X o xI! / X / °11-233"OC ■”11V JS a.- i Z ( )\ O —

[1373] 1 u)« r o °— —

[1374] jl 1

[1375] I L V _Q

[1376] 'Nz$ ' X

[1377] M \ A'-X^N' CO / o " \ H o A® 1 HF3C< LL co CO c> X

[1378] X

[1379] FoC JWJ ] H LL LL

[1380] „RG" T

[1381] OX yL. F l

[1382] XO' y<'F

[1383] F D3COzyY‘ FFF

[1384] O. XX

[1385] oNH2

[1386] F3CyA [ H

[1387] XM C CM

[1388] T

[1389] , 2A Xk H 2-*—

[1390] ?s0-YYF

[1391] y V473X / o i — — >

[1392] 1 F

[1393] / \ zX 6—

[1394] X / QT) Ll_ / LL— V —ZI~ 6 ■”X y 32Z 3 - J,o2Z —

[1395] p ) ( o o o / --— — — o 0< XZ-NH2 O^NH2o / O W “H- o y y JX^vzNH2X 'Z y. T \s 1 jf ON / uJ C>*'' ' * n cn H ( 1 J LL. LL > JR; H

[1396] F3C' F3C F3C'”< J H F3C— ( 1 H

[1397] M C

[1398] r '•o' y A

[1399] z

[1400] F (\ F _X^OYZAXF

[1401] / WJ / ) o — — F F

[1402] O / =U_ / A ZI— °~ XA\ ^n.

[1403] p

[1404] ) \ o °~ — O^Y^HZ O^NH2 ' / / O W= ~n> —.

[1405] o y

[1406] % zz- o / " FxyKX^N «

[1407] u.

[1408] 1 11N F3CY^YANXX

[1409] | H

[1410] XJ "

[1411] O'^ y^F

[1412] i t 1

[1413]

[1414] Patent Application LTGO-019 / 01WO 36088 / 124

[1415] ^ LUZ7!^- Q ) ( o — —

[1416] v° \ / —

[1417] oO^_-NH HJ>2

[1418] Oo> ) ( b — 0 X tH ’ ' ' ' / z' ArA XZz- X M M A JU u.

[1419] F3C X-HF3C*

[1420] M C: X: w

[1421] HO. JI ( / VX i F i £ X / Onc= U-- F

[1422] _

[1423] °

[1424] A Q / LL ZX- —A ' *C

[1425] Q; U_- — —

[1426] ( O— —“ O^NH2O.yNH, 7 f i O — ° I

[1427] Q Z" '

[1428] Li_ io co A’^ (i llN

[1429] Lt? '

[1430] X M C F3C'HX#

[1431] 2 Z _ _ T F3C

[1432] \ Zw~

[1433] z O O^' Y^F Q> XZYLLF

[1434] /

[1435] J ^o=3u, ZI— / AF

[1436] o_ A — '

[1437] ) f O — 'x

[1438] ^ x5 o rN'

[1439] An“

[1440] c co c t)> x <* ~ o

[1441] U. LL

[1442] X / ^'Z^NA'

[1443] CM T: X?) H

[1444] , Z i

[1445] Z \

[1446] 1F"CY Xl

[1447] \ / Q=^ U-A io— ° F

[1448] ) ( c i —

[1449] I \? A° — '

[1450] r-NH N-NH N-NH O XJ X o i-' / / I * £, N / / A £; LL IL X A.NO J

[1451] ° o x z^r 'N'^- H £ 15!i X*N

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[1462] Patent Application LTGO-019 / 01WO 36088 / 124

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[1510] Patent Application

[1511] LTGO-019 / 01WO 36088 / 124

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[1564]

[1565] Patent Application LTGO-019 / 01WO 36088 / 124 In another aspect, the invention provides inhibitors of a voltage gated sodium channel Nav1.8, Tire inhibitors may have a defined chemical structure, such as the structure of any of the compounds described above.

[1566] 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.

[1567] 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, 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, 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 (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 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 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 pain, post-stroke pain, post-surgical pam, 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 glandPatent Application LTGO-019 / 01WO 36088 / 124 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, 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.

[1568] 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 those described above, in a subject.

[1569] Detailed Description

[1570] Definitions

[1571] 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 described subject matter belongs. The definitions provided below are intended to supplement and illustrate, not preclude, the definitions that would be apparent to one of ordinary skill in the art upon review of the present disclosure.

[1572] 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 “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 group substituent may have another substituent off it, such as another aryl group, which is further substituted at one or more positions).

[1573] When the term ‘'independently selected” is used, the substituents being referred to (e.g., R groups, such as groups Ri, R. and the like, or variables, such as “m” and “n”), can be identical or different. For example, both R< and R? can be substituted alkyls, or Ri can be hydrogen and R?. can be a substituted alkyl, and the like.

[1574] The terms “a,” “an,” or “a(n)5” 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.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different.Patent Application LTGO-019 / 01WO 36088 / 124 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.

[1575] 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 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 principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.

[1576] Unless otherwise explicitly defined, a “substituent group,” as used herein, includes a functional group selected from one or more of the follow ing moieties, which are defined herein.

[1577] The term hydrocarbon, as used herein, refers to any chemical group comprising hydrogen and carbon. Tire 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, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-buty l, ethynyl, cyclohexyl, and the like.

[1578] Tire 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., C1-10means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7. 8, 9, and 10 carbons). In particular embodiments, the term “alkyl” refers to Cu 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.

[1579] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, 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.Patent Application LTGO-019 / 01WO 36088 / 124 “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 8 carbon atoms (i.e., a C1-8alkyl), 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.

[1580] 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 but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. There 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.

[1581] Thus, the term “substituted alkyl” includes alkyl groups, as defined herein, in which one 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.

[1582] 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 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 quatemized. Tire 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 winch alkyl 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.

[1583] 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’R”. -NR’R”, -OR', -SR, -S(O)R, and / or -S(O2)R’

[1584] “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 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 oxy gen, sulfur or substituted or unsubstituted nitrogenPatent Application LTGO-019 / 01WO 36088 / 124 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 cyclopentyd, cyclohexyl, and cycloheptyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, and the like.

[1585] The term ‘'e cloalky ialky 1,” 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 Cl -20 alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[1586] 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.

[1587] The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of from about 3 to about 15 ring members in which at least one ring member is a heteroatom, such as N, 0, or S Unless otherwise specified, a heterocyclyl may be saturated, partially saturated (i.e., have one or more double ortriple bonds), or aromatic. Examples of saturated and partially unsaturated non-aromatic heterocyclic groups include, but are not limited to, 3 -oxetan 1, 2-oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl. dihydropyranyl. 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, isothiazolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the aforementioned groups.

[1588] 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 (0), or sulfur (S). Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3 -morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2 -piperazinyl, and tire like.

[1589] 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 and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. Examples include, but are not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-Patent Application LTGO-019 / 01WO 36088 / 124 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 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.

[1590] 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-(L4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[1591] The term “alkenyl” as used herein refers to a monovalent group derived from a C2-20 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, l-methyl-2-buten-l-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[1592] The term “cycloalkenyl” as used herein refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[1593] Tire term “alkynyl” as used herein refers to a monovalent group derived from a straight or branched C2-20 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyT’ include ethynyl. 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.

[1594] 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. Tire alkylene group can be straight, branched, or cy clic. Tire alkylene group also can be optionally unsaturated and / or substituted with one or more ‘'alkyl group substituents.” There can be optionally 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-, -CH2CH2CH2CH2CH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2)q-Patent Application LTGO-019 / 01WO 36088 / 124 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-).

[1595] The term “heteroalkylene” by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH- ( H - For heteroalkylene groups, heteroatoms also can occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedi oxo, 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 formula -C(O)OR - represents both -C(O)OR -and -R’OC(O)- The term “spirocycl 1” 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 rings having a single carbon or other atom, e.g.. nitrogen, in common.

[1596] 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. lire term “heteroaryl” refers to and groups (or rings) that contain from one to four 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 quatemized. 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, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyI, 5-isoxazolyl, 2 -thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2 -thienyl, 3-thienyl, 2-pyridyI, 3-pyndyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5 -isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 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 divalent forms of and and heteroaryl, respectively

[1597] 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.Patent Application LTGO-019 / 01WO 36088 / 124 Each of the above terms is meant to include both substituted and unsubstituted forms of the indicated group. Optional substituents are provided below.

[1598] Substituents can be one or more of a variety of groups selected from, but not limited to: -OR’,:::O, =NR =N-0R’, -NR’R” -SR; -halogen, -SiR’R’ R”. -0C(0)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 Cl-4 alkyl, and -NO2 in 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-limiting examples of substituents include (Ci-Cejalkyl, (C2-C8)alkenyl, (C3-C8)alkynyl, halogen, halo(Ci-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)(Ci-C6)alkyi, -C(O)NR’R”, -S(O)(Cl-C6)alkyl, -S(O)NR’R”. -S(O)2(Ci-Cejalkyl. -S(O). NR R”, -O(Ci-C6)alkyl-S(O)(Ci-C6)aikyl, -O(Ci-C6)alkyl-S(O)NR’R”, -O(Ci-C6)alkyl-S(O)2(Ci-C6)alkyl, and -O(Ci-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.

[1599] 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 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, l-pyrrolidinyl and 4-morpholinyl. From the above 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., -CF3and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like)

[1600] 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) —. -S(O)2NR’- or a single bond, and r is an integer of from 1 to 4.Patent Application LTGO-019 / 01WO 36088 / 124 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)? NR’-. The substituents R, R’, R” and R” may be independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[1601] 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)-, 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.

[1602] lire terms “aikoxyl” 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 C1.20 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo -hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl. and the like.

[1603] The term “alkoxy alkyl” as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl or an ethoxymethyl group.

[1604] “Aryloxyl” refers to an aiyl-O- group wherein the aiyl group is as previously described, including a substituted aryl. The term “aryloxyl” as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo, or aikoxyl substituted phenyloxyl or hexyloxyl.

[1605] “Aralkyl” refers to an aryl -alkyl -group wherein ar. 1 and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[1606] “Aralkyloxyl” refers to an aralkyl-O- group wherein the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5CH2-O-. An aralkyloxyl group can optionally be substituted.Patent Application LTGO-019 / 01WO 36088 / 124 “Alkoxycarbonyl” refers to an alkyI-O-C(=O)- group. Exemplary- alkoxy carbonyl groups include methoxy carbonyl, ethoxy carbonyl, butyloxy carbonyl, and tert -butyloxy carbonyl.

[1607] “Aryloxycarbonyl” refers to an aryl-O-C(:::O)- group. Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl.

[1608] “Aralkoxycarbonyl” refers to an aralkyl -O-C(=O)- group An exemplary aralkoxycarbonyl group is benzyloxy carbonyl.

[1609] “Carbamoyl” refers to an amide group of the formula -C(=O)NH2.

[1610] “Alkylcarbamoyl” refers to a R'RN -C(;::O) group wherein one of R and R’ is hydrogen 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.

[1611] The term “carbonyldioxyl,” as used herein, refers to a carbonate group of the formula -OC(=O)-OR.

[1612] “Acyloxyl” refers to an acyl-O- group wherein acyl is as previously described.

[1613] Tire term “amino” refers to the -NH group 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 tenns “acyl amino” and “alkylamino” refer to specific N-substituted organic groups with acyl and alkyl substituent groups respectively.

[1614] 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 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 -NUR’ 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 independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR’R”R”’, 'herein 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)k where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidine, trimethylamino, and propylamine.Patent Application LTGO-019 / 01WO 36088 / 124 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.

[1615] 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.

[1616] ■‘Acylamino” refers to an acyl-NH- group wherein acyl is as previously described. “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.

[1617] The term “carbonyl” refers to the -C(=O)- group, and can include an aldehyde group represented by the general formula R-C(=O)H

[1618] The term “carboxyl” refers to the COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.

[1619] Hie term “cyano” refers to the -CN group.

[1620] The terms “halo,” “halide.” and “halogen” refer to fluoro, chloro, bromo, and iodo groups.

[1621] 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(C 1 -4)alkyl” includes, but is not limited to, tri fluoromethyl. 2,2.2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[1622] Hie terms “halocycloalky” and “cyclohaloalkyl” refer to a cycloalkly group with one or more halogens.

[1623] The term ‘‘hydroxyl” refers to the -OH group.

[1624] The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group.

[1625] The term “mercapto” refers to the -SH group.

[1626] The term “oxo”' refers to an oxygen atom that is double bonded to a carbon atom or to another element.

[1627] The term “nitro” refers to the -NO? group.Patent Application LTGO-019 / 01WO 36088 / 124 The term “thio” refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.

[1628] The term “sulfate” refers to the - SO4 group.

[1629] The term thiohydroxyl or thiol, as used herein, refers to a group of the formula -SH.

[1630] More particularly, the term “sulfide” refers to compound having a group of the formula -SR. The term “sulfone” refers to compound having a sulfonyl group -S / OdR’

[1631] The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R and encompasses both enantiomers.

[1632] The term ureido refers to a urea group of the formula -NH-C0-NH2.

[1633] 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 where such isomers and mixtures exist.

[1634] 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 arc encompassed within the scope of the present disclosure. Tire 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 other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[1635] 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 diastereomenc mixtures of the present compounds are within the scope of the disclosure

[1636] 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 fonn to another.Patent Application LTGO-019 / 01WO 36088 / 124 Unless otherwise stated, structures depicted herein are also meant to include compounds 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 by13C- or14C-enriched carbon are within the scope of this disclosure.

[1637] The compounds of the present disclosure may also contain unnatural proportions of atomic 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 (’ 'll or carbon-14 (l4C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[1638] The compounds of the present disclosure may exist as salts, and particularly as 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. (-t-)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared bymethods known to those skilled in art. Also included 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 acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic. or 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 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.

[1639] The neutral forms of the compounds may be regenerated by contacting the salt w ith a base or acid and isolating the parent compound in the conventional manner.

[1640] The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.Patent Application LTGO-019 / 01WO 36088 / 124 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 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.

[1641] 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 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 m 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.

[1642] 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 cd. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups.

[1643] 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. 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.

[1644] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically 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.

[1645] Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former arc stable and can be subsequently' removed by metal or pi-acid catalysts. For example, an ailyl-Patent Application LTGO-019 / 01WO 36088 / 124 blocked carboxylic acid can be deprotected with apalladium(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. 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.

[1646] Compounds

[1647] Tire invention provides compounds that modulate, e.g., inhibit, the activity’ of voltage gated sodium channels.

[1648] In one aspect, the invention provides a compound of Formula (XIII):

[1649]

[1650] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein:

[1651]

[1652] X2= CRi2, N, orX+-O';

[1653] X3or X3= CRi3, N, or N+-O-;

[1654] X4= X, N‘-O-, or CRI4;

[1655] X5= CR15; N or N+-O-;

[1656] X6= CRi6, N or X+-O\

[1657] Z1is CR4bor N;

[1658] Z2is CR4cor N;

[1659] Z3is CR4dor N;

[1660] Z4is CR4eor N;Patent Application LTGO-019 / 01WO 36088 / 124 R1a, R1b, R2b, R3a, and R3bare independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, C3-C6cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluormated, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-Ce alkenyl. Cz-Cealkynyl, -[C(R6)(R?)]m-C3- C g -cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(Rb)(R?)]m-C3-C8 heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0. S, and N;

[1661] wherein any of said alkyl or alkenyl moieties in R1a, R1b, R2b, R3a, R3bmay be further substituted with one, two, three or four R5substituents, where each R5is independently selected from halo, Ci-Cg alkyl, Cs-Ce cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Cs alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, and m = 0 to 2;

[1662] R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo. C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C7, alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-C« haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, C1-C6-haloalkoxy wherein the C1-C6alkoxy may be fully or partially halogenated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Cs alkyl chain may be folly or partially deuterated, cyano, -S(O)qRs, -P(O)(Ct-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R, C(=NR6;,)NRR7, -C(O)NR6R7, -NHC(=O)-alkyl - NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)rnC(;::O)NR, R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C'3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein said Ci-Cb haloalkyl, Ci-Ce alkyl, Ci-Ce alkoxy, cycloalkoxy, Ci-Ce haloalkoxy are optionally further substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C4-C4alkyl, or Rssubstituents; wherein R8is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;

[1663] wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy;Patent Application LTGO-019 / 01WO 36088 / 124 R6and R6aare individually and independently selected from the group consisting of H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;

[1664] R7is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;

[1665] R12is selected from the group consisting of hydrogen, OH, -OC1-C6alkyl, -OC1-C6alkoxyl, C1-C6alkyl, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[1666] R13, R14, R15, and R16are independently selected from hydrogen, deuterium, hydroxy, oxo, -C(O)NR6R7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR5R7, cyano, halo, Ci-Cealkyl, deuterated Ci-Ch alkyl wherein the Ci-C6alkyl chain may be frilly or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloCi- i alkyl wherein the C1-C4 alkyl chain may be folly or partially halogenated, C4-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or folly fluorinated, Ci-C4alkoxy, C4-C4 deuteroalkoxy wherein the C1-C4 alkyoxy chain may be folly or partially deuterated, cycloalkoxy -S(O)qR-5, -NR6NR7, -NHS(O)2Rs, -C^NRsONRsR?, -NHC(=O)-Ci -C4-alkyl, - NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cj-Cs cycloalkyl, Cj-Cs cycloalkenyl, substituted or unsubstituted Ce-Cio aryl, substituted or unsubstituted Cs-Cs heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[1667] R20is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6deuteroalkyl wherein the alkyl may be fully or partially deuterated, haloalkyl wherein the alkyl may be fully or partially halogenated, fluoroalkyl wherein the alkyl may be fully or partially fluorinated, C3-C8cycloalkyl, C3-C8fluorocycloalkyl wherein the cycloalkyl may be fully or partially fluorinated, and substituted or unsubstituted -[C(R6)(R7)]m-Cj,-Ci o-aryl;

[1668] m is 1-5;

[1669] n is 0-3; and

[1670] q is 0-2.

[1671] In another aspect, the invention provides a compound of Formula (XIV):Patent Application LTGO-019 / 01WO 36088 / 124

[1672]

[1673] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R1a, R1b, R2b, R3b, R4a, R20, Z1, Z2, Z3, and Z4are defined above; and R2ais independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, C3-C6 cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain ma) be fully or partially deuterated, Ci-Ck fluoroalkyi wherein the alkyl chain may be fully or partially fluorinated, C-Cs alkoxy, Ci -Cb deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially- halogenated, Ca-Cs alkenyl, Cz-Cs alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R,)(R?)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S. and N..

[1674] In another aspect, the invention provides a compound of Formula (XV):

[1675] O

[1676]

[1677] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R1a, R1b, R2b, R3a, R3b, R4a, R20, Z1, Z2, Z3, Z4, X2, X3, X4, X5, and X6are defined above.

[1678] In another aspect, the invention provides a compound of Formula (XVI):Patent Application LTGO-019 / 01WO 36088 / 124 o

[1679]

[1680] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R1a, R1b, R3a, R3b, R4a, R20, Z1, Z2, Z3, Z4, X2, X3, X4, X5, and X6are defined above.

[1681] In certain embodiments, in compounds of Formula (XIII) and Formula (XIV), Ring A is selected from the group consisting of:

[1682]

[1683] Patent Application LTGO-019 / 01WO 36088 / 124

[1684]

[1685] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), wherein Z1is CR4b; Z2is CR4c; Z3is CR4d; and Z4is CR4e.

[1686] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), R4ais selected from the group consisting of -CF3, -OCH3, -OCH2-CH3, -OH. -OCD3, -CH3. -O-cyclopropyl, -CH2-OH, -CHF2, -CH-(CH3)2, -O-CHF2, -CH(CH3)-OH, -O-CH(CH3)2. and -O-CH2-CH2-O-CH3.Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, in compounds of Formula (XIII), Formula (XIV). Formula (XV), and

[1687]

[1688] In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV). and Formula (XVI), R?.o is selected from the group consisting of C1-C3 alkyl, partially or completely halogenated C1-C3 alkyl, partially or completely deuterated C1-C3 alkyl, 6-membered ary 1, and partially or completely halogenated 6-membered aryl.Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, in compounds of Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI), R20is selected from the group consisting of -CH3, -CF3, -CHF2, -CDs, -CFF-phenyl, phenyl, fluoro-phenyl, and -CH2-CF3.

[1689] In another aspect, the instant invention provides a compound of Formula (I):

[1690]

[1691] or a tautomer thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: —represents a single or double bond;

[1692] X - C(Ria) (Rib)

[1693] X

[1694]

[1695] 2= CRi2, N, orN+-O\

[1696] X3or X3= CR13, N, or N+-O-;

[1697] X = N, N -O', or CRI4;

[1698] X5= CR15; N or N+-O-;

[1699] X6= CR16, N or N+-O-;

[1700] Ring B is Cs-Cio aryl, Cs-Cs heteroaryl, monocyclic, bicyclic, or spirocyclic cycloalkyl ring, or a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains one or more heteroato s independently selected from N, 0, and S, and wherein the B ring is substituted with one or more R4 substituents;

[1701] Ria, Rib, R a, R2b, Ria, Rib are independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, Ci-Cb cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be fully or partially deuterated. Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated. Ci- Ce alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be frilly or partially deuterated, haloalkoxy wherein the alkoxy may be folly or partially halogenated, C2-C.6 alkenyl, C2-Ce alkynyl, -[C iXROJm-Cs- Cg-cycloalkoxy, cyano, -[CfReXRrXm-Cs-Cs cycloalkyl, -[ R^XRrXm-Cs-Cs cycloalkenyl, -[CfRsXR?)]™-N(Re)(R7), or -[CXReXRrXm-C -Cg heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0. S, and N:Patent Application LTGO-019 / 01WO 36088 / 124 wherein any of said alkyl or alkenyl moieties in Ria, Rib, R2a, Rib Rsa, R?b may be further substituted with one, two, three or four Rs substituents, where each Rs is independently selected from halo, Ci-C? alkyl, Cs-Ce cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkvl wherein the alkyl chain may be hilly or partially fluorinated, C ■ -C6alkoxy, Ci-Cg deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, and m:::0 to 2;

[1702] wherein any of Ria, Rib, R. R2b, Rsa, or Rsb may be optionally connected to another of Ria, Rib. R2a, R?b, Rs®, or R;,b through individual alkyl, fluoroalkyl, or alkoxy moieties to form a spirocyclic ring;

[1703] R4 is hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluormated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Ci-Ce haloalkyl wherein the alkyl may be folly or partially halogenated, Ci- C galkoxy, C Ce deuteroalkoxy wherein the C -( alkyoxy chain may be folly or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cg alkyl wherein the Ci-Cg alkyl chain may be folly or partially deuterated, cyano, S(O)qRg, -NRgNR?, -(CH2)nS(O)2NRgR7, -(CH2)nC(O) NR5R7, -NHS(O)2R6, -C(===NR6a)NRgR7, -C(O)NRgR7, -NHC(===O)-alkyl -NH(C=O)N SR7, -SO(=NH)R5, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C’i4alkyl, -C(R5)(R7)-cycloalkyl, substituted or unsubstituted C?-Cs cy cloalkyl, C?,-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N, and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R-; substituents maybe further optionally substituted with one or more hydroxy, alkoxy or Cs-C4alkyl substituents;

[1704] R and Rgaare individually and independently selected from the group consisting of H, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxy! alkyl, or Ci-Cs folly or partially fluorinated fluoroalkyl;

[1705] R? is H, Ci-Cg alkyl, deuterated Ci-C4alkyl wherein C1-C4 lkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs folly or partially fluorinated fluoroalkyl;

[1706] R-12IS selected from the group consisting of hydrogen, OH. -OCi-Cgalkyl, -OCi-Cf.alkoxyl, Ci-Cealkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[1707] Ri2a is selected from the group consisting of hydrogen, Ci-Cgalkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;Patent Application LTGO-019 / 01WO 36088 / 124 RIB, Ri4. RIS, and Rie are independently selected from hydrogen, deuterium, hydroxy, oxo, -C(O)NReR7, -(CH2)nS(O)2NRdR7, -(CH2)nC(O)NRf, R7, cyano, halo, Ci-Cgalkyl, deuterated Ci-C* alkyl wherein the Ci-Cf, alkyl chain may be fully or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or un substituted alk ny 1, haloC-Cb alkyl wherein the C1-C4 alkyl chain may be folly or partially halogenated, C -C 4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or fully fluorinated, Ci-C4alkoxy, C1-C4 deuteroalkoxy wherein the C1-C4 alkyoxy chain may be fully or partially deuterated, cycloalkoxy -S(O)qRb, -NRoNR?, -N;HS(O): R,. -C^NRraXNRsR?, -NHC(=O)-Ci-C alkyl, -NH(C=O)NR6R7, -SO(=NH)R^ -O-(CH2)mC(=O)NR;R7, -O-(CH2)m-O-C;.4 alkyl.-C(R«)(R7)-cycloalkyl, substituted or unsubstituted Ch-Cs cycloalkyl, Cj-Cs cycloalkenyl, substituted or unsubstituted Ce-Cio aryl, substituted or unsubstituted Cs-Cs heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O. S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[1708] m is 1-5;

[1709] n is 0-3;

[1710] q is 0-2.

[1711] In certain embodiments, X is -C(R1a) (R1b)

[1712] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (II):

[1713]

[1714] (II)

[1715] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein

[1716] Zi is CRib orb);

[1717] / is CR4C orN;

[1718] Z2is CRud orN;

[1719] Z4 is C de or N;

[1720] Ria, R 1,, Rte, rd, and i, are individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl. Ci-Ce fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Cqalkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy,Patent Application LTGO-019 / 01WO 36088 / 124 Ci-Cg deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be folly or partially deuterated, Ci-Cs- fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be folly or partially deuterated, cyano, -S(O)qRf,, -P(O)(Ci-C4alkyl). -NR6NR7, -(CHAnS / OpNRsRy, -(CH2)nC(O)NRsR7, -NHS(O)2R6, C(=NR6a)NR6R7, -CfOlNR O, -NHC(=O)-alkyl -NH(C=O)NR6Ry, -SO(=NH)R<5, -O-(CH2)mC(=O)NR6R7, -O-(CII2)m-O-Ci.4alkyI, - C(R<5)(R7)-cydoalkyl, substituted or unsubstituted C3-Cs cycloalkyl, Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or R8substituents: wherein Rs is H, Ci-Cs alkyl, deuterated Ci-C4alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyd, or Ci-Cs folly' or partially fluormated fluoroalkyl;

[1721] wherein each Rg and Rio are independently selected from the group comprising H, Ci-Cs alkyl, Ci-Cs cycloalkyl, C2-Ce alkenyl. Ci-Cg haloalkyl, Ci-Cs alkoxy, r C -C haloalkoxy.

[1722] In some embodiments, R^, Rib. R4c. R4J, and.. are independently selected from halogen, F, -OCH3, -GIL, -OCFs, -CII(CH3)2, and -OCHF2.

[1723] In some embodiments. Ria, Rib, R4c, Rid, and R4e are independently selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[1724] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (III):

[1725]

[1726] or a tautomer, a phar aceutically acceptable salt, hydrate or solvate thereof, wherein

[1727] Zi is CR-ib orN;

[1728] Z2is CRdc or N;

[1729] Z? is CRw or bl;

[1730] Z4is CRde or N;Patent Application LTGO-019 / 01WO 36088 / 124 Ra, TGb, Rc, R-4d, and R 4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted Cd-Ce alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherein the C -< alkyoxy chain may be fully or partially deuterated, Ci-Cs-fluoroalkoxy wherein the C1-C0 alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C.5 alkyl wherein the Ci-Ce alkyl chain may be Hilly or partially deuterated, cyano, -S(O)qR, -P(O)(Ci-C4alkyl), -NRNR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC =O)-alkyl -NH(C=O)NR6R7. -SO(=NH)Rf;, -O-(CH2)mC(=O)NRR7, -O-CCIfclm-O-Ct^alkyl, - C(.5)(R7)-cycloalkyl, substituted or unsubstituted C3-Cg cycloalkyl, C3-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy. -NR9R10. C1-C4 alkyl, or Rg substituents;

[1731] wherein each R« and Rio are independently selected from the group comprising H. Ci-Cs alkyl, Ci-Cg cycloalkyl, C2-Cs alkenyl, Ci-Cg haloalkyl, Ci-Cg alkoxy, or Ci-Cg haloalkoxy.

[1732] In some embodiments, ia, Rib, Rc, Rd, and Reare independently selected from halogen, F, - OCRs, -CH3, -0CF3, -CH(CHJ)2, and -OCHF2.

[1733] In some embodiments,a, R4b, R-v. R4d, and R; are independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[1734] In some embodiments, R4a, R b, Rc. Rd, andsare independently selected from those depicted in the compounds listed in Table I, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[1735] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (IV):

[1736]

[1737] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinPatent Application LTGO-019 / 01WO 36088 / 124 Zi is OR* orN;

[1738] Z2is C ic orN;

[1739] Z: is CRM or N:

[1740] Z: is CR.4e or N;

[1741] R4a. R&, RM, M, and Rieare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C -C alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, Cj-Cealkoxy, Ci-Cg deuteroalkoxy wherein the ( -C alkyoxy chain may be folly or partially deuterated, Ci-Cs- fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qR,, -P(O)(Ci- C4alk 1), -NRbNRv, -(CH2)nS(O)2NR6R- / , -(CH2)nC(O)NR6R7, -NHS(O)2R, C(=NR,a)NR> R7, -C(0)NRR7, -NHC(=O)-alkyl -NH(C=O)NRR7, -SO(=NH)R6, -0-(CH2)mC(=0)NRR7, -O-(CH2.)m-O-Cn4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cg-Cs cycloalkyl. Cg-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rs substituents;

[1742] wherein each R9 and Rio are independently selected from the group comprising H, Ci-Cs alkyl, Ci -Cs cycloalkyl, C2-Ce alkenyl, Ci-Cs haloalkyl, Ci-C alkoxy, or Ci-Cs haloalkoxy; p is 0-3;

[1743] Yi is C(Rga)(Rsb), O orN (Rd):

[1744] Y2= C(Rga)(Rgb), O or N (R);

[1745] each Y3is independently C(Rsa)(Rsb), O or N (Re); and with the proviso that only one of Yi, Y2, and Yj can be N;

[1746] each Rgaand Rgb are independently: hydrogen, -OH. deuterium, halo, cyano, Ci-Caalkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, Ci-Ce alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4 alkyl wherein the C1-C4 alkyl may be full x or partially deuterated, or Ci-Cg folly or partially fluorinated fluoroalkyl.

[1747] In some embodiments, Zi is CRib. Z? is CRdc Zg is CR4d,and 4 is CR.i,

[1748] In some embodiments, Ria, R-ib, u, Rdd, and Rte are independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Ccalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or folly fluorinated, branched alkyl, substituted or unsubstituted C2-Coalkenyl, substituted orPatent Application LTGO-019 / 01WO 36088 / 124 unsubstituted C2-C4alkynvl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Cs alkyoxy chain may be fully or partially deuterated, Ci -Cs-fluoroalkoxy wherein the Ci -Cr, alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, -S(O)qRs, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NRR7, -NHS(O)2R5, C(=NR6a)NRR7, - C(O)RRR7, -NHC(:=O)-alkyl -NH(C==O)NR6R7, -SORNH)R6, -O4CH2)I;'CA))NR. IR7. -O-(CH2)m-O-CT 4alkyl, -C(Ro)(R7)-cycloalkyl, substituted or unsubstituted Cs-Cs cycloalkyl, Ch-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N.

[1749] In some embodiments. Ra, R4b, R4a, R4J, and R4eare independently selected from halogen, F, -OCR,, -CH3, -OCFs, -CH(CH3)2, and -OCHF2.

[1750] In some embodiments, Ra, Rb, Rc, Rd, and Reare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[1751] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula ( V):

[1752]

[1753] or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof is as defined above and described in embodiments herein, both singly and in combination.

[1754] In some embodiments, Zi is CR4b. Z2is CR4c, Z is CR4rj, and Z4is C R

[1755] In some embodiments. ia, Rb, R4c, Rd, and Reare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ct, fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-C4alkynvl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cgalkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Cg, alkyl chain may be fully or partially deuterated, cyano, -S(O)qR,Patent Application LTGO-019 / 01WO 36088 / 124 -P(O)(Ci-C4alkyl), -NR6NR7, -(€H2)nS(O)2NRR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NRa)NR6R7, - C(O)NRR7, -NHC(=O)-alkyl -NH(O0)NRR7, -SO(===NH)R6, -O-(CH2)mC(===O)NRR7, -O-(CH2)m-O-Ci.! ky 1, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C3-Cg cycloalkyl, Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl composes at least one heteroatom independently selected from 0, S, and N.

[1756] In some embodiments, Ra, Rb,;. Rd, and Reare independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[1757] In some embodiments, Ra, Rib, Rc, Rd, and Rsare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB. Table 2, Table 2A, or Table 2B.

[1758] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (VI):

[1759]

[1760] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R2b, R3a, b, Ra, Zi, Z2, Z3, and Z4is as defined above and described in embodiments herein, both singly and in combination.

[1761] In some embodiments, Zi is CR4b. Z2is CRc, Z is CR-w, and Z is C R..

[1762] In some embodiments,3, b, R4c. Rd, and Reare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl. Ci-Ct, fluoroalkyl wherein the Ci-Cf, fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Cg haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, Ci-Ckalkoxy, Ci-Cb dcutcroalkoxy wherein the Ci-Cc alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Cg alkyl chain may be folly or partially deuterated, cyano, -S(O)qR, -P(O)(Ct-C4alkyl). -NR6NR7, -(CH2)„S(O)2NRR7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NRa)NRR7, -C(0)NRR7, -NHC(=O)-alkyl -NH(C=0)NRR7, -S0(=NH)R, -O-(CH2)mC(=O)NRR7. -O-(CH2)m-O-Ci4alkyl, -C(R)(R7)-cycloalkyl, substituted or unsubstituted C -Cg cycloalkyl, C3-Cg cycloalkenyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and M.

[1763] In some embodiments, R;a, u>, i=, Rw. and Risare independently selected from halogen. F, - OCH3, -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[1764] In some embodiments. Ria, Rib, Ric, R4, and R7aare independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[1765] In some embodiments, R^, R*, R4c, RJ< I, and R4aare independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[1766] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (VII):

[1767]

[1768] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R2b, R3a, R3t, R4a, Zi, Z2, Z3, and Z4 is as defined above and described in embodiments herein, both singly and in combination.

[1769] In some embodiments, Zi is CR4b. Z2is CR4C. Z3 is CR4d.and4is CR.

[1770] In some embodiments, Rda. Ra,, ICc. Rid, and Rte are independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Csalkyl, Ci-C6fluoroalkyl wherein the Ci-C6fluoroalkyl is partially or folly fluorinated, branched alkyl, substituted or unsubstituted Cj-Cg alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci -Co haloalky 1 wherein the alkyl may be fully or partially halogenated, hydroxy, C i-C. salkoxy, C1-C0 deuteroalkoxy wherein the Ci-Cg alkyoxy chain may be fully or partially deuterated, Ci -Cs-fluoroalkoxy wherein the C 1 -Co alkoxy may be folly or partially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Cg alkyl chain may be folly or partially deuterated, cyano, -S(O)qRd, -P(O)(Cl-C4alky4), -NR6NR7, -(CH3)nS(O)2NRiR7, -(CH2)nC(O)NR6R7. -NHS(O)2R6, C(=NR,a)NR6R7, -C(O)NR5R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R,5, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-Cu4alky 1, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, C3-Cs cycloalkenyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and M.

[1771] In some embodiments, R;a, Rn„ R^, RM. and Rz,. are independently selected from halogen. F, - OCH3, -CHS, -OCR, -CH(CH?.)2, and -OCHF2.

[1772] In some embodiments, R_ra, JS, te, R«, and R^ are independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[1773] In some embodiments, R4... Rib, R4c, R4d, and R. are independently selected from those depicted in the compounds listed in Table 1, Table L\, Table IB. Table 2, Table 2A, or Table 2B.

[1774] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (VIII):

[1775] o

[1776] V-x3

[1777] X^-XK

[1778] 6a

[1779]

[1780] (VIII)

[1781] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of X, R2a, Rjb, Rs?., Rsb, Ku, Zt, Z2, Zj, Z4, X2, X3 / X3, X4, X5, and X6is as defined above and described in embodiments herein, both singly and in combination.

[1782] In some embodiments, Zi is CRib Z2is CRic. Zs is CR4d.andZ4is CR.

[1783] In some embodiments, R4a, R b, Rdc, R4. and R4eare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl, Ci-Cs fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Cb alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cf.alkoxy, Ci-Co deuteroalkoxy wherein the Ci-Co alky oxy chain may be fully or partially deuterated, Ci -Ce-fluoroalkoxy wherein the C i -C« alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C.5 alkyl wherein the Ci-Cb alkyl chain may be fully or partially deuterated, cyano, -S(O)qRs, -P(O)(Ci-C4alkyl), -NRcNR?, -(CH2)nS(O)2N 5R7, -(CH2)nC(O)NR6R7, -NHS(O)2Rb. C(=NRsa)NR«R7, - C(O)NRb, R?, -NHC(=O)-alkyl -NH(C=O)NRcR7, -SO(=NH)R5, -O-(CH2)mC(=O)N;R7, -O-(CH2)m-O-Ci4alkyl, -C(R<5)(R7)-cycloalkyI, substituted or unsubstituted Cj-Cs cycloalkyl, Cj-Cs cycloalkcnyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and M.

[1784] In some embodiments, R;a, Rib, i=, RM. and RM are independently selected from halogen. F, - OCH3, -CH3, -OCR, -CH(CH3)3, and -OCHF2.

[1785] In some embodiments. Ria, Rib, Ru, R-w, and

[1786]

[1787] are independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[1788] In some embodiments, R^, R*, RM, R«, and RM are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[1789] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (IX):

[1790] o

[1791]

[1792] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ria, Rib, R2a, R?.b, Ria, R3b, Ria, Zi, Z3. Z, Z4, X2. X2. X4. X5. and Xs is as defined above and described in embodiments herein, both singly and in combination

[1793] In some embodiments, Zi is C ib, Z3is C M, Z3is C u, and Z is C;,

[1794] In some embodiments, |a, ib, ic, M, and Rqeare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ch fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C -C alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci -Cr, haloalkyl herein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Cs deuteroalkoxy wherein the Ci-Cr, alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or parti ally fluorinated, cycloalkoxy, deuterated Ci-C alkyl wherein the C:-C<5 alkyl chain may be fully or partially deuterated, cyano, -S(O)qRb, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH;)nS(O)2X5R7, -(CH2)nC(O)NR6R7, -NHS(O)2RA, -NR^NReRr, -C(O)N 5R7. -NHC(=O)-alkyl -NH(C=O)NReR7, -SO(=NH)R6, -O-(CH2)mC(=O)NRR7, -O-(CH2)m-O-Ci 4alkyl, -C(Rb)(R7)-cycloalkyl, substituted or unsubstituted C3-C« cycloalkyl, C3-Cs cycloalkenyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and X.

[1795] In some embodiments, R;a, M, R=, Rw. and Rsare independently selected from halogen. F, - OCH3, -CH3, -OCR, -CH(CH3)2, and -OCHF2.

[1796] In some embodiments, Ra, Rib,4,. Rd, and Reare independently selected from those depicted in the compounds listed in Table 1 or Table 2.

[1797] In some embodiments, Ra, Rb, M. Rid, and R. are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB. Table 2, Table 2A, or Table 2B.

[1798] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (X):

[1799]

[1800] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R2a, R?b. R3a. R?b, Ria, Zi. Z2. Z3, Z, X2, X’. Xi. Xs, and Xe is as defined above and described in embodiments herein, both singly and in combination.

[1801] In some embodiments. Zi is CRb, Z3is C, Z3is CRd,andZ4is CRe

[1802] In some embodiments, R4a, b, RM, Rid, and M are independently selected from tire group consisting of hydrogen, deuterium, halo, Ci-Csalkyl, Ci-Ch fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C -( alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherem the alkyl may be fully or parttally halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherem the Ci-Cr, alkyoxy chain may be hilly or partially deuterated, Ci-C's-fluoroalkoxy wherem the Ci-Ce alkoxy may be hilly orpartially fluorinated, cycloalkoxy, deuterated Cj-Ce alkyl wherein the Ci-Cs alkyl chain may be fully- or partially deuterated, cyano, -S(O)qRe, -P(O)(Ci-C4alkyl), -NRNR7, -(CH2)„S(O)2XRR7, -(CH2)„C(O)NR6R7, -NHS(0)2R, C(-NRa)NRR7, - C(O)XRR7. -NHC(=O)-aIkyl -NH(C=0)NRR, -SO(=NH)Re„ -O-(CH2)mC(=O)NRR7, -O-(CH2)m-O-Ci.

[1803] 4alkyl. -C(R)(R7)-cycloalkyL substituted or unsubstituted C3-Cg cycloalkyl. C3-Cg cycloalkenyl, or 3-7Patent Application LTGO-019 / 01WO 36088 / 124 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and X.

[1804] In some embodiments, R;a, Rib, i=, Rw. and,sare independently selected from halogen. F, - OCH3, -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[1805] In some embodiments. Ria, Rib, Ric, R-w, and

[1806]

[1807] are independently selected from those depicted in Table 1 below.

[1808] In some embodiments, the present disclosure provides a compound of Formula (I), wherein the compound is a compound of Formula (XI):

[1809] o

[1810]

[1811] 1~Z2

[1812] or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ria, Rib. R2a, R2b, R?,a, R?b, R-ia, Zi, Z2. Z3_ Z4, X2, X3, X4, X3, and X7is as defined above and described in embodiments herein, both singly and in combination.

[1813] In some embodiments. Zi is CR4b, Z2is C u Zs is CR4d,andZd is CRje

[1814] In some embodiments, Ria, Rab, ic, Rvi, and R7eare independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Coalkyl, Ci-Cs fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C(5 alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cealkoxy, Ci-Ce deuteroalkoxy wherein tire Ci-Ce alkyoxy chain may be frilly or partially deuterated, Ci-Cs-fluoroalkoxy wherein the Ci-Cs alkoxy may be folly or partially fluorinated, cycloalkoxy, deuterated Cj-Ce alkyl wherein the Ci-Cs alkyl chain may be folly or partially deuterated, cyano, -S(O)qRe, -P(O)(Ci-C4alkyl), -N 5NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2Rs, C(=NR6a)NRsR7, -C(O)Nft. R,. -NHC(:=O)-alkyl -NH(C-O)NRbR7, -SO(-NH)R6, -O-(CH2)mCC=O)NRcR7, -O-(CH2)m-O-Ci. alkyl. -C(Ro)(R7)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, Cj-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and NPatent Application LTGO-019 / 01WO 36088 / 124 In some embodiments. Ria, R411, Rdc, Rvi. and Ra, are independently selected from halogen, F, - OCH3. -CH3, -OCF3, -CH(CH3)2, and -OCHF2.

[1815] In some embodiments, the present disclosure provides a compound of Formula (XII):

[1816]

[1817] or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein R]a, Ri, R.. zb, Ria, R?>b arc defined above, or R)a, Rib, Ria, Rib, Ria, Rib arc independently selected from the group consisting ofH, deuterium, halo, hydroxyl, Ci-Cs alkyl. Ci-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Cg alkoxy. Ci-Cs deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, haloalkoxy wherein the alkoxy may be folly or partially halogenated, C2-Cs alkenyl, C2-Cs alkynyl, -[C(R«)(R7)]ni-C3-Cs-cycloalkoxy, cyano, -[C(Rs)(R7)]m-C3-Cs cycloalkyl, -[C(Rs)(R7)]m-C3-Cs cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C / Rsl / Rvllm-Cj-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and X:

[1818] wherein any of said alkyl or alkenyl moieties above may be further substituted with one, two, three or four R, substituents, where each Rs is independently selected from halo, Ci-Cs alkyl, Cs-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C.5 alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, and m - 0 to 2'

[1819] R2aand R2b may be independently selected from aryl or heteroaryl and may optionally together form a substituted or unsubstituted exocyclic alkene, wherein alkene substituents are selected from H. deuterium, fluoro, Ci-Cgalkyl, aryl or heteroaryl;

[1820] wfierein at least one of R, R2?. and R3aare selected from the group comprising hydroxyl, Ci-C« alkoxy. Ci -Co deuteroalkoxy herein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C3-Cs cycloalkoxy, C3-Cg fluorocycloalkoxy wherein the cylcoalkoxy may be fully or partially fluorinated, and substituted or unsubstituted -0-[C(Rs)(R7)]m-Ce- Cui-aryl,Patent Application LTGO-019 / 01WO 36088 / 124 represents a single or double bond;

[1821]

[1822] X2- CRi2, N, or N -O:

[1823] X3= CRI3, N, orbF-O’;

[1824] X4= N, N'-0-, orCRu;

[1825] X? = CRi?: NorbT-O’;

[1826] X CRie, N orN+-O';

[1827] Ring B is selected from the group consisting of a Crt-Cio membered aryl ring. Cs-Cs membered hctcroaryl ring; monocyclic, bicyclic, or spirocyclic cycloalkyl ring; or monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl ring or the Cri-C2heteroaryl ring contain one or more heteroatoms independently selected from N. 0, and S. and wherein Ring B is substituted with one or more R substituents;

[1828] R4 is hydrogen, deuterium, halo. Ci-Cealkyl, Ci-Cs fluoroalkyl wherein the Ci-C's fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, C.-Cs haloalkyl wherein the alkyl may be fully or partially halogenated, Ci- Ce,alkoxy, C1-C& deuteroalkoxy wherein the Ci-C. alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cg alkoxy may be frilly or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the C1-C0 alkyl chain may be folly or partially deuterated, cyano. S(O)qR6, -NR6NR7. -(CH2):;S(O)2NR6R7, -(CH2)nC(O) NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, - C(O)NRGR7;-NHC(=O)-alkyl -NH(C-O)NR5R7, -SO(===NH)R6, -O-(CH2)mC(===O)NR:, R7, -O-(CH2)ffi- O-C1 4 alkyl, -C(Rc)(R7)-cycloalkyl, substituted or unsubstituted C2-Cg cycloalkyl, Cj-Cg cycloalkcnyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N; and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R4 substituents maybe further optionally substituted with one or more hydroxy, alkoxy or Ci-C alkyl substituents;

[1829] R and Rg.a are individually and independently selected from the group consisting of H, Ci-Cs alkyl, deuterated C1-C alkyl wherein C -C. alkyl is frilly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cg fully or partially fluorinated fluoroalkyl;Patent Application LTGO-019 / 01WO 36088 / 124 R7 is II, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydrox alkyl, alkoxyl alkyl, or Ci-C fully or partially fluorinated fluoroalkyl;

[1830] Ki IS selected from the group consisting of hydrogen, OH, -OCs-Cealkyl, -OCi-Cf.alkoxyl, Ci-Csalkyl, deuterated C1-C4 alkyl wherein the ( ' -C: alky! chain may be fully or partially deuterated, Ci-Cg fluoroalkyl wherein the Cj-Cs fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[1831] R a is selected from the group consisting of hydrogen, Ci-Csalkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the Ci- Cs fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;

[1832] Ri?,, R14, RI and Rie are independently selected from the group consisting ofhydrogen, deuterium, hydroxy, oxo, -C(O)NR6R7, -(CI-TTSCORNRsRy, -(CH2)nC(O)NR6R7. cyano, halo, C;-C6alkyl, deuterated Ci-Ce alkyl wherein the Ci-Cs alkyl chain may be folly or partially deuterated, branched alkyl, substituted or unsu bstituted alkenyl, substituted or unsubstituted alkynyl, haloC 1 -C4 alkyl wherein the C 1 -Ch alkyl chain may be folly or partially halogenated, C1-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or fully fluorinated, Ci-C4alkoxy, ( -C: deuteroalkoxy wherein the C1-C4 alkyoxy chain may be folly or partially deuterated, cycloalkoxy -S(O)qR6, -NRsNRr, -NHS(O)2R6, -C(=NR6a)NRfiR7, -NHC(=O)-C, -C.;-;iik) l. -NH(C=O)NR6R7, -SO(===NH)R6, -O-(CH2)mC(==O)NR6R7. -O-(CH2)m-O-Ci.4 alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cj-Cs cycloalkyl, Cj-Cs cycloalkenyl, substituted or unsubstituted Cs-Cio aryl, substituted or unsubstituted Cs-Cs heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0. S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13, R14. Ri.% and Rie substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;

[1833] m is 1-5;

[1834] n is 0-3; and

[1835] q is 0-2.

[1836] In some embodiments, R a, Rib, ic, R4d, and Rseare independently selected from those depicted in the compounds listed in Table 1. Table 1A, Table 2, or Table 2A.Patent Application LTGO-019 / 01WO 36088 / 124 O

[1837] In some embodiments, Ring

[1838]

[1839] A is In some embodiments, Ring A is

[1840]

[1841] In some embodiments, Ring A is

[1842]

[1843] In some embodiments. Ring A is O

[1844] . In some embodiments, Ring

[1845]

[1846] A is H. In some embodiments. Ring A is

[1847]

[1848] . In some embodiments, Ring

[1849]

[1850] A is. In some embodiments, Ring A is

[1851]

[1852] Patent Application LTGO-019 / 01WO 36088 / 124

[1853]

[1854] embodiments, Ring

[1855]

[1856] A is In some embodiments, Ring

[1857]

[1858] A is In some

[1859] embodiments, Ring

[1860]

[1861] A is In some embodiments, Ring

[1862]

[1863] A is

[1864] embodiments, Ring

[1865]

[1866] A is In some embodiments. Ring

[1867]

[1868] A is In some

[1869] embodiments, Ring A

[1870]

[1871] is O

[1872] some embodiments, Ring A

[1873]

[1874] is

[1875] embodiments, Ring

[1876]

[1877] A is In some embodiments, Ring

[1878]

[1879] A isPatent Application LTGO-019 / 01WO 36088 / 124 NH2NH2

[1880] N embodiments, Ring A

[1881]

[1882] is. In some embodiments. Ring

[1883]

[1884] A is. In some O NH NH

[1885] O2o2

[1886] embodiments. Ring A

[1887]

[1888] is H In some embodiments. Ring

[1889]

[1890] A is 0<^NH2

[1891] In other embodiments. Ring A is

[1892]

[1893] embodiments, Ring A is o<. NH2

[1894] ,„F

[1895] NH2

[1896] f 'N

[1897]

[1898] . In some embodiments, Ring A is Fl. In some embodiments. Ring OH

[1899] O.^NH

[1900] N

[1901] A

[1902]

[1903] is H. In some embodiments, Ring A is H In some embodiments.

[1904] O N

[1905] Ring A

[1906]

[1907] is In some embodiments, Ring

[1908]

[1909] A is In some embodiments.

[1910] N NH O O

[1911] ' N

[1912] r N f N

[1913] Ring A is

[1914]

[1915] Fl. In some embodiments. Ring A is Fl. In some embodiments, RingPatent Application LTGO-019 / 01WO 36088 / 124

[1916]

[1917] . In some embodiments, Ring A is. In some embodiments, Ring A

[1918] In some embodiments, Ring A

[1919] O

[1920]

[1921] In some embodiments,

[1922] Ring A is. In some embodiments. Ring A is In some embodiments.

[1923]

[1924] In some embodiments. Ring A is selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[1925] In some embodiments, Ring B is phenyl, a ring selected from a Cg-Cio membered and ring, a ( ’■-Cg membered heteroaryl ring; a monocyclic, bicyclic, or spirocyclic cycloalkyl ring; or a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl ring or the C₅-C₈ heteroaryl ring contain one or more heteroatoms independently selected from N. 0, and S, and wherein Ring B is substituted with one or more R4 substituents.

[1926] In some embodiments, Ring B is a C₆-C₁₀ membered aryl ring substituted with one or more R₄ substituents. In some embodiments, Ring B is a C₅-C₈ membered heteroaryl ring having one or more heteroatoms independently selected from N, 0, and S; and substituted with one or more R4 substituents. In some embodiments, Ring B is a monocyclic, bicyclic, or spirocyclic cycloalkyl ring substituted with one

[1927] illPatent Application LTGO-019 / 01WO 36088 / 124 or more substituents. In some embodiments, Ring B is a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring having one or more heteroatoms independently selected from N, 0. and S; and substituted with one or more R substituents.

[1928] In some embodiments, Ring

[1929]

[1930] B is wherein

[1931] Z1is CR4bor N;

[1932] Z2is CR4cor N;

[1933] Z3is CR4dor N;

[1934] Z4is CR4eor N;

[1935] R4a, R4b, R4c, R4d, and R4eare independently selected from the group consisting of hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C4alkynyl, C1-C6haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C6alkyl wherein the C1-C6alkyl chain may be fully or partially deuterated, cyano, -S(O)qR6, -P(O)(C1-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, -C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N; wherein the C1-C6alkyl, C1-C6fluoroalkyl, haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4alkyl, or R8substituents; wherein R8is independently selected from H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;

[1936] wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy.

[1937] In some embodiments, Z1is CR4b, Z2is CR4c, Z3is CR4d, and Z4is CR4e

[1938] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from the group consisting of hydrogen, deuterium, halo, C1-C6alkyl, C1-C6fluoroalkyl wherein the C1-C6fluoroalkyl isPatent Application LTGO-019 / 01WO 36088 / 124 partially or fully fluorinated, branched alkyl, substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstituted C₂-C₄ alkynyl, C₁-C₆ haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C₁-C₆alkoxy, C₁-C₆ deuteroalkoxy wherein the C₁-C₆ alkoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C₁-C₆ alkyl wherein the C₁-C₆ alkyl chain may be fully or partially deuterated, cyano, -S(O)qRe. -P(O)(Ci-C4alkyl), -NR6NR7, -(CH^S / O^NRdG, -(CH2)riC(O)NR6R7, -NHS(O)2R5, CO R^NRJG, - C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NReR7, -SO(=NH)R6, -O-(CH2)mC(=O)NRR / , -O-(CH2)m-O-Ci...alkyl. -C(Rd)(R7)-cycloalkyl, substituted or unsubstituted C2,-Cg cycloalkyl. C3-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N

[1939] In some embodiments, R4a, R4b, R4c, R4d, and R4eare independently selected from hydrogen, halogen, F, Cl, -OCH3, -O-CH2CH3, -CH3, -OCF3, -OCD3, -CH(CH3)2, -CF3, and -OCHF2.

[1940] In some embodiments, R₄ₐ, R₄ᵇ, R₄ᶜ, R₄ᵈ, and R₄ᵉ are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B.

[1941] In some embodiments, Ring B is substituted phenyl. In some embodiments. Ring B is phenyl with

[1942] one ormore R4substituents. In some embodiments. Ring

[1943]

[1944] B is F. In some embodiments, Ring

[1945] In some embodiments. Ring B

[1946]

[1947]

[1948] In some embodiments, Ring B is F. In some embodiments, Ring B isPatent Application LTGO-019 / 01WO 36088 / 124

[1949] F F

[1950]

[1951] . In some embodiments, Ring B is F. In some embodiments. Ring B is

[1952] F

[1953] . In some embodiments, Ring B IS. In some embodiments. Ring B

[1954] F

[1955] In some embodiments. Ring B is

[1956]

[1957] F F F

[1958] F

[1959] . In some embodiments, Ring

[1960]

[1961] B is. In some embodiments, Ring B

[1962] In some embodiments, Ring B is

[1963]

[1964] F. In some embodiments, Ring B is

[1965]

[1966] In some embodiments, Ring B is

[1967]

[1968] In some embodiments. Ring B is

[1969] . In some embodiments, Ring B is. In some embodiments. Ring B is

[1970] HO HO

[1971] F

[1972]

[1973] . In some embodiments, Ring B is In some embodiments. Ring B

[1974] F F

[1975] . In some embodiments, Ring B. In some embodiments, Ring B is

[1976]

[1977] Patent Application LTGO-019 / 01WO 36088 / 124

[1978] F

[1979]

[1980] In some embodiments, Ring B is F. In some embodiments, Ring B is

[1981] F

[1982] . In some embodiments, Ring B is

[1983]

[1984] Cl. In some embodiments, Ring B is

[1985] F F

[1986] In some embodiments, Ring B is substituted cyclohexyl. In some embodiments, Ring B is

[1987]

[1988] In some embodiments, Ring A is selected from those depicted in the compounds listed in Table 1 or Table 2.

[1989] In some embodiments, Ring A is selected from those depicted in the compounds listed in Table 1A or Table 2.

[1990] In some embodiments, Ring A is selected from those depicted in the compounds listed in Table 1B or Table 2B

[1991] In some embodiment, X is 0. In some embodiments, X is or -C(Ri.a)(Rib). In some embodiments, X is CH2.

[1992] In some embodiments, X is selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B.

[1993] In some embodiments, R₁ₐ and R₁ᵇ are independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, C₁-C₈ alkyl, C₃-C₆ 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 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-C₆ alkenyl, C₂-C₆ alkynyl, -[C(R₆)(R₇)]ₘ-C₃-C₈-cycloalkoxy, -[C(R₆)(R₇)]ₘ-C₃-C₈ cycloalkyl, -[C(R₆)(R₇)]ₘ-C₃-C₈Patent Application LTGO-019 / 01WO 36088 / 124 cycloalkenyl, -[C(R₆)(R₇)]ₘ-N(R₆)(R₇), or -[C(R₆)(R₇)]ₘ-C₃-C₈ heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N.

[1994] In some embodiments, R₁ₐ and R₁ᵇ are both hydrogen.

[1995] In some embodiments, R₂ₐ and R₂ᵇ are independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, C₁-C₈ alkyl, C₃-C₆ 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 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-C₆ alkenyl, C₂-C₆ alkynyl, -[C(R₆)(R₇)]ₘ-C₃-C₈-cycloalkoxy, -[C(R₆)(R₇)]ₘ-C₃-C₈ cycloalkyl, -[C(R₆)(R₇)]ₘ-C₃-C₈ cycloalkenyl, -[C(R₆)(R₇)]ₘ-N(R₆)(R₇), or -[C(R₆)(R₇)]ₘ-C₃-C₈ heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N.

[1996] In some embodiments, R₂ₐ and R₂ᵇ are both -CH₃. In some embodiments, R₂ₐ and R₂ᵇ are independently -CF₃ and -CH₃. In some embodiments, R₂ₐ and R₂ᵇ are independently -CF₃ and -OCH₃. In some embodiments, R₂ₐ and R₂ᵇ are independently hydrogen and -OCHF₂. In some embodiments, R₂ₐ is H and R₂ᵇ is alkoxy or fluoroalkoxy. In some embodiments, R₂ₐ is H and R₂ᵇ is alkyl, aryl or fluoroalkyl. In some embodiments, R₂ₐ is aryl or heteroaryl and R₂ᵇ is alkoxy. In some embodiments, R₂ₐ is -OH and R₂ᵇ is alkyl or fluoroalkyl. In some embodiments, R₂ₐ is -OH and R₂ᵇ is -CF₃. In some embodiments, R₂ₐ is H and R₂ᵇ is benzyloxy. In some embodiments, R₂ₐ is H and R₂ᵇ is trifluoroethoxy. In some embodiments, R₂ₐ is H and R₂ᵇ is -OCF₃. In some embodiments, R₂ₐ is H and R₂ᵇ is phenoxy or substituted phenoxy. In some embodiments, R₂ₐ is H and R₂ᵇ is 4-fluorophenoxy. In some embodiments, R₂ₐ is H and R₂ᵇ is isopropoxy.

[1997] In some embodiments, R₂ₐ and R₂ᵇ together with the carbon they attach from form an optionally substituted 3-6 membered cycloalkyl spirocyclic ring. In some embodiments, R₂ₐ and R₂ᵇ together with the carbon they attach from form an optionally substituted 3-6 membered heterocycloalkyl spirocyclic ring having heteroatoms selected from N or O. In some embodiments, R₂ₐ and R₂ᵇ together with the carbon they attach from form an optionally substituted cyclopropyl, cyclobutyl, or cyclopentyl spirocyclic ring. In some embodiments, R₂ₐ and R₂ᵇ together with the carbon they attach from form an optionally substituted heterocyclopropyl, hetero cyclobutyl, or heterocyclopentyl spirocyclic ring having heteroatoms selected from N or O. In some embodiments, R₂ₐ and R₂ᵇ together with the carbon they attach from form anPatent Application LTGO-019 / 01WO 36088 / 124

[1998] optionally substituted spirocyclic ring [image]. In some embodiments, R₂ₐ and R₂ᵇ together with the

[1999] carbon they attach from form an optionally substituted spirocyclic ring

[2000]

[2001] .

[2002] In some embodiments, R2aand R2b are selected from those depicted in Table 1 below.

[2003] In some embodiments, R-.a and R2b are selected from those depicted in Table 1A below.

[2004] In some embodiments, R₂ₐ and R₂ᵇ are selected from those depicted in Table 1B below.

[2005] In some embodiments, R1aand R,b are independently selected from the group consisting of H, deuterium, halo, hydroxyl, -CN, Cj-Cs alkyl. Cs-Cg cycloalkyl, deuterated Cj-Cg alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C1-C.5 alkoxy, Ci-Ce deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, ( ■( alkenyl, C2-Ce alkynyl, -[C(R;)(R / )]m-Cj-C8-cycloalkoxy, -[C(R6)(R7)]m-C3-C8 cycloalkyl, -[C(R6)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C5-C8 heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroaioms independently selected from 0, S, and N.

[2006] In some embodiments, R₃ₐ and R₃ᵇ are both hydrogen

[2007] In some embodiments, R₃ₐ and R₃ᵇ are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B.

[2008] In some embodiments, R4 is hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Cs fluoroalkyl wherein the C1-C6 fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ( •( haloalkyl wherein the alkyl may be fully or partially halogenated, Ci-Csalkoxy, Ci-Cg deuteroalkoxy wherein the Ci-Cg alk oxy chain may be fully or partially deuterated. Ci -Cs-fluoroalkoxy w herein the Ci-Ce alkoxy may be folly or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be fully or partially deuterated, cyano, S(O)qRe, -NR6NR7, -(CH2)nS(O)2MRsR7, -(CH2)nC(O) NR> R7, -NHS(0):R6, (=NRia)NReR7, -C(O)NRgR7, -NHC(=O)-alkyl -NH(C=0)NRsR7, -SO(=NH)Rs, -O-(CH2)mC(=O)NR6R7, -0-(CH2)m-0-Ci4alkyl, -C(Rs)(R7)-cycloalkyl, substituted or unsubstituted C?-Cg cycloalkyl. Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, R4 is halogen. In some embodiments, R4 is F. In some embodiments, R- is -OCH3. In some embodiments, R₄ is -CH₃. In some embodiments, R is -OCF3. In some embodiments, R₄ is -CH(CH₃)₂ In some embodiments. R4 is -OCHF2. In some embodiments, R is -OCH2CH3. In some embodiments, R4 is -OCD3 In some embodiments, R₄ is cyclopyloxy. In some embodiments, R4 is hydroxymethyl. In some embodiments, R₄ is -CF₂H. In some embodiments, R4 is -CF3. In some embodiments, R₄ is -OCH₂CH₂OCH₃. In some embodiments, R4 is Cl.

[2009] In some embodiments, R4is selected from those depicted in Table 1 below.

[2010] In some embodiments, R₄ is selected from those depicted in Table 1A below.

[2011] In some embodiments, R₄ is selected from those depicted in Table 1B below.

[2012] In some embodiments, R₅ is H, C₁-C₆ alkyl, C₁-C₆ cycloalkyl, C(O)NR₆R₇, C₁-C₆ alkoxy or C₁-C₆ cycloalkoxy; wherein the forgoing alkyl, cycloalkyl, alkoxy and cylcoalkoxy fragments of R₅ maybe further substituted with one or more substituents selected from halogen, OH, C₁-C₄ alkoxy.

[2013] In some embodiments, X₂ is CR₁₂. In some embodiments, X₂ is N. In some embodiments, X₂ is N⁺-O⁻. In some embodiments, X₂ is CR₁₂ and R₁₂ is H.

[2014] In some embodiments, X2is selected from those depicted in the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[2015] In some embodiments, X3 is CR13. In some embodiments X3 is, N. In some embodiments, X3 is N+-0

[2016] In some embodiments, X₃ is CR₁₃ and R₁₃ is H. In some embodiments, X₃ is CR₁₃ and R₁₃ is -CN. In some embodiments, X₃ is CR₁₃ and R₁₃ is -C(O)NH₂. In some embodiments, X₃ is CR₁₃ and R₁₃ is -C(O)N(CH₃)₂. In some embodiments, X₃ is CR₁₃ and R₁₃ is -OH. In some embodiments, X₃ is CR₁₃ and R₁₃

[2017] is

[2018]

[2019] . In some embodiments, X₃ is CR₁₃ and R₁₃ is -Cl. In some embodiments, X₃ is CR₁₃ and R₁₃ is -NH₂. In some embodiments, X₃ is CR₁₃ and R₁₃ is -S(O)₂NH₂. In some embodiments, X₃ is CR₁₃ and R₁₃ is -S(O)(NH)CH₃. In some embodiments, X₃ is CR₁₃ and R₁₃ is -C(O)NHCH₃.

[2020] In some embodiments, X3 is selected from those depicted in the compounds listed in Table I, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[2021] In some embodiments, X₄ is N. In some embodiments, X₄ is N⁺-O⁻. In some embodiments, X₄ is CR₁₄. In some embodiments, X₄ is NH.Patent Application LTGO-019 / 01WO 36088 / 124 In some embodiments, X4 is selected from those depicted in the compounds listed 111 Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[2022] In some embodiments, X? is N. In some embodiments. Xs is N’-O. in some embodiments, X< is CRi s. In some embodiments, Xs is ( ().

[2023] In some embodiments, Xs is selected from those depicted in the compounds listed in Table 1, Table 1 A, Table IB, Table 2, Table 2A, or Table 2B

[2024] In some embodiments, X₆ is N. In some embodiments, X₆ is N⁺-O⁻. In some embodiments, X₆ is CR₁₆.

[2025] In some embodiments, Xg is selected from those depicted in the compounds listed 111 Table 1, Table 1A, Table IB. Table 2, Table 2A, or Table 2B

[2026] In some embodiments, R₁₃ is hydrogen. In some embodiments R₁₃ is -CN. In some embodiments, R₁₃ is -C(O)NH₂. In some embodiments, R₁₃ is -OMe. In some embodiments, R₁₃ is -OH. In some

[2027] embodiments R₁₃ is [image]. In some embodiments, R₁₃ is -Cl. In some embodiments, R₁₃ is -NH₂. In some embodiments, R₁₃ is -C(O)N(CH₃)₂. In some embodiments, R₁₃ is -C(O)N(CH₃)₂. In some embodiments, R₁₃ is -S(O)₂NH₂. In some embodiments, R₁₃ is -S(O)(NH)CH₃. In some embodiments, R₁₃ is -C(O)NHCH₃.

[2028] In some embodiments, R13 is selected from those depicted 111 the compounds listed in Table 1, Table 1A, Table IB, Table 2, Table 2A, or Table 2B.

[2029] In some embodiments, R₄ₐ, R₄ᵇ, R₄ᶜ, R₄ᵈ, and R₄ᵉ are independently selected from those depicted in the compounds listed in Table 1, Table 1A, Table 1B, Table 2, Table 2A, or Table 2B.

[2030] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 1.

[2031] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 1A.

[2032] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table IB.Patent Application LTGO-019 / 01WO 36088 / 124 In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2.

[2033] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2A.

[2034] In certain embodiments, the compound of the invention is a compound selected from the group set forth in Table 2B.

[2035] In certain embodiments, the compounds of the invention do not include one or more compounds selected from the group consisting of the compounds provided in Table AA below.

[2036]

[2037] Patent Application LTGO-019 / 01WO 36088 / 124

[2038]

[2039] Patent Application LTGO-019 / 01WO 36088 / 124

[2040]

[2041] Patent Application LTGO-019 / 01WO 36088 / 124

[2042]

[2043] Patent Application LTGO-019 / 01WO 36088 / 124

[2044]

[2045] Patent Application LTGO-019 / 01WO 36088 / 124

[2046]

[2047] Patent Application LTGO-019 / 01WO 36088 / 124

[2048]

[2049] Patent Application LTGO-019 / 01WO 36088 / 124

[2050]

[2051] 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.

[2052] 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.

[2053] 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, acute itch, acute pain, acute pain in major trauma / injury, airways hyperreactivity, allergic dermatitis, allergies, ankylosingPatent Application LTGO-019 / 01WO 36088 / 124 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 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 sensor}’ polyneuropathy (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 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 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 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 pain, stump pain, subacute cough, temporomandibular joint disorders, tension-type headache, 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.

[2054] 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 those described above, in a subject.

[2055] CompositionsPatent Application LTGO-019 / 01WO 36088 / 124 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 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 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 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 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.

[2056] 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 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

[2057] 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 of the invention is encapsulated in an enteric coating.

[2058] 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 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 aliphaticPatent Application LTGO-019 / 01WO 36088 / 124 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 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.

[2059] Oily suspensions may be formulated by suspending the compounds in a vegetable oil, for 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.

[2060] 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.

[2061] 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 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.

[2062] Syrups and elixirs may be formulated -with sweetening agents, such as glycerol, propylene 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 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 suspendingPatent Application LTGO-019 / 01WO 36088 / 124 medium. For this purpose, any bland fixed oil may be employed, including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[2063] 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 embodiments, the formulation does not contain a polymer surface stabilizer. In certain embodiments, the formulation is not an aqueous suspension.

[2064] The composition may be formulated for administration by a particular mechanism. Tire composition may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The composition may be formulated for administration by injection or on an implantable medical device (e.g., stent or drug-eluting stent or balloon equivalents).

[2065] 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.

[2066] Methods of treating conditions

[2067] 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 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.

[2068] 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 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 py rophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic itch, chronic low back pain, chronic pam, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndromes, constant unilateral facial pam 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 antiretroviral therapyPatent Application LTGO-019 / 01WO 36088 / 124 (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 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 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 dcntoalvcolar 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 disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropath, 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, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash associated disorder.

[2069] 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, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonarily, rectally, subcutaneously, topically, transdermally, by injection, or w ith or on an implantable medical device.

[2070] 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.

[2071] 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 twoPatent Application LTGO-019 / 01WO 36088 / 124 days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week.

[2072] 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 may be provided as multiple tablets, capsules, pills, etc.

[2073] 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.

[2074] Examples

[2075] 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 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.

[2076] All reactions were performed in flame-dried or oven-dried glassware under a positive 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 arc not optimized The chemical names were generated using the ChemDraw Professional 19.1, available from PerkinElmer or chemAxon.

[2077] Reactions were monitored by' thin layer chro atography’ (TLC) using 0.25 mm silica gel 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'.

[2078] Prep Method 1

[2079] Equipment: Shimadzu LCMS 2020 mass-directed preparative HPLC System; column: Gemini 5 um C18 column, 150 * 21.2 mm; General gradient: 30% to 90% MeCN / H2O containing 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;

[2080] Prep Method 2Patent Application LTGO-019 / 01WO 36088 / 124 Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um C18 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.

[2081] Prep Method 3

[2082] Equipment: Shimadzu LC-20AP Preparative HPLC System; column: Gemini 5 um Cis 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.

[2083] Analytical LCMS were collected using one of following methods

[2084] Analytical Method 1

[2085] Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C18 2.7 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: 50 °C; Wavelength: 214 and 254 nm PDA.

[2086] Analytical Method 2

[2087] Equipment: Shimadzu LCMS 2020 Mass Spectrometer; XBridge BEH C18 2.5μm, 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 °C; Wavelength: 214 and 254 nm PDA.

[2088] Analytical Method 3

[2089] Equipment: Shimadzu LCMS 2020 Mass Spectrometer; Column: HALO C18 2.7 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: 50 °C; Wavelength: 214 and 254 nm PDA.

[2090] SFC chiral resolution was performed on Shimadzu Nexera UC Preparative SFC System (SFE-30A. LC-30ADsr, SFC-30A) using following methods:

[2091] Analytical Method 4

[2092] 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: 40 °C; Flow rate: 38 mL / min.

[2093] Analytical Method 5

[2094] 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: 40 °C; Flow rate: 38 mL / min.Patent Application LTGO-019 / 01WO 36088 / 124 Analytical Method 6

[2095] Column: Daicel chiralpak-OD-H 5 um 250x20 mm; Mobile Phase: CCL / MeOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[2096] Analytical Method 7

[2097] Column: Daicel chiralpak-AD-H 5 um 250x20 mm; Mobile Phase: CO2 / i-PrOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[2098] Analytical Method 8

[2099] Column: Daicel chiralpak-IC 5 um 250x20 mm; Mobile Phase: CO2 / EtOH, ratio varies for different compounds; Oven temperature: 40 °C; Flow rate: 38 mL / min.

[2100] Unless otherwise stated, 'H nuclear magnetic resonance spectroscopy (NMR) spectra were recorded on a Bruker AVANCE NEO 400 MHz Digital NMR Spectrometer. Chemical shifts, 5, are quoted in parts per million (ppm) relative to TMS and calibrated using residual un-deuterated solvent as an internal reference. Tire 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.

[2101] Abbreviations and Acronyms

[2102] When the following abbreviations are used herein, they have the following meaning:

[2103] AC2O acetic anhydride

[2104] anhy Anhydrous

[2105] B2Pin2 (Pin2B2) Bis(pinacolato)diboron

[2106] BAST Bis(2-methoxyethyl)aminosulfur trifluoride

[2107] n-BuOH n-butanol

[2108] t-BuOH t-butanol

[2109] CD3OD methanol-d4

[2110] Celite ® diatomaceous earth filter agent, ® Celite Corp.

[2111] CH2CI2 methylene chloride

[2112] DCM dichloromethane

[2113] CI-MS chemical ionization mass spectroscopy

[2114] cone concentrated

[2115] dec decomposition

[2116] bs broad singlet

[2117] br broad

[2118] DME dimethoxyethane

[2119] DMF N,N-dimethylformamide

[2120] DMSO dimethylsulfoxide

[2121] DMSO-d6 dimethylsulfoxide-d6

[2122]

[2123] ELSD evaporative light scattering devicePatent Application LTGO-019 / 01WO 36088 / 124 Et ethyl

[2124] EtOAc ethyl acetate

[2125] EtOH ethanol (100%)

[2126] Et2O diethyl ether

[2127] Et3N triethyl amine

[2128] HPLC ESI-MS high performance liquid chromatography-electrospray

[2129] mass spectroscopy

[2130] Me methyl

[2131] MPLC medium pressure liquid chromatography

[2132] NMR nuclear magnetic resonance spectroscope

[2133] TOF-MS time-of-flight-mass spectroscopy

[2134] NMM 4-methylmorpholine

[2135] Ph3P triphenylphosphine

[2136] Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[2137] Pd(OAc)2 palladium(II) acetate

[2138] P(O)C13phosphorous oxychloride

[2139] Rf TLC retention factor

[2140] Rt retention time (HPLC)

[2141] rt room temperature

[2142] MS Mass spectra

[2143] TBAF Tetrabutylammonium fluoride

[2144] THF tetrahydrofuran

[2145] THP tetrahydropyranyl

[2146] TFA trifluoroacetic acid

[2147] TLC thin layer chromatography

[2148] LC-MS (ESI) liquid chromatography-mass spectroscopy (electrospray ionization) DIEA diisopropylethylamine

[2149] DEA diethylamine

[2150] DPPE 1, 2-Bis(diphenylphosphino)ethane

[2151] Et3N tri ethylamine

[2152] MsCl Methanesulfonylchloride

[2153] HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide

[2154] HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium

[2155] hexafl uorophosphate

[2156] EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride AcOH acetic acid

[2157] HC1 hydrochloric acid

[2158] H2SO4 sulfuric acid

[2159] HNO3 nitric acid

[2160] HBr hydrobromic acid

[2161] CDCl3 chloroform-d

[2162] CHCl3 chloroform

[2163]

[2164] H2O waterPatent Application LTGO-019 / 01WO 36088 / 124 NaOAc sodium acetate

[2165] KOH potassium hydroxide

[2166] NaOH sodium hydroxide

[2167] NaCl sodium chloride

[2168] NaHCO3 sodium bicarbonate

[2169] Na2CO3sodium carbonate

[2170] K2CO3 potassium carbonate

[2171] Na2SO4 sodium sulfate

[2172] MgSO4 magnesium sulfate

[2173] MeOH methanol

[2174] SiO2 silica gel

[2175] K3PO4 potassium phosphate

[2176] NH4CI ammonium chloride

[2177] AIBN 2,2′-azobisisobutyronitrile

[2178] DMAP N, N-dimethylpvridin-4-amine

[2179] PIDA (Diacetoxyiodo)benzene

[2180] TBS tert-butyldimethylsilyl

[2181] TsCl p-toluenesul fonyl ch lori de

[2182] TsOFI p-toluenesulfonic acid

[2183] PG protecting group

[2184] NBS N-Bromosuccinimide

[2185] NIS N-Iodosuccinimide

[2186] NCS N-Chlorosuccinimide

[2187] PE Petroleum ether

[2188] FA Formic acid

[2189] ee Enantiomeric excess

[2190]

[2191] atm Atmosphere

[2192] General synthetic schemes

[2193] Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. The substituent designations are intended to apply within the referenced schemes and may differ from the substituent labels in the Formula of the invention. The present invention further provides processes for the preparation of compounds of structural Formula 1 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. Tire following examples are provided for the purpose of illustration only and are not to be construed as limitations on the disclosed invention.

[2194] General Synthetic Schemes

[2195] Scheme APatent Application LTGO-019 / 01WO 36088 / 124

[2196]

[2197] As illustrated in Scheme A, in general, compounds of the invention can be prepared from the substituted cyclohexane- 1,3-dione by converting to the corresponding diazo- cyclohexane- 1.3 -di one to afford intermediate Al. Converting Al to the corresponding substituted-2-oxocyclopentane-l-carboxylate methyl ester by ring constriction by heating in toluene in the presence of MeOH to afford intermediate A2.

[2198] Intermediate A2 can be converted to corresponding 2 -cyclopentenol inflate- 1 -carboxylate methyl ester A3 by treating A2 with base such as KHMDS and followed by 2-|N, N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine. Intermediate A3 can be converted to corresponding 2-aryl-cyclopent-l-ene-l -carboxylate methyl ester A4 by palladium mediated coupling reaction of A3 with the appropriate aryl boronic acid. Intermediate A4 can be converted to corresponding acid A5 by treating A4 with base such as LiOH in aqueous THF or MeOH. Reacting A4 with an appropriate amine utilizing appropriate amide coupling afforded A6. Cyclization of A6 under basic conditions gave the desired compounds A7. Rf could be further functionalized with appropriate reagents. If R5 involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others.

[2199] Scheme BPatent Application LTGO-019 / 01WO 36088 / 124

[2200]

[2201] As illustrated in Scheme B, in general, compounds of the invention can be prepared by hydrogenation of appropriately functionalized carboxylic acid ester A4 to afford Bl. Intermediate Bl can be converted to corresponding acid B2 by treating Bl with base such as LiOH in aqueous THF or MeOH. Reacting B2 with an appropriate amine utilizing appropriate amide coupling afforded the desired compounds B3 Cyclization of B3 under basic conditions gave the desired compounds B4, Rs could be further functionalized with appropriate reagents. If Rs involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others.

[2202] Scheme C

[2203] o

[2204] 82C1

[2205]

[2206] As illustrated in Scheme C, in general, compounds of the invention can be prepared by converting the carboxylic acid B2 to carboxamide Cl. Intermediate Cl can be converted to B2 under Pd-mediated coupling conditions. Cyclization of C2 under basic conditions gave the desired compounds C3. Rs couldPatent Application LTGO-019 / 01WO 36088 / 124 be further functionalized with appropriate reagents. If Rs involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others.

[2207] Scheme D

[2208]

[2209] D2 D3

[2210] As illustrated in Scheme D, in general, compounds of the invention can be prepared by reaction of appropriately ester Bl with lithium salt of 3,5-dimethylisoxazole to afford DI. Heating DI in the presence of molybdenum hexacarbonyl to afford D2. D2 could be further functionalized with appropriate reagents to give D3.

[2211] Scheme E

[2212]

[2213] As illustrated in Scheme E, in general, compounds of the invention can be prepared by reaction of appropriately ester A4 with lithium salt of 3.5-dimethylisoxazole to afford El. Heating El in the presencePatent Application LTGO-019 / 01WO 36088 / 124 of molybdenum hexacarbonyl to afford E2. E2 could be further functionalized with appropriate reagents to give E3.

[2214] Scheme F

[2215] F2

[2216]

[2217] F4

[2218] As illustrated in Scheme F, in general, similar to Scheme B, Ester Fl can be converted to corresponding acid F2 by treating Fl with base such as LiOH in aqueous THF or MeOH. Reacting F2 with an appropriate amine utilizing appropriate amide coupling afforded the desired compounds F3. Cyclization of F3 under basic conditions gave the desired compounds F4. Rs could be further functionalized with appropriate reagents. If Rs involved a protecting group, then a subsequent deprotection step was carried out to remove the protecting group, such as Boc or others.

[2219] 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 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.

[2220] Intermediates

[2221] Intermediate 1

[2222] 7rans-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-l-carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124

[2223]

[2224] Reagents & conditions: a) 4-m ethylbenzenesulfonyl azide, TEA, DCM; b) MeOH, toluene, M. W., 140 °C; c) 2-[N, N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine, KHMDS, THF; d) Pd(PPh3)4, K3PO4, dioxane / H2O, 100 °C; e) H2. Pd / C, Pd(OH)2. 50 °C; t) LiOH, THF / H2O / MeOH

[2225] Step 1: To a solution of 5, 5-dimethylcyclohexane-l, 3-dione (5 g, 35.7 mmol) in DCM (80 mL) was added 4-methylbenzenesulfonyl azide (14.08 g. 71.4 mmol) and TEA (10.84 g, 107.1 mmol) slowly. The mixture was stirred at room temperature for 16 hours Then the resulting mixture was diluted with water (100 mL) and extracted with DCM (80 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, 0% to 50%) to give 2-diazo-5,5-dimethylcyclohexane-1,3-dione (6 g, 96% yield) as a yellow oil. HNMR (400 MHz, DMSO-d6, ppm) 52.44 (s, 4 H), 1.03 (s, 6 H).

[2226] Step 2: To a solution of 2 -diazo-5, 5-dimethylcyclohexane-l, 3-dione (6 g, 36.1 mmol) in toluene (60 mL) was added MeOH (1.16 g, 36.1 mmol). The mixture was heated at 140 °C in a microwave reactor for 20 minutes. The organic solvent was removed under reduced pressure. Then the resulting mixture was 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, 0% to 30%) to give methyl 4, 4-dimethyl-2 -oxocyclopentane- 1- carboxylate (5 g, 77.29% yield) as a yellow oil. ‘H NMR (400 MHz, CDCL, ppm) δ 3.75 (s, 3 H), 3.39 (dd, J = 11.0, 8.8 Hz, 1H), 2.36-2.01 (m, 4 H), 1.24 (s, 3 H), 1.06 (s, 3 H).

[2227] Step 3: To a solution of methyl 4,4-dimethyl-2 -oxocyclopentane- 1 -carboxylate (2.5 g, 14.7 mmol) in dry THF (30 mL) was added KHMDS (IM in hexane, 17.6 mL, 17.6 mmol) dropwise at room temperature under an atmosphere of N2. After addition, the solution was stirred at room temperature for 40 minutes. Then 2-[N,N-Bis(trifluoromethylsulfonyl)amino]-5-chloropyridine (6.93 g, 17.6 mmol) was added dropwise. Tire resulting solution was stirred for 2 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 withPatent Application LTGO-019 / 01WO 36088 / 124 brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 20%) to give methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (3.5 g, 74.83% yield) as a yellow oil. LCMS (ESI) calcd. for C10H14F3O5S [M + H]+m / z 303.05, found 303.1.

[2228] Step 4: To a solution of methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-1 -carboxylate (3.5 g, 11.6 mmol) in 1,4-dioxane / H2O (10 / 1, 40 mL) was added (3,4-difluoro-2-methoxyphenyl)boronic acid (2.4 g, 12.7 mmol), Tetrakis(triphenylphosphine)Palladium (1.34 g, 1.1 mmol) and tripotassium phosphate (7.39 g, 34.8 mmol) slowly under N2. The mixture was heated at 100 °C for 16 hours. Then the resulting mixture was diluted with water (80 mL) and extracted with EtOAc (80 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, 0% to 20%) to give methyl 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-1-ene-1-carboxylate (3.5 g, 91.38% yield) as a yellow oil.

[2229] Step 5: A mixture of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-l-carboxylate (1.5 g, 5.0 mmol), Pd / C (500 mg) and Pd(OH)2(500 mg) in isopropyl alcohol (15.0 mL) was heated at 50 °C under an atmosphere of H2(2.5 MPa) for 16 hours in a high-pressure reactor Then the mixture was filtered through celite. The filtrate was concentrated under vacuum to give crude methyl 2- (3, 4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-l -carboxylate (1.5 g) which was used directly in next step without further purification.

[2230] Step 6: To a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-l-carboxylate (1.5 g, 5.0 mmol) in MeOH / H2O / THF (1 / 1 / 1. 20 mL) was added Lithium hydroxide (0.24 g, 10.0 mmol). Tire mixture was stirred at 25 °C for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3). The aqueous solution was adjusted to pH 2-3 with 2N HCI and then extracted with EtOAc (30 111L x 3) to provide trans-2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-1-carboxylic acid (1.2 g. 76% yield) as a yellow' oil. LCMS (ESI) calcd. for C15H19F2O3[M + H]+m / z 285.13. found 285.1.

[2231] Intermediate 2

[2232] 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-l-carboxamide

[2233]

[2234] Patent Application LTGO-019 / 01WO 36088 / 124 Reagents & conditions: a) LiOH, THF, MeOH, H2O; b) HATU, DIEA, NH3. MeOH, DMF Step 1: To a solution of methyl 2-(3.4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-1 -carboxylate (200 mg, 0.67 mmol) in MeOH / THF / H2O = 1 / 1 / 1 (9 mL) was added LiOH (162 mg, 6.75 mmol). The mixture was stirred at 25 °C for 2 hours. Tire reaction was monitored by LCMS The aqueous solution was adjusted to pH 2-3 with 2N HC1. 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 DCM / MeOH =10 / 1) to provide 2-(3.4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-1 -carboxylic acid (180 mg, 90% yield) as a white solid. LCMS (ESI) calcd. for C15H17F2O3[M + H]+m / z 283.12, found 282.7.

[2235] Step 2: To a solution of 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-l-carboxylic acid (180 mg, 0.63 mmol) in 7M NH3 in McOH (5 mL) and DMF (5 mL) was added HATU (404 mg, 1,06 mmol) and DIEA (274 mg, 2.12 mmol), Tire mixture was stirred at 25 °C for 1 hour. Tire reaction was monitored by LCMS. 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 DCM / MeOH = 20 / 1) to provide 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopent-l-ene-l-carboxaroide (150 mg, 81% yield) as a yellow oil. LCMS (ESI) calcd. for C15H18F2NO2[M + H]+m / z 282.13, found 281.7.

[2236] Intermediate 3

[2237] (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(tnfluoromethyl)cyclopentane-l-carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124

[2238]

[2239] Reagents & conditions: a) DCM, r.t.; b) NaOEt, EtOH, reflux; c) NaOH, FLO, reflux: d) 4-methylbenzenesulfonyl azide, TEA, DCM; e) MeOII, toluene, M. W, 140 °C; f) KHMDS, THF; g) Pd(PPh3)4, K3PO4, dioxane / H2O, 100 °C: h) H2, Pd / C, Pd(OH)2, 50 °C; i) NaOMe / MeOH

[2240] Step 1: To a solution of ethyl 2-(triphenyl-15-phosphaneylidene)acetate (62 g, 0.18 mmol) in DCM (600 mL) was added 1,1,1,1-trifluoropropan-2-one (20 g, 0.18 mmol) dropwise at 0°C. Tire mixture was stirred at room temperature for 8h. After the reaction was completed. The mixture was concentrated in vacuum. The residue was triturated with Et2O. Then the mixture was filtered through celite and the filtrate was concentrated under vacuum to give crude ethyl (E)-4,4,4-trifluoro-3-methylbut-2-enoate (25 g) which was used directly in next step without further purification.

[2241] Step 2: To a solution of EtONa (20% in EtOH, 18.68 g, 54.94 mmol) in EtOH (100 mL) was added ethyl 3-oxobutanoate (7.14g, 54.94 mmol). The mixture was stirred at room temperature for 0.5 h. Then ethyl (E)-4,4,4-trifluoro-3-methylbut-2-enoate (10 g, 54.94 mmol) was added to the mixture. The mixture was stirred at room temperature for 0.5 h and then heated at 80 °C for 8 h. After the reaction was completed. Hie mixture was concentrated under vacuum. The residue was diluted with water. The mixture was adjusted PH to 3-4 with 3N H2SO4and extracted with DCM (50 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 Cis column, 150*21.2 mm, eluting with 50% to 95% MeCN / H2O containing 0.1% FA) to provide ethyl 2-methyl-4,6-dioxo-2-(trifluoromethyl)cyclohexane-l-carboxylate (2.3 g. 16% yield) as yellow solid LCMS (ESI) calcd. for C11H14F3O4[M + H] m / z 267.09, found 266.95.Patent Application LTGO-019 / 01WO 36088 / 124 Step 3: A solution of ethyl 2-methyl-4,6-dioxo-2-(trifluoromethyl)cyclohexane-l-carboxyIate (5.4 g, 20.22 mmol) and NaOH (4.0 g. 101.12 mmol) in H2O (60 mL) was heated at 100 °C for 4 hours. After the reaction was completed. The mixture was adjusted PH to 3-4 with 3N ^SC and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to give 5-methyl-5-(trifluoromethyl)cyclohexane-l, 3-dione (2.2 g, 56% yield ) as a yellow solid. LCMS (ESI) calcd. for C8H10F3O2[M + H] m / z 195.07, found 195.20.

[2242] Step 4: To a solution of 5-methyl-5-(trifluoroniethyl)cyclohexane-l, 3-dione (2.8 g, 14.35 mmol) in DCM (30 mL) was added 4-methylbenzenesulfonyl azide (4,24 g, 21,53 mmol) and TEA (4.35 g, 43.07 mmol) slowly The mixture was stirred at room temperature for 16 hours. Then the resulting mixture was diluted with water (60 mL) and extracted w ith DCM (50 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, 0% to 30%) to give 2-diazo-5-mcthyl-5-(trifluoromethyl)cyclohexane-l, 3-dione (2.7 g, 86% yield) as a yellow oil

[2243] Step 5: To a solution of 2-diazo-5-methyl-5-(trifluoromethyl)cyclohexane-l.3-dione (1.4 g, 6.36 mmol) in toluene (10 mL) was added MeOH (244 mg, 7.63 mmol). The mixture was heated at 140 °C in a microwave reactor for 30 minutes. The organic solvent was removed under reduced pressure. Then the resulting mixture was diluted with water 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, 0% to 30%) to give methyl 4- methyl-2-oxo-4-(tnfluoromethyl)cyclopentane-l -carboxylate (1.2 g, 85% yield) as a yellow oil. LCMS (ESI) calcd. for C9H12F3O3 [M + H]+m / z 225.08, found 225.20.

[2244] Step 6: To a solution of methyl 4-methyl-2-oxo-4-(trifluoromethyl)cyclopentane-1-carboxylate (1.2 g, 5.33 mmol) in dry THF (10 mL) was added KHMDS (IM in hexane, 6.4 mL, 6.40 mmol) dropwdse at room temperature under an atmosphere of N2. After addition, the solution was stirred at room temperature for 40 minutes. Then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N- ((trifluoromethyl)sulfonyl)methanesuJfonamide (2,5 g, 6.40 mmol) was added dropwise, Tire resulting solution was stirred for 2 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 chromatography (eluting with PE / EtOAc, 0% to 20%) to give methyl 4-methyl-4-(trifluoromethyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1 -carboxylate (1.6 g, 85% yield) as a yellow' oil.

[2245] Step 7: To a solution of methyl 4-methyl-4-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (1.5 g, 4.21 mmol) in 1,4-dioxane / H2O (4 / 1, 15 mL) was added (3,4-difluoro-2-methoxyphenyl)boronic acid (1.1 g, 6.32 mmol), Pd(PPh3)4 (483Patent Application LTGO-019 / 01WO 36088 / 124 mg, 0.42 mmol) and K3PO4 (2.6 g. 12.63 mmol) slowly under N2. The mixture was heated at 100 °C 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 under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 20%) to give methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l-ene-l-carboxylate (1.4 g, 95% yield) as a yellow solid. LCMS (ESI) calcd. for C16H16F5O3[M + H]+m / z 351.10, found 351.05.

[2246] Step 8: A mixture of methyl 2-(3.4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l-ene-l-carboxylate (700 mg. 1.99 mmol), 10% Pd / C (350 mg) and 10% Pd(OH)2 / C (350 mg) in MeOH (10 mL) was heated at 50 °C under an atmosphere of H2(4 MPa) for 16 hours in a high-pressure reactor. 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 PE / EtOAc, 0% to 20%) to give methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxylate (400 mg, 57% yield) as a yellow solid. LCMS (ESI) calcd. for C16H18F5O3[M + H]+m / z 353.12, found 352.70.

[2247] Step 9: To a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylate (380 mg, 1.08 mmol) in MeOH (5 mL) was added 30% MeONa in MeOH (5 mL). Tire mixture was stirred at 80 °C for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was adjusted to pH 5-6 with 4N aqueous HC1 and extracted with EtOAc (30 mL x 3). Tire combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 20%) to give (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylic acid (350 mg, 96% yield) as a yellow solid. LCMS (ESI) calcd. for C15H14F5O3[M - H]-m / z 337.08, found 337.00.

[2248] Intermediate 4

[2249] 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)c\ clopent- 1 -ene-1 -carboxylic acid

[2250] a step 1

[2251]

[2252] Reagents & conditions: a) Li OH, THF, MeOH, H2OPatent Application LTGO-019 / 01WO 36088 / 124 Step 1: To a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l-ene-l -carboxylate (500 mg, 1.43 mmol) in THF / MeOHTLO (1 / 1 / 1, 12 mL) was added LiOH (801 mg, 14.3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was adjusted to pH = 3-4 with aqueous IM aqueous HC1. Then the solution was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide crude 2-(3,4-difluoro-2-methoxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l-eiie-l -carboxylic acid (350 mg) as a yellow' solid, which was used directly in next step without further purification. LCMS (ESI) calcd. for C15H12F5O3 [M - H] m / z 335.07, found 334.90.

[2253] Intermediate 5

[2254] (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(difluoromethoxy)cyclopentane-1-carboxylic acid

[2255]

[2256] Reagents & conditions: a) Pd(OAc)2, Sphos. 80 °C; b) Pd(PPhs)4, 1.2-bis(diphenylphosphino)ethane, THF, reflux; c) NalO4, K2OsO4, dioxane / H2O; d) NaBHi, THF; e) TMSCF. Br, KOAc. H2O. DCM; f) LiOH, THF, MeOH, H2O

[2257] Step 1: To a solution of l-bromo-3,4-difluoro-2-methoxybenzene (2.0 g, 9.0 mmol) in DMF (20 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (4.1 g. 18.0 mmol), Pd(OAc)2 (0.1 g, 0.45 mmol), Sphos (0.4 g, 0.9 mmol) and K3PO4 (5.7 g, 27 mmol). The mixture was stirred at 80 °C for 16 hours under N₂ atmosphere. Then the resulting mixture was diluted with ater (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 = 10 / 1) to provide ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (2.2 g, 62% yield) as a yellow oil.Patent Application LTGO-019 / 01WO 36088 / 124 Step 2: To a solution of ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (2.2 g, 9.1 mmol) in THF (20 mL) was added 2-((triinethylsilyl)inethyl)allyl acetate (3.1 g, 16.3 mmol), Pd(PPh3)4 (0.7 g, 0.6 mmol) and 1,2-Bis(dipheiiylphosphmo)ethane (0.2 g, 0.5 mmol). The mixture was heated at reflux for 16 hours. Then the resulting mixture was diluted with water (60 mL) and extracted with EtOAc (60 rnL 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 ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methyienecyclopentane-l-carboxylate (2.0 g, 67% yield) as a yellow oil.

[2258] Step 3: To a solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methylenecyclopentane- 1 -carboxylate (300 mg, 1 0 mmol) in l,4-dioxane / H2O (4 / 1, 10 mL) was added NaIO4 (860 mg, 4.0 mmol) and K2OsO4(37 mg, 0.1 mmol). The mixture was stirred at 25 °C for 2 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 chromatography (eluting w ith PE / EtOAc =10 / 1) to provide ethyl (trans)-2-(3,4-difluoro- 2-methoxyphenyl)-4-oxocyclopentane-l -carboxylate (300 mg, 93% yield) as a yellow oil. LCMS (ESI) ealed. for C15H17F2O4[M + H]+m / z 299.11, found 298.7.

[2259] Step 4: To a solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-oxocyclopentane-l- carboxylate (1,5 g, 5 mmol) in THF (5 mL) was added NaBH4(0.57 g, 15.0 mmol) at 0 °C. Tire mixture was stirred at 25 °C for 8 hours. The mixture was quenched with MeOH and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to provide ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxycyclopentane-l-carboxylate (1.57 g, 90% purity) as colorless oil. LCMS (ESI) calcd. for C15H19F2O4[M + H]+m / z 301 12, found 300.55.

[2260] Step 5: To a solution of ethyl (trans)- 2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxycyclopentane-1 -carboxylate (1.57 g, 90% purity) in DCM (20 mL) and H2O (20 mL) was added TMSCF2Br (2.20 g, 11.0 mmol) and KO Ac (2.04 g, 21.0 mmol). The mixture was stirred at 25 °C for 24 hours. The mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed w ith 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 ethyl (trans)- 2-(3,4-difluoro-2-methoxyphenyl)-4-(difluoromethoxy)cyclopentane-l -carboxylate (880 mg) as a colorless oil. LCMS (ESI) calcd. for C16H19F4O4[M + H]+m / z 351.12, found 350.70.

[2261] Step 6: To a solution of ethyl (trans)- 2-(3.4-difluoro-2-methoxyphenyl)-4-(difluoromethoxy)cyclopentane- 1 -carboxylate (1000 mg, 2.85 mmol) in THF / EtOH / H2O = 1 / 1 / 1 (15 mL) was added LiOH (342.6 mg, 14.27 mmol). The mixture was stirred at 25 °C for 8 hours. After the reaction was completed, the solution was adjusted to pH = 5-6 with saturated HQ solution (IM). Then the mixturePatent Application LTGO-019 / 01WO 36088 / 124 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 (DCM / MeOH = 10 / 1) to provide trans-2-(3,4-difluoro-2-methoxyphenyl)-4-(difluoromethoxy)cyclopentane-1-carboxylic acid (890 mg, 87% yield) as colorless oil. LCMS (ESI) calcd. for C14H15F4O4[M + H]+m / z 323.09, found 322.65.

[2262] Intermediate 6

[2263] (trans)-4,4-dimethyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)cydopentane-l-carboxylic acid

[2264] a step 1

[2265]

[2266] Reagents & conditions: a) Pd(PPh3)4, K3PO4, dioxane, H O. 100 °C; b) Pd / C, Pd(OH)2, 50 °C; c) NaOMe, MeOH, 60 °C

[2267] Step 1: To a solution of methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-1-carboxylate (2.6 g, 8.60 mmol) in l,4-dioxane / Fl2O (4 / 1, 30 mL) was added (2-methyl-4-(trifluoromethoxy)phenyl)boromc acid (2.84 g, 12.9 mmol), Tetrakis(triphenylphosphine)palladium (994 mg, 0.86 mmol) and tripotassium phosphate (5.48 g, 25.8 mmol) slowly under N2. The mixture was heated at 100 °C for 2 hours. Then the resulting mixture was diluted with water (80 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. Hie residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0%to 10%) to give methyl 4.4-dimethyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)cyclopeiit-l-ene-1 -carboxylate (2.4 g. 85% yield) as a yellow oil. LCMS (ESI) calcd. for C17H20F3O3 [M + H]4m / z 329.14, found 329.05.

[2268] Step 2: A mixture of methyl 4,4-dimethyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)cyclopent-l-ene-1 -carboxylate (2.4 g, 7.31 mmol), 10% Pd / C (1.2 g) and 10% Pd(OH)2(1.2 g) in MeOH (25 mL) was heated at 50 °C under an atmosphere of H2(2.5 MPa) for 16 hours in a high-pressure reactor. Then the mixture was filtered through celite. The filtrate was concentrated under vacuum to give crude methyl 4,4- dimethyl-2-(2-methyI-4-(trifluoromethoxy)phenyl)cyclopentane-l -carboxylate (24 g) which was used directly in next step without further purification. LCMS (ESI) calcd. for C17H22F3O3[M + H]+m / z 331.15, found 331.05.

[2269] Step 3: To a solution of crude methyl 4,4-dimethyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)cyclopentane-1-carboxylate (2.4 g, 7.27 mmol) in MeOH (20 mL) was addedPatent Application LTGO-019 / 01WO 36088 / 124 30% MeONa in MeOH (20 mL). The mixture was stirred at 60 °C for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was adjusted to pH 5-6 with 4N aqueous HC1 and extracted with EtOAc (30 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 DCM / MeOH, 0% to 5%) to give (trans)-4,4-dimethyl-2-(2-methyI-4-( trifluoromethoxy )phenyl)cyclopentane-l -carboxylic acid (1.8 g) as a yellow oil. LCMS (ESI) calcd. for C16H18F3O3 [M - H]⁻ m / z 315.12. found 315.00.

[2270] Intermediate 7

[2271] (trans)-7-(3,4-difluoro-2-methoxyphenyl)spiro|3.4]octane-6-carboxylic acid

[2272]

[2273] Reagents & conditions: a) 4-methylbenzenesulfonyl azide, TEA, DCM; b) MeOH, toluene, MW, 120 °C; c) Tf2O, DIEA, DCM; d) Pd(PPh3)4, K2PO4, dioxane, H2O, 100 °C; e) H2, Pd / C, Pd(OH)2, 50 °C; f) NaOMe. MeOH, 70 °C

[2274] Step 1: To a solution of spiro[3.5]nonane-6, 8-dione (5 g, 33 mmol) in DCM (50 mL) was added 4-methylbenzenesulfonyl azide (12.98 g, 66 mmol) and TEA (9.97 g, 99 mmol). The resulting mixture was stirred at 25 °C for 4 hours. The mixture was mixture with silica gel and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc / PE =1 / 5) to provide 7- diazospiro[3,5]nonane-6, 8-dione (5.6 g, 95% yield) as a yellow- oil. LCMS (ESI) calcd. for C9H11N2O2 [M + H]+m / z 179.08, found 178.60.

[2275] Step 2: To a solution of 7-diazospiro[3.5 |nonane-6, 8-dione (5.6 g, 31 mmol) in toluene (70 mL) was added MeOH (1.11 g, 35 mmol). The mixture was heated at 120 °C for 2.0 min in a microwave reactor (sealed tube). Then the mixture was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 10) to provide methyl 7-oxospiro[3.4]octane-6-carboxylate (5.27 g, 93% yield) as a colorless oil. LCMS (ESI) calcd. for C 10H15O3 [M + H]+m / z 183.10, found 182.65.Patent Application LTGO-019 / 01WO 36088 / 124 Step 3: To a solution of methyl 7-oxospiro[3.4]octane-6-carboxylate (5.27 g, 29 mmol) in DCM (70 mL) was added DIEA (11.21 g, 87 mmol) at -78 °C under N2. Then Tf2O (17.94 g, 64 mmol) was added to the mixture at the same temperature. I’he mixture was warmed to 25 °C and stirred for 1 hour. Then the 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, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc / PE ===1 / 10) to provide methyl 7-(((trifluoromethyl)sulfonyl)oxy)spiro[3.4]oct-6-ene-6-carboxylate (8.6 g, 80% purity) as a yellow oil. LCMS (ESI) calcd. for C11H14F3O5S [M + H]+m / z 315.05, found 314.60.

[2276] Step 4: To a solution of methyl 7-(((trifluoromethyl)sulfonyl)oxy)spiro[3.4]oct-6-ene-6-carboxylate (8.6 g, 80% purity), (3,4-difluoro-2-methoxyphenyl )boronic acid (5 15 g, 27 mmol) and K3PO4 (17.45 g, 82 mmol) in dioxane / H2O=10:l (110 mL) was added Pd(PPh3)4 (3.17 g, 2.7 mmol). The mixture was stirred at 100 °C for 16 hours under N2. The mixture was filtered through celite. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 10) to provide methyl 7-(3,4-difluoro-2-methoxyphenyl)spiro[3.4]oct-6-ene-6-carboxylate (8 02 g) as a yellow oil. LCMS (ESI) calcd. for C17H19F2O3 [M + H]+m / z 309.13, found 308.65.

[2277] Step 5: To a solution of methyl 7-(3.4-difluoro-2-methoxyphenyl)spiro[3.4]oct-6-ene-6- carboxylate (4 g, 13 mmol) in MeOH (70 mL) was added 10% Pd / C (2.08 g, 20 mmol) and 10% Pd(OH)2(2.01 g, 14 mmol). Tire mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture w as stirred at 50 °C for 8 hours. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum to provide crude methyl 7-(3.4-difluoro-2-methoxyphenyI)spiro[3.4]octane-6-carboxylate (8 g) as a colorless oil. LCMS (ESI) calcd. for C17H21F2O3 [M + H]+m / z 311.15, found 311.05.

[2278] Step 6: Methyl 7-(3,4-difluoro-2-methoxy'phenyl)spiro[3.4]octane-6-carboxylate (4 g, 13 mmol) was dissolved in 30% MeONa in MeOH (70 mL). Hie solution was stirred at 70 °C for 2 hours. The mixture was concentrated under vacuum. Hie residue was diluted with water (100 mL) and adjusted to pH = 5 with 3 M HC1 and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide crude (trans)-7-(3,4-difluoro-2-methoxyphenyl)spiro[3.4|octane-6-carboxylic acid (3.6 g, 57% yield) as a yellow oil. LCMS (ESI) calcd. for CifiH19F2O3[M + H]+m / z 297.13, found 296.70.

[2279] Intermediate 8

[2280] (trans)-3-(3,4-difluoro-2-methoxyphenyl)spiro

[0044] nonane-2 -carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124

[2281]

[2282] Reagents & conditions: a) 4-m ethylbenzenesulfonyl azide, TEA, DCM; b) MeOH, toluene, MW, 120 °C; c) Tf2O, DIEA, DCM; d) Pd(PPh3)4, K3PO4, dioxane, H2O, 100 °C; e) H2, Pd / C, Pd(OH)2, 50 °C; f) NaOMe, MeOH, 70 °C

[2283] Step 1: To a solution of spiro[4.5]decane-7, 9-dione (5 g, 30.08 mmol) in DCM (50 mL) was added 4-metliylbenzenesulfonyl azide (11.87 g. 60.16 mmol) and TEA (9.13 g. 90.24 mmol). The resulting mixture was stirred at 25 °C for 4 hours. The mixture was mixture with silica gel and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 5) to provide 8-diazospiro[4.5]decane-7, 9-dione (5.5 g, 95% yield) as a yellow solid. LCMS (ESI) calcd. for C10H13N2O2[M + H]+m / z 193.10, found 192.65.

[2284] Step 2: To a solution of 8-diazospiro[4.5]decane-7, 9-dione (5 g. 26 mmol) in toluene (70 mL) was added MeOH (0.83 g. 26 mmol). The mixture was heated at 120 °C for 20 min in a microwave reactor (sealed tube). Then the mixture was concentrated under vacuum The residue was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 10) to provide methyl 3-oxospiro

[0044] nonane-2-carboxylate (4 8 g, 94% yield) as a colorless oil. ’H NMR (400 MHz. DMSO-d6, ppm) 8 3.64 (s. 3 H), 3.51 (dd, J = 10.6, 9.2 Hz, 1 H), 2.26 (s, 2 H), 2.16-2.10 (m, 2 H), 1.66-1.55 (m, 6 H), 1.52-1.42 (m, 2 H).

[2285] Step 3: To a solution of methyl 3-oxospiro[4.4]nonane-2 -carboxylate (4.5 g, 22.9 mmol) in DCM (50 mL) was added DIEA (5.92 g, 45.8 mmol) at -78 °C under N2. Then Tf2O (12.92 g, 45.8 mmol) was added to the mixture at the same temperature. Hie mixture was warmed to 25 °C and stirred for 1 hour. Then the mixture was diluted with water (100 mL) and extracted with DCM (100 mL x 3). Tire 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 (EtOAc / PE ===1 / 10) to provide methyl 3-(((tnfluoroniethyl)sulfonyl)oxy)spiro[4.4]non-2-ene-2-carboxylate (4.66 g) as a yellow oil. LCMS (ESI) calcd. for C12H16F3O5S [M + H]+m / z 329.07, found 328.65.

[2286] Step 4: To a solution of methyl 3-(((trifluoromethyl)sulfonyl)oxy)spiro[4.4]non-2-ene-2-carboxylate (4.66 g, 14.2 mmol), (3,4-difhioro-2-methoxyphenyl)boronic acid (3.2 g, 17.04 mmol) andPatent Application LTGO-019 / 01WO 36088 / 124 K3PO4 (9.04 g, 42.6 mmol) in dioxane / H2O = 4 / 1 (50 mL) was added Pd(PPh3)4 (1.64 g, 1.42 mmol). The mixture was stirred at 100 °C for 2 hours under N2. The mixture was filtered through celite. The filtrate was concentrated under vacuum, The residue was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 10) to provide methyl 3-(3,4-difluoro-2-methoxyphenyl)spiro[4.4]non-2-ene-2-carboxylate (4.2 g, 91% yield) as a yellow oil. LCMS (ESI) calcd. for

[2287]

[2288] [M + H]+m / z 323.14, found 322.70.

[2289] Step 5: To a solution of methyl 3-(3,4-difluoro-2-methoxyphenyl)spiro[4.4]non-2-ene-2-carboxylate (4.2 g, 13 mmol) in MeOH (70 mL) was added 10% Pd / C (2.08 g, 19.8 mmol) and 10% Pd(OH)2 (2.01 g, 14,9 mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred at 50 °C for 16 hours. After cooling to ambient temperature, the mixture was filtered through celite, and the filtrate was concentrated under vacuum. The reside was purified by flash column chromatography on silica gel (EtOAc / PE = 1 / 10) to provide methyl 3-(3,4-difluoro-2-mcthoxyphcnyl)spiro[4.4]nonanc-2 -carboxylate (3.1 g, 66% yield) as a colorless oil LCMS (ESI) calcd. for C18H23F2O3 [M + H]+m / z 325.16, found 324.70.

[2290] Step 6: methyl 3-(3.4-difluoro-2-methoxyphenyl)spiro[4.4]nonane-2 -carboxylate (2.6 g, 8 mmol) was dissolved in 30% MeONa in MeOH (70 mL) The solution was heated at 70 °C for 16 hours. The mixture was concentrated under vacuum. The residue was diluted with water (100 mL) and adjusted to pH = 5 with 3M HC1 and extracted with 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 silica gel (MeOH / DCM = 1 / 10) to provide (trans)-3-(3,4-difluoro-2- methoxyphenyl)spiro[4.4]nonane-2-carboxylic acid (2.3 g. 93% yield) as a yellow' solid. LCMS (ESI) calcd. for C17H21F2O3 [M + H]+m / z 311.15, found 310.70.

[2291] Intermediate 9

[2292] (trans)-2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l-carboxylic acid

[2293]

[2294] Patent Application LTGO-019 / 01WO 36088 / 124 Reagents & conditions: a) Pd(PPh3)4, K3PO4, dioxane, H2O, 100 °C; b) Pd / C, Pd(OH)2, H2, iPrOH, 70 °C, c) NaOH, MeOH, 70 °C

[2295] Step 1: To a solution of methyl 4-methyl-4-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-l -ene-1 -carboxylate (300 mg, 0.84 mmol) in 1,4-Dioxane / H2O = 4 / 1 (10 mL) was added 2-(3,4-difluoro-2-isopropylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (284 mg, 1.00 mmol), Pd(PPh3)4 (97 mg, 0.08 mmol) and K3PO4 (534 mg. 2.52 mmol) under N2. The mixture was stirred at 100 °C for 4 hours. Then the resulting 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, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 10%) to give methyl 2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l -ene-1 -carboxylate (280 mg, 92% yield) as a clear oil. LCMS (ESI) calcd. for C18H20F5O2 [M + H]+m / z 363.14, found 362.80.

[2296] Step 2: A mixture of methyl 2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4- (trifluoromethyl)cyclopent-l -ene-1 -carboxylate (280 mg, 0.77 mmol). 10% Pd / C (164 mg. 1.54 mmol) and 10% Pd(OH)2 (216 mg, 1.54 mmol) in i-PrOH (5 mL) was heated at 70 °C under an atmosphere of H2(30 atm) for 16 hours in a high-pressure reactor. Then the mixture was filtered through celite The filtrate was concentrated under vacuum to give crude methyl 2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylate (280 mg) which was used directly in next step without further purification. LCMS (ESI) calcd. for C18H22F5O2 [M + H]+m / z 365.15. found 364.75.

[2297] Step 3: To a solution of methyl 2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4-(trifluorometbyl)cyclopentane-l -carboxylate (280 mg, 0.76 mmol) in MeONa (15% in MeOH, 5 mL) The mixture was stirred at 70 °C for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was adjusted to pH 5-6 with 4N aqueous HC1 and extracted with EtOAc (30 mL x 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 DCM / MeOH, 0% to 5%) to give (trans)-2-(3,4-difluoro-2-isopropylphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylic acid (240 mg, 89% yield) as a clear oil. ’H hlMR (400 MHz, DMSO-d6 ppm) 8 12.40 (s, 1 H), 7.24 (q, J = 8.7 Hz. 1 H), 7.16 (dd, J = 8.8, 4.5 Hz, 1 H), 3.74 (td, J = 11.7, 7.4 Hz, 1 H), 3.44-3.36 (m, 1 H), 3.06 (q, J= 10.5 Hz, 1 H), 2.44 (dd, J= 13.9, 8.5 Hz, 1 H), 1.98- 1.91 (m, 1 H), 1.85-1.77 (m, 2 H), 1.35 (s, 3 H), 1.30 (t, J= 6.6 Hz, 6 H),

[2298] Intermediate 10

[2299] (trans)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylcyclopentane-l-carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124

[2300]

[2301] F F Reagents & conditions: a) BB13, DCM; b) sodium chlorodifluoroacetate, K2CO3, DMF; c) LiOH, THF, MeOH, H2O

[2302] Step 1: To a solution of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4,4-dimethylcyclopentane-1-carboxylate (1.5 g, 5.0 mmol) in DCM (20 mL) was added BBr3 (3.76 g, 15.0 mmol) dropwise at -78 °C under N2. Then the mixture was stirred at 25 °C for 8 hours. The mixture was quenched with MeOH and concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide methyl 2-(3,4-difluoro-2-hydroxyphenyl)-4,4-dimethylcyclopentane-1 -carboxylate (1.45 g, 90% purity, 91% yield) as a yellow oil. LCMS (ESI) calcd. for C15H19F2O3 [M + H]+m / z 285.13, found 284.70.

[2303] Step 2: To a solution of methyl 2-(3,4-difluoro-2-hydroxyphenyl)-4,4-dimethylcyclopentane-1-carboxylate (1.45 g. 90% purity) in DMF (10 mL) was added sodium chlorodifluoroacetate (0.93 g, 6.10 mmol) and K2CO3 (0.85 g, 6.10 mmol). The mixture was stirred at 115 °C 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 (EtOAc / PE = 1 / 20) to provide methyl 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-4.4-dimethylcyclopentane-l-carboxylate (1.06 g) as a yellow oil. LCMS (ESI) calcd. for C16H19F4O3 [M + H| m / z 335.13. found 334.70.

[2304] Step 3: To a solution of methyl 2-(2-(difluoromethoxy)-3,4-difluorophenyl)-4.4- dimethylcyclopentane-1 -carboxylate (1.06 g, 3.20 mmol) in THF / MeOH / H2O = 1 / 1 / 1 (15 mL) was added LiOH (0.38 g, 16.0 mmol). Tire mixture was stirred at 25 °C for 3 hours. The residue ’as diluted with water (30 mL) and adjusted to pH = 5 with 3 M HC1. Then the mixture was extracted with EtOAc (30 mL × 3). Hie combined organic layers were washed with brme, dried over sodium sulfate, concentrated under vacuum to provide crude (trans)-2-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,4-dimethylcyclopentane-1-carboxylic acid (1 g) as a yellow oil, which was used directly in subsequent steps without further purification.

[2305] Intermediate 11

[2306] (trans)-4-methyl-2-(2-methyl-4-(tri fluoromethoxy )phenyl)-4-(trifluoromethyl)cyclopentane-l-carboxyhc acidPatent Application LTGO-019 / 01WO 36088 / 124

[2307]

[2308] Reagents & conditions: a) Pd(PPhj)+, KjPCfi, dioxane, H O. 100 °C; b) Pd / C, Pd(OH)2, H2, iPrOH, 70 °C: c) NaOMe, MeOH, 60 °C

[2309] Step 1: A solution of methyl 4-methyl-4-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (4 g, 11.24 mmol), (2-methyl-4-(trifluoromethoxy)phenyl)boronic acid (2.97 g, 13.48 mmol). K3PO4 (7.15 g. 33.72 mmol) and Pd(PPh3)4 (1.29 g, 1.12 mmol) in dioxane / H2O (80 mL, 4 / 1) was heated at 100 °C for 8 hours under N2 atmosphere LCMS showed the reaction was completed. Then the mixture was concentrated in vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 3 / 1) to provide methyl 4-methyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)cyclopent-l-ene- 1 -carboxylate (2.85 g, 66% yield) as a yellow oil. LCMS (ESI) calcd. for C17H17F6O3 [M + H]+m / z 383.11, found 383.05.

[2310] Step 2: A mixture of methyl 4-methyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)cyclopent-l-ene-l -carboxylate (2.8 g, 7.33 mmol), 10% Pd / C (1.4 g) and 10% Pd(OH)2 / C (1.4 g) in MeOH (300 mL) was heated at 60 °C under an atmosphere of H2(4 MPa) for 16 hours in a high- pressure reactor. 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 PE / EtOAc, 0% to 20%) to give methyl 4-methyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)cyclopentane-l-carboxylate (2 1 g, 74% yield) as a yellow oil. LCMS (ESI) calcd. for C17H19F6O3 [M + IT|’ m / z 385.12, found 384.75.

[2311] Step 3: To a solution of methyl 4-methyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (2.1 g, 5,45 mmol) in MeOH (40 mL) was added McONa (2.36 g, 43.64 mmol). The mixture was heated at reflux for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was adjusted to pH 5-6 with 4N aqueous HC1 and extracted with EtOAc (50 mL x 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 DCM / MeOH, 0% to 10%) to give (trans)-4-methyl-2-(2-methyl-4-(trifluoromethoxy)phenyl)-4-(trifluoromethyl)cyclopentane-l -carboxylic acid (1.7 g, 84% yield) as a yellow solid. LCMS (ESI) calcd. for C16H15F6O3[M - H]-m / z 369.09, found 368.75.

[2312] Intermediate 12Patent Application LTGO-019 / 01WO 36088 / 124 (trans)-4-methyI-4-(trifluoromethyl)-2-(4-(trifluoromethyl)cyclohexyl)cyclopentane-l -carboxylic acid

[2313]

[2314] Reagents & conditions: a) Pd(dppf)Cl2, K2CO3, dioxane, H2O, 100 °C; b) Pd / C, Pd(OH)2, H2, MeOH, 70 °C; c) NaOH, MeOH, 60 °C

[2315] Step 1: A solution of methyl 4-methyl-4-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (4 g, 11.24 mmol), 4.4,5,5-tetramethyl-2- (4-(trifluoromethyl)cyclohex-l-en-l-yl)-l,3,2-dioxaborolane (3.41 g, 12.36 mmol), K3PO4 (7.15 g, 33.72 mmol) and Pd(pph3)4 (1.29 g, 1.12 mmol) in dioxane / H2O (80 mL, 4 / 1) was heated at 100 °C for 8 hours, LCMS showed the reaction was completed. Then the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 3 / 1) to provide methyl 4-methyl-4-(trifluoromethyl)-2-(4-(trifluoromethyl)cyclohex- 1 -en- 1 -yl)cyclopent- 1 -ene- 1 -carboxylate (3.5 g, 87% yield) as a yellow oil. LCMS (ESI) calcd. for C16H19F6O2 [M + H]+m / z 357.13, found 356.75.

[2316] Step 2: A mixture of methyl 4-methyl-4-(trifluoromethyl)-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)cyclopent-1-ene-1-carboxylate (1.8 g, 5.04 mmol), 10% Pd / C (0.9 g) and 10% Pd(OH)2 / C (0.9 g) in MeOH (50 niL) was heated at 60 °C under an atmosphere of H2 (4 MPa) for 16 hours in a high-pressure reactor. 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 PE / EtOAc, 0% to 20%) to give methyl 4-methyl-4-(trifluoromethyl)-2-(4-(trifluoromethyl)cyclohexyl)cyclopentane-l-carboxylate (1.6 g, 88% yield) as a yellow oil. LCMS (ESI) calcd. for C17H23F6O2 [M + H]+m / z 361.16, found 360.85.

[2317] Step 3: To a solution of methyl 4-methyl-4-(trifluoromethyl)-2-(4- (tri fluoromethyl )cyclohexyl)cyclopentane-l -carboxyl ate (1,6 g, 4.44 mmol) in MeOH (30 mL) was added MeONa (1.92 g, 35.56 mmol). Tire mixture was heated at 80 °C for 16 hours. Then the organic solvent was removed under reduced pressure. Then the resulting mixture was adjusted to pH 5-6 with 4N aqueous HC1 and extracted with EtOAc (50 mL * 3). Hie combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under vacuum. 'Lire residue was purified by silica gel column chromatography (eluting with DCM / MeOH, 0% to 10%) to give (trans)-4-methyl-4-(trifluoromethyl)-2-(4-(trifluoromethyl)cyclohexyl)cyclopentane-1-carboxylic acid ( 1.3 g, 85% yield) as a yellow' solid.

[2318] Intermediate 13

[2319] rraw.y-2-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)cyclopentane-l -carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124

[2320]

[2321] Reagents & conditions: a) TBAF, NH4Cl, TMSCF3, THF; b) Mel. Ag2O, MeCN; c) LiOH

[2322] Step 1: Dissolve ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-oxocyclopentane-1-carboxylate (800 mg, 2.68 mmol) m THF (8 ml) under argon atmosphere. Add TMSCF3(571 mg, 4.02 mmol) to the reaction mixture within 5 minutes then add TBAF (1 M in THF, 0.80 ml, 0.80 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 hours. Add saturated ammonium chloride (16 ml) to the reaction mixture. Stir the reaction mixture for 20 minutes and add TBAF solution (1 M in THF, 5.60 ml, 5.60 mmol) again. Then the mixture was stirred at 25 °C for 1 hour. After the reaction was completed, the resulting solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to give ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-4-(trifluoromethyl)cyclopentane- 1 -carboxylate (400 mg, 40%yield) as yellow oil. LCMS (ESI) calcd. for C16H18F5O3 [M + H]+m / z 369.11, found 369.00.

[2323] Step 2: A solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-4- (tri fluoromethyl )cyclopentane-l -carboxylate (200 mg, 0.54 mmol), MeI (231 mg, 1.62 mmol) and Ag2O (1.26 g, 5.42 mmol) in MeCN (5 ml) under argon atmosphere. Then the mixture was heated at 80 °C for 16 hours. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to give ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)cyclopentane-1-carboxylate (120 mg, 52% yield) as yellow oil. LCMS (ESI) calcd. for C17H20F5O4 [M + H]+m / z 383.13, found 382.80.

[2324] Step 3: A solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)cyclopentane-1-carboxylate (120 mg, 0.31 mmol) in THF / MeOH / H2O (1 / 1 / 1, 6 mL) was added LiOH (75 mg, 3.13 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 (IM). Then the solution was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide trans-2-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-4-(trifluoromethyl)cyclopentane-l -carboxylic acidPatent Application LTGO-019 / 01WO 36088 / 124 (103 mg, 83% yield) as an off-white solid. LCMS (ESI) ealed. for C15H14F5O4 [M - H]’m / z 353.08, found 352.90.

[2325] Intermediate 14

[2326] trans-2-(2-methoxy-4-(trifluoromethyl)phenyl)-4,4-dimethylcyclopentane-1-carboxylic acid

[2327]

[2328] Reagents & conditions: a) Pd(PPh,)4, K PO4, dioxane, H / O. 100 °C; b) Pd / C, Pd(OH)2, H2, McOH, 50 °C; c) NaOMe, MeOH

[2329] Step 1: To a solution of methyl 4,4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-1-ene-1-carboxylate (3.57 g, 11.8 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (2.6 g, 11.8 mmol) and K3PO4 (7.51 g, 35.0 mmol) in dioxane / H2O = 10 / 1 (55 mL) was added Pd(PPh3)4 (1.36 g, 1.2 mmol). Tire mixture was stirred at 100 °C for 16 hours under N2. The mixture was concentrated under vacuum. The residue was directly purified by flash column chromatography on silica gel (EtOAc / PE 1 / 10) to provide methyl 2-(2-methoxy-4-(trifluoromethyl)phenyl)-4,4-dimethylcyclopent-l-ene-l-carboxylate (3.62 g, 93% yield) as a yellow oil, LCMS (ESI) calcd. for C17H20F3O3 [M + H]+m / z 329.14, found 328.70.

[2330] Step 2: To a solution of methyl 2-(2-methoxy-4-(trifluoromethyl)phenyl)-4,4-dimethylcyclopent-1-ene-l -carboxylate (3 62 g, 11 0 mmol) in MeOH (70 mL) was added 10% Pd / C (1.17 g) and 10% Pd(OH)2(1.54 g). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen, Tire resulting mixture was stirred at 50 °C for 8 hours under hydrogen atmosphere. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum to provide crude methyl 2-(2-methoxy-4-(trifluoromethyl)phenyl)-4,4-dimethylcyclopentane-1 -carboxylate (3.22 g) as a colorless oil. LCMS (ESI) calcd. for C17H22F3O3 [M + H]+m / z 331.15, found 330.75.

[2331] Step 3: Crude methyl 2-(2-methoxy-4-(trifluoromethyl)phenyl)-4,4-dimethylcyclopentane-l- carboxylate (3.22 g, 9.7 mmol) was dissolved in 30% MeONa in MeOH (70 mL). The solution was stirred at 70 °C for 2 hours. The mixture was concentrated under vacuum. The residue was diluted w ith water (100Patent Application LTGO-019 / 01WO 36088 / 124 mL) and adjusted to pH = 5 with 3M HO. Then the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide crude trans-2-(2-methoxy-4-(tnfluoromethyl)phenyl)-4,4-dimethylcyclopentane- 1 -carboxylic acid (3 g) as a white solid. LCMS (ESI) calcd. for C16H20F3O2, [M + H] m / z 317.14, found 316.75

[2332] Intermediate 15

[2333] (trans)~2-(4-methoxy-2-(trifluoromethyl)phenyl)-4,4-dimetliylcyclopentane-l -carboxylic acid

[2334]

[2335] Reagents & conditions: a) Pd(PPh3)4. K3PO4. dioxane, H O. 100 °C: b) Pd / C, Pd(OH)2, I I. MeOH. 50 °C; c) NaOMe, MeOH

[2336] Step 1: A solution of (4-methoxy-2-(trifluoromethyl)phenyl)boronic acid (2.5 g, 11.36 mmol), methyl 4, 4-dimethyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (3.43 g, 11.36 mmol), Pd(PPh3)4(1.31 g, 1.13 mmol) and K3PO4(7.24 g, 34.10 mmol) in Dioxane / H2O (10 / 1. 55 mL) was heated at 100 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (150 ml..) and extracted with EtOAc (150 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 10 / 1) to provide methyl 2-(4-methoxy-2-(trifluoromethyl)phenyl)-4,4-dimethylcycIopent-l-ene-l -carboxylate (3.5 g, 94% yield) as a light yellow solid. LCMS (ESI) calcd. for C17H20F3O3[M + H]+m / z 329.14, found 328.75.

[2337] Step 2: A solution of methyl 2-(4-methoxy-2-(trifluoromethyl)phenyl)-4,4-dimethylcyclopent-I- ene-1 -carboxylate (3.5 g. 10.67 mmol) in MeOH (100 mL) was added 10% Pd / C (3 g) and 10% Pd(OH)2 / C (3 g). The mixture was stirred at 50 °C for 16 hours under an atmosphere of H2LCMS showed the reaction was completed. The mixture was filtered through celite The filtrate was diluted with water (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide crude methyl 2-(4-methoxy-2-Patent Application LTGO-019 / 01WO 36088 / 124 (trifluoromethyl)phenyl)-4,4-dimethyIcyclopentane-l -carboxylate (2.5 g) as colorless oil. LCMS (ESI) calcd. for C17H22F3O3[M + H]+m / z 331.15, found 330.80.

[2338] Step 3: A solution of crude methyl 2-(4-methoxy-2-(trifluoromethyl)phenyl)-4,4-dimethylcyclopent-1 -ene-1 -carboxylate (2.5 g, 7.57 mmol) in MeOH (30 mL) was added MeONa (2.86 g). Tire mixture was heated to 70 °C and refluxed for 16 hours. LCMS showed the reaction was completed. The residue was adjusted to pH = 3-4 with aqueous HC1 (IM). Then the solution was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum to provide crude (trans)-2-(4-methoxy-2-(trifluoromethyl)phenyl)-4.4-dimethylcyclopentane- 1 -carboxylic acid (2 g) as a white solid. LCMS (ESI) calcd. for C16H20F3O3[M + H]+m / z 317.14, found 316.70

[2339] Intermediate 16

[2340] (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethoxy)cyclopentane-l -carboxylic acid

[2341] a step 1

[2342]

[2343] Reagents & conditions: a) AgOTf, KF, selectF, TMSCF3, 2 -fluoropyridine; b) LiOH, THF / MeOH / FEO Step 1: AgOTf (8.48 g, 33 mmol), KF (2.56 g, 44 mmol) and Selectfluor (3.2 g, 16.5 mmol) was added ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxycyclopentane-l-carboxylate (3.3 g, 11 mmol) in EtOAc (40 mL) under N2.. Then the mixture was added 2 -fluoropyridine (3,2 g, 33 mmol) and TMSCF3(4.69 g, 33 mmol) dropwise at 0 °C. Tire reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. The 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, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to provide ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4- (trifluoromethoxy)cyclopentane-l -carboxylate (1.28 g, 32% yield) as a yellow oil. LCMS (ESI) calcd. for C16H18F5O4[M + H]+m / z 369.11, found 368.75.

[2344] Step 2: A solution of ethyl (trans)-2-(3,4-difluoro-2-raethoxyphenyl)-4-(trifluoromethoxy)cyclopentane-l -carboxylate (1.05 g. 2.85 mmol) and LiOH (683 mg, 28.5 mmol) in THF / MeOH / H2O = 1 / 1 / 1 (10 mL) was stirred at room temperature for 3 hours. LCMS showed the reaction was completed. The mixture was adjusted to pH = 3-4 with 1 M HC1. Then the aqueous solution was extracted with EtOAc (30 mL x 3) The combined organic layers were washed with brine, dried over sodiumPatent Application LTGO-019 / 01WO 36088 / 124 sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to provide (trans)-2-(3.4-difluoro-2-methoxyphenyl)-4- (tnfluoromethoxy)cyclopentane-l -carboxylic acid (940 mg, 97% yield) as a yellow oil. LCMS (ESI) calcd. for C14H12F5O4[M - H] m / z 339.06, found 339.05.

[2345] Intermediate 17

[2346] (trans)-2-(2-ethoxy-3,4-difluorophenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l-carboxylic acid

[2347]

[2348] Reagents & conditions: a) BBrs, DCM; b) Etl, K2CO3. DMF; c) NaOMe, MeOH

[2349] Step 1: To a solution of methyl 2-(3,4-difluoro-2-hydroxyphenyl)-4-methyl-4- (trifluoromethyl)cyclopentane-l -carboxylate (3 g. 8.5 mmol) in dry DCM (30 mL) was added BBrs (1 M in DCM, 17 mL, 17 mmol) dropwise at -78 ”C under an atmosphere of N2. After addition, the solution was stirred at -78 °C for 1 hour 'then the resulting mixture was quenched with MeOH, diluted with water (90 mL) and extracted with EtOAc (90 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 PE / EtOAc 2 / 1) to provide methyl 2-(3,4-difluoro-2-hydroxyphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylate (1.8 g, 62% yield) as a yellow oil. LCMS (ESI) calcd. for C15H16F5O3[M + H]+m / z 339 10, found 338.65.

[2350] Step 2: To a solution of methyl 2-(3,4-difluoro-2-hydroxyphenyl)-4-methyl-4-(tnfluoromethyl)cyclopentane-l -carboxylate (1.8 g, 5.3 mmol) in DMF (20 mL) was added iodoethane (099 g, 6.3 mmol) and K2CO3 (1.46 g, 10.6 mmol). The mixture was stirred at 25 °C for 3 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 = 3 / 1) to provide methyl 2-(2-ethoxy-3,4-difluorophenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxylate (1.6 g. 83% yield) as a yellow oil. LCMS (ESI) calcd. for C17H20F5O3[M + H]+m / z 367.14, found 366.70.

[2351] Step 3: To a solution of methyl 2-(2-ethoxy-3,4-difluorophenyi)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylate (1.6 g, 4.4 mmol) in MeOH (10 mL) was added 30%MeONa in MeOH (10 mL). The mixture was heated at 80 °C for 3 hours. The residue was diluted with water (30 mL) and adjusted to pH = 5 with 3M HC1. Then the mixture w7as extracted with EtOAc (30 mL x 3), HiePatent Application LTGO-019 / 01WO 36088 / 124 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 (trans)-2-(2-ethoxy-3,4-difluorophenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l-carboxylic acid ( 1.3 g, 84% yield) as a yellow oil. LCMS (ESI) calcd. for CisHiaFsO? [M + H]4m / z 353.12, found 352.70.

[2352] Intermediate 18

[2353] (trans)-2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l -carboxylic acid

[2354] a b step 1 step 2

[2355]

[2356] Reagents & conditions: a) Pd(PPh3)4, K3PO4, dioxane / FLO, 100 °C; b) Pd / C, Pd(OH)z, H2, zPrOH, 70 °C; c) NaOMe, MeOH, 70 °C

[2357] Step 1: To a solution of methyl 4-methyl-4-(trifluoromethyl)-2- (((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l -carboxylate (1.5 g, 4.20 mmol) in 1,4-Dioxane / H2O = 4 / 1 (30 mL) was added 2-(4-fluoro-2-methoxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.34 g, 5.04 mmol), Pd(PPh3)4(0.49 g, 0.42 mmol) and K3PO4 (2.67 g, 12.60 mmol) under N2. Tire mixture was heated at 100 °C for 4 hours. Then the resulting mixture was diluted with w-ater (90 mL) and extracted with EtOAc (90 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 provide methyl 2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4-(trifluoromethyl)cyclopent-l-ene-l-carboxylate (480 mg, 33% yield) as a yellow' oil. LCMS (ESI) calcd. for C17H19F4O3 [M + H]+m / z 347.13, found 346.70.

[2358] Step 2: A mixture of methyl 2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4-(tri fluoromethyl )cy clopent- 1-ene-l -carboxy late (480 mg, 1.38 mmol), 10% Pd / C (588 mg) and 10% Pd(OH)2 / C (776 mg) in iPrOH (10 mL) was heated at 70 °C under an atmosphere of H2(30 atm) for 16 hours in a high-pressure reactor. Then the mixture w as filtered through celite. The filtrate was concentrated under vacuum to provide crude methyl 2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-1-carboxylate (430 mg) as a clear oil. LCMS (ESI) calcd. for C17H21F4O3 [M + H] m / z 349.14, found 348.70.Patent Application LTGO-019 / 01WO 36088 / 124 Step 3: To a solution of crude methyl 2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4- (trifluoromethyl)cyclopentane-l -carboxylate (430 mg, about 1 mmol) in MeONa (15% in MeOH, 20 mL) was heated at 70 °C for 16 hours. The residue was diluted with water (30 mL) and adjusted to pH = 5 with 3M HC1. Then the mixture was 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 (DCM / MeOH 20 / 1) to provide trans-2-(4-fluoro-2-methoxy-3-methylphenyl)-4-methyl-4-(trifluoroniethyl)cyclopentane-l-carboxylic acid (360 mg) as a yellow oil. LCMS (ESI) calcd. for C16H19F4O3, [M + H]+m / z 335.13, found 334.60.

[2359] Intermediate 19

[2360] (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-isopropylcyclopentane-1-carboxylic acid

[2361]

[2362] Reagents & conditions: a) 4-m ethylbenzenesulfonyl azide, TEA, DCM; b) MeOH, toluene, MW, 130 °C; c) Tf2O, DIEA, DCM; d) (3,4-difluoro-2-methoxyphenyl)boranediol, Pd(PPh3)4, K3PO4, dioxane, H2O, 100 °C; e) H2, Pd / C, Pd(OH)2, 50 °C; f) NaOMe, MeOH, 70 °C

[2363] Step 1: To a solution of 5-isopropylcyclohexane-l.3-dione (3 g. 19.45 mmol) in DCM (50 mL) was added 4-methyl benzenesulfonyl azide (7.67 g, 38.91 mmol) and TEA (5,89 g. 58.36 mmol). The mixture was stirred at 25 °C for 4 hours. Then the resulting mixture was diluted with water (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. Ihe residue was purified by silica gel column chromatography (eluting with PE / EtOAc =3 / 1) to give 2-diazo-5-isopropylcyclohexane-1,3-dione (3 1 g, 89% yield) as a yellow solid. LCMS (ESI) calcd. for C9H13N2O2[M + H]+m / z 181.10, found 180.60.

[2364] Step 2: To a solution of 2 -diazo-5-isopropylcyclohexane-l, 3-dione (3 g. 16.64 mmol) in toluene (30 mL) was added MeOH (533 mg, 16.64 mmol). The mixture was heated at 130 °C in a microwave reactor for 0.5 hours under an atmosphere of N2. Then the reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =10 / 1) to give methylPatent Application LTGO-019 / 01WO 36088 / 124 4-isopropyl-2-oxocyclopentane-l-carboxylate (2.8 g, 92% yield) as a yellow oil. LCMS (ESI) calcd. for C10H17O3 [M + H]+m / z 185.12, found 184.60.

[2365] Step 3: To a solution of methyl 4-isopropyl -2 -oxocyclopentane- 1 -carboxylate (1.8 g. 9.77 mmol) in DCM (30 mL) was added Tf2O (4.13 g, 14.65 mmol) and DIEA (1.89 g, 14.65 mmol) slowly at -78 °C under N2. The mixture was stirred at 25 °C for 1 hours. Tire final mixture was quenched with saturated aqueous NFLC1 solution and extracted with DCM. Hie combined organic layers were washed with water and brine, dried with sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 10 / 1) to give methyl 4-isopropyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l-carboxylate (2.2 g, 71% yield) as a yellow' oil. LCMS (ESI) calcd. for C11H16F3O5S [M + H]+m / z 317.07, found 316.60

[2366] Step 4: To a solution of methyl 4-isopropyl-2-(((trifluoromethyl)sulfonyl)oxy)cyclopent-l-ene-l- carboxylate (1.5 g, 4.74 mmol) in 1,4-Dioxane / H2O = 10 / 1 (22 mL) was added (3,4-difluoro-2-methoxyphenyl)boranediol (1.07 g, 5.68 mmol) and Pd(PPh3)4(547 mg, 0.46 mmol) and K3PO4(3.02 g, 14.22 mmol) under N2. The mixture was heated at 100 °C for 4 hours. LCMS showed the reaction was completed. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc = 20 / 1) to give methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-isopropylcyclopent-l-ene-l -carboxylate (1.3 g, 88% yield) as a yellow oil. LCMS (ESI) calcd. for C17H21F2O3[M + H]+m / z 311.15, found 310.75.

[2367] Step 5: To a mixture of methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-isopropylcyclopent-l-ene-l- carboxylate (1 g, 3.2 mmol), 10% Pd / C (1 g) and 10% Pd(OH)2 / C (1 g) in IPA (50 mL) was heated at 70 °C for 16 hours under 3 MPa of H2After the reaction was completed, the reaction mixture was filtrated and collected the filtrate. Tire filtrate concentrated under vacuum. The residue -was purified by silica gel column chromatography (eluting with PE / EtOAc, 0% to 10%) to give methyl 2-(3,4-difluoro-2- methoxyphenyl)-4-isopropylcyclopentane-l -carboxylate (660 mg, 73% yield) as a colorless oil. LCMS (ESI) calcd. for C17H23F2O3[M + H]+m / z 313.16, found 312.65.

[2368] Step 6: methyl 2-(3,4-difluoro-2-methoxyphenyl)-4-isopropylcyclopentane-l -carboxylate in MeOH (2 mL) and MeONa (4 mL, 30wt% in MeOH) was heated at 70 °C for 16 hours After the reaction was completed, the reaction mixture was adjusted pH to 3-4 with 1 M HC1 and extracted with EtOAc (30 mL x 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 DCM / MeOH, 0%to 10%) to give (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-isopropylcyclopentane-l-carboxylic acid (480 mg, 76% yield) as a yellow' solid. LCMS (ESI) calcd. for C16H21F2O3[M + H] m / z 299.15, found 298.65.

[2369] Intermediate 20Patent Application LTGO-019 / 01WO 36088 / 124 (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)cyclopentane-l-carboxylic acid

[2370]

[2371] Reagents & conditions: a) Pd(dppf)Cl2, Na2CO3, dioxane / HjO, 100 °C; b) Pd(PPh3)4, DPPE, THF, 60 °C; c) NaIO4, K2OsO4, dioxane / H2O; d) TMSCF3, TBAF, THF; e) DMAP. SOCl2, pyridine, DCM; f) Rh, H2, IPA; g) EtONa, EtOH

[2372] Step 1: To a solution of l-bromo-3,4-difluoro-2 -methoxybenzene (10.8 g, 48.4 mmol), ethyl (E)-3-(4,4.5.5-tetramethyl-l,3.2-dioxaborolan-2-yl)acrylate (21.88 g, 96.8 mmol), Pd(dppf)Cl2(3.54 g, 4.84 mmol) and Na2CO3(15.39 g. 145.2 mmol) in 1,4-dioxane / H2O=5 / 1 (120 ml..) was heated at 100 °C under N2for 16 hours. Then the resulting mixture was diluted with water (300 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 give ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (9.5 g, 81% yield) as a white solid. LCMS (ESI) calcd. for C12H13F2O3[M +

[2373]

[2374] m / z 243.09, found 243.05.

[2375] Step 2: To a solution of ethyl (E)-3-(3,4-difluoro-2-methoxyphenyl)acrylate (8.4 g, 34.7 mmol), 2-((trimethylsilyl)methyl)allyl acetate (12.93 g, 69.4 mmol), DPPE (0.55g, 1.38 mmol) and Pd(PPh3)4(2 g, 1.73 mmol) in THF (80 mL) was stirred at 60 °C for 16 hours. Tire reaction mixture were concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc =Patent Application LTGO-019 / 01WO 36088 / 124 10 / 1) to give ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-methylenecyclopentane-l -carboxylate (8 g, 78% yield) as a yellow oil. LCMS (ESI) calcd. for C16H19F2O3 [M + H]+m / z 297.13, found 296.70.

[2376] Step 3: To a solution of ethyl (traiis)-2-(3,4-difluoro-2-methoxyphenyl)-4-methylenecyclopentane-1 -carboxylate (8 g, 27 mmol) in dioxane / H2O=4 / 1 (1000 mL) was added NaIO4(23.11 g, 108 mmol) and K2OsO4·2H2O (0.99g, 2.7 mmol) at 0 °C. Tire mixture was stirred at 25 °C for 16 hours. Hie resulting mixture was filtered and collected the filtrate. Tire filtrate was concentrated under vacuum. The residue was diluted with water (200 mL) and extracted with EtOAc (100 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 PE / EtOAc = 5 / 1) to give ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-oxocyclopentane-l -carboxylate (6.1 g, 75% yield) as a colorless oil. LCMS (ESI) calcd. for C15H17F2O4 [M + H]+m / z 299.11, found 299.00.

[2377] Step 4: To a mixture of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-oxocyclopentane-1-carboxylate (4 g, 13.4 mmol) in THF (40 mL) under N2 at 0 °C was added TMSCF3 (3.81 g. 26.8 mmol) and TBAF in THF (26.8 mL, 1 mol / L). The reaction was stirred at 25 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers wwere washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 5 / 1) to provide ethyl (trans)-2-(3,4-difhioro-2-methoxyphenyl)-4-hydroxy-4-(trifluoromethyl)cyclopentane-l -carboxylate (2.2 g, 45% yield) as a yellow oil. LCMS (ESI) calcd. for C16H18F5O4[M + H]+m / z 369.11, found 368.70.

[2378] Step 5: To a solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-4- (tri fluoromethyl )cyclopentane-l -carboxylate (2 1 g, 5.7 mmol) and DMAP (70 mg, 0.57 mmol) in 1,4-dioxane (20 mL) was added SOCl2(8.14 g, 68.4 mmol) and pyridine (5.41 g, 68.4 mmol) at 0 °C. The reaction was stirred at 80 °C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with water (100 mL) at 0 °C 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 = 20 / 1 ) to provide ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(tnfluoromethyl)cyclopent-3-ene-l-carboxylate (1.64 g, 83% yield) as a yellow oil. LCMS (ESI) calcd. for C16H16F5O3[M + H]+m / z 351.10, found 350.65.

[2379] Step 6: To a solution of ethyl (trans)-2-(3,4-difiuoro-2-methoxyphenyl)-4- (tri fluoromethyl )cy clopent-3 -ene-1 -carboxy late 6 (1.59 g, 4.5 mmol) and Rh / C (1.39 g, 13.5 mmol) in IPA (20 mL) was stirred at 25 °C for 16 hours under H2. LCMS showed the reaction was completed. The mixture was filtered and collected the filtrate. The combined organic layers were washed with brine, dried over sodium sulfate, concentrated under vacuum. Hie residue was purified by flash columnPatent Application LTGO-019 / 01WO 36088 / 124 chromatography on silica gel (PE / EtOAc = 20 / 1) to provide ethyl (trans)-2-(3,4-difluoro-2- methoxyphenyl)-4-(trifluoromethyl)cyclopentane-l -carboxylate (1.48 g. 93% yield) as a colorless oil. LCMS (ESI) calcd. for C16H18F5O3[M + H]+m / z 353.12, found 352.65.

[2380] Step 7: To a solution of ethyl (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)cyclopentane-1-carboxylate (1.3 g, 3.69 mmol) in EtOH (10 mL) was added 30% EtONa in EtOH (10 mL). The mixture was heated at 80 °C for 3 hours. The residue was diluted with water (30 mL) and adjusted to pH = 5 with 3M HC1. Then the mixture was 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 flash column chromatography on silica gel (DCM / MeOH = 20 / 1 ) to provide crude (trans)-2-(3,4-difluoro-2-methoxyphenyl)-4-(trifluoromethyl)cyclopentane-l -carboxylic acid (900 mg) as a yellow oil, which was used directly.

[2381] Intermediate 21

[2382] (trans)-2-(2-ethoxy-4-fluorophenyl)-4-methyl-4-(trifluoromethyl)cyclopentane-l-carboxylic acid

[2383] OH

[2384]

[2385] Reagents & conditions: a) Pd(PPh3)4, K3PO4, dioxane / H2O, 100 °C; b) P...

Claims

1. Patent Application LTGO-019 / 01WO 36088 / 124 Claims1. A compound of Formula (XIII):or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein:Ring Ais X2= CR12, N, or N+-O-;X3or X3= CR13, N, or N+-O-:X4= N, N+-O-, or CR14;X5= CR15; N or N+-O-:X6= CR16, N or N+-O";Zi is CR* orN;Z2is CRic or N;Z3is CR4dor N;Z4is CR4e or N;Ria, Rib. R2b, Rsa, and R3b are independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, Cs-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be folly or partially fluorinated, Ci-Ce alkoxy, Ci-C« deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6 alkenyl, C2-C6 alkynyl, -[C(Rs)(R7)]m-C3-Cs-cycloalkoxy, cyano, -[C(R6)(R7)jm-C3-Cs cycloalkyl, -[C(Rb)(R7)]m-C3-C8 cycloalkenyl, -[C(Rb)(R7)jm-Patent Application LTGO-019 / 01WO 36088 / 124 N(Ro)(R?), or -[C(R6)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0. S, and N:wherein any of said alkyl or alkenyl moieties in Ria, Rib. R?b, Ria. Rib may be further substituted with one. two, three or four Rs substituents, where each Rs is independently selected from halo, Ci-Cs alkyl, Cs-Ce cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cg fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Cs alkoxy, Ci-C, deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, and m = 0 to 2;R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Csalkyl. Ci-Ce fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or frilly fluorinated, branched alkyl, substituted or unsubstituted Cri-Ce alkenyl, substituted or unsubstituted Ch-Ci alkynyi, Ci-Cg haloalkyl wherein the alkyl may be frilly or partially halogenated, hydroxy, Ci-Chalkoxy, Ci-Cg deuteroalkoxy wherein the Cj-Ce alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Cj-Ce alkoxy may be fully or partially fluorinated. Ci-Ce-haloalkoxy wherein the Ci-Cg alkoxy may be frilly or partially holgenated, cycloalkoxy, deuterated Ci-Cg alkyl herein the Ci-Cg alkyl chain may be fully or partially deuterated, cyano, -S(O)qRg, -P(O)(Ci-C4alkyl). -NRgNR7. - (CH2)nS(O)2NR«R7, -(CH2)nC(O)NR«R7, -NHS(O)2R<„ C(=NRga)NRgR7, -C(0)NR> R7, -NHC(=O)-alkyl - NH(C=0)NR€, R7, -SO(=NH)Rg, -O-(CH2)mC(=O)NR6R7, -O-(CH7Jm-O-Ci.4alkyl, -C(Rg)(R7)-cycloalky1, substituted or unsubstituted Cs-Cs cycloalkyl, Cs-Cg cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein said Ci-Cg haloalkyl, Ci-Cs alkyl. Ci-Cg alkoxy, cycloalkoxy, Ci-Cg haloalkoxy are optionally further substituted -with one ortnore substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rssubstituents; wherein Rgis H, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein Ci -Chalky! is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxy 1 alkyl, or Ci-Cs fully or partially fluorinated fluoroalkyl:wherein each R9 and Rio are independently selected from the group comprising H. Ci-Cs alkyl, Ci -Cs cycloalkyl, C2-Cg alkenyl, Ci-Cs haloalkyl, C-.-Cs alkoxy, or Ci-Cs haloalkoxy;Rg and R& are individually and independently selected from the group consisting ofH, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein (: alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs frilly or partially fluorinated fluoroalkyl;R7is H, Ci-Cs alkyl, deuterated Ci-C4alkyl wherein Ci-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs fully or partially fluorinated fluoroalkyl:R. is selected from the group consisting of hydrogen, OH, -OCi-Cgalkyl, -OCi-Chalkoxyl, Ci-Chalkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be frilly or partially deuterated, Ci-CgPatent Application LTGO-019 / 01WO 36088 / 124 fluoroalkyl wherein the CI-CR fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;Ri3. RM. RUS and Rie are independently selected from hydrogen, deuterium, hydroxy, oxo, -C(O)NR6R7, -(CH2)„S(O)2NR6R7, -(CH2)„C(O)NR6R7, cyano, halo, Ci-C6alkyl, deuterated Ci-C6alkyl wherein the Ci-Cs alkyl chain may be folly or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloC j-Cd alkyl wherein the C1-C4 alkyl chain may be folly or partially halogenated, C1-C4 fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or folly fluorinated, Ci-C4alkoxy, Cj-C4 deuteroalkoxy wherein the C1-C alkyoxy chain may be folly or partially deuterated, cycloalkoxy -S(O)qRfi. -NR6NR7, -NHS(O)2Rfi, -C(=NR6a)NR6R7, -NHC(=O)-Ci-C4-alkyl, - NH(C-O)NR6R7, -S0(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-Ci.4alkyl,-C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cj-Cs cycloalkyl, C.i-Cs cycloalkenyl, substituted or unsubstituted Ce-Cio ary l, substituted or unsubstituted C3-Cs hctcroaiyl or 3-7 membered hctcrocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O. S. and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13 substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;R is selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Cs deuteroalkyl wherein the alkyl may be folly or partially7deuterated, haloalkyl wherein the alkyl may be folly or partially halogenated, fluoroalkyl wherein the alkyl may be folly' or partially fluorinate, C3-C8 cycloalkyl, C3- Cs fluorocycloalkyl wherein the cycloalkyl may be folly or partially fluorinated, and substituted or unsubstituted -[C(Rb)(R7)]m-C6-Cio-aryl:m is 1-5;n is 0-3; andq is 0-2.

2. A compound of Formula (XIV):(XIV)or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of Ring A, R>a, Rib. R?.b, R?,b, ia, R20. Zi, Z-. Z2, and Z4 are defined above in claim 1; and R2aisPatent Application LTGO-019 / 01WO 36088 / 124 independently selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, C Cg cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be fully or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluormated, Ci-Ce alkoxy. Ci-Ce deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy¬ may be fully or partially halogenated, C2-C.5 alkenyl, C2-C6 alkynyl, -[C(Rb)(R7)]m-C3-Cs-cycloalkoxy, cyano, -[ ReXI Jm-Cj-Cs cycloalkyl, -[C(R6)(R?)]m-C3-C8 cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or-[C(Rc)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and N.

3. A compound is a compound of Formula (XV):Oor a tautomer thereof, or a pharmaceutically acceptable salt, hydrate and solvate thereof, wherein each of R1a, Rb, R2b, sa, R?,b, R4a, Rzo, Zi, Z2, Z3, Z4, X2, X3, X4, X5, and Xs are defined above in claim 1 or claim 2.

4. A compound of Formula (XVI):oor a tautomer thereof, or a pharmaceutically acceptable salt, hy drate and solvate thereof, wherein each of Ria, Rib, Rja, Rsb,;a, R30, Zi, Z2, Z3, Z4, X2, X3, X4, X;, and X6arc defined above in any of claims 1-3.

5. Hie compound of claim 1 or claim 2, wherein Ring A is selected from the group consisting of:Patent Application LTGO-019 / 01WO 36088 / 124Patent Application LTGO-019 / 01WO 36088 / 1246. The compound of any of claims 1-5, wherein Z; is CR&; Z is CR^; Z3 is CRjdl andZ is ( R.

7. The compound of claim 6, wherein R^a is selected from the group consisting of -CF3, -OCH3, -OCH2-CH3, -OH, -OCD3, -CII3, -O-cyclopropyl, -CH2-OH, -CHF?, -CH-(CH3)2. -O-CHF2. -CH(CH3)-OH, -O-CH(CH3)2, and -O-CH2-CH2-O-CH3.Patent Application LTGO-019 / 01WO 36088 / 1249. The compound of any of claims 1-4, wherein R?o is selected from the group consisting of C1-C3 alkyl, partially or completely halogenated Cj-Cs alkyl, partially or completely deuterated C1-C3 alkyl, 6-membered aryl, and partially or completely halogenated 6-membered aryl.

10. The compound of any of claims 1-4, wherein R2o is selected from the group consisting of -CH,, -CF?,, -CHF?, -CD,, -CH?-phcnyl, phenyl, fluoro-phenyl, and -CH?-CF,.

11. A compound of Formula (I):Patent Application LTGO-019 / 01WO 36088 / 124or a tautomer thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: =^= represents a single or double bond:X = C(Rla) (Rib)X2= CRi2, N, or N+-O“;X3or X3= CRi3, N, or N’-O';X4= N, Ni-O’, or CRI4;X5= CRj5; N orNi-O-;X6= CR)6, N or N+-O”;Ring B is Ce-Cio aryl, C -(\ heteroary l, monocyclic, bicyclic, or spirocyclic cycloalkyl ring, or a monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl contains one or more heteroatoms independently selected from N, 0, and S, and wherein the B ring is substituted with one or more R4 substituents;R-la, Rib, Rza, R2b, Rsa, Rjb are independently' selected from the group consisting of H, deuterium, halo, hydroxyl, Ci-Cs alkyl, Cy-Ce, cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkyl wherein the alkyl chain may be hilly' or partially fluorinated, C Ce alkoxy. Ci -Cg deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be folly or partially halogenated, C2-Cg alkenyl. C2-Cg alkynyl, -|C(Rt)(R7)]::!-C3- Cg-cycloalkoxy, cyano, -[CfRgX iXIm-Cs-Cs cycloalkyl, -[C / RgJ / Jm-Cs-Cs cycloalkenyl, -[C(Rg)(R7)]m- NfRs R?), or -[C(R,)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from 0, S, and N;Patent Application LTGO-019 / 01WO 36088 / 124 wherein any of said alkyl or alkenyl moieties in Ria, Rib, R2a, Rib Rsa, Rib may be further substituted with one, two, three or four Rs substituents, where each Rs is independently selected from halo, Ci-C? alkyl, Ci-Ce cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkvl wherein the alkyl chain may be hilly or partially fluorinated, C ■ -C6alkoxy, Ci-Cg deuteroalkoxy wherein the alkoxy may be folly or partially deuterated, and m:::0 to 2;wherein any of Ria, Rib, R. R2b, Rsa, or R2b may be optionally connected to another of Ria, Rib. R2a, R?b, Rs®, or R;,b through individual alkyl, fluoroalkyl, or alkoxy moieties to form a spirocyclic ring;R4 is hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluormated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, C1-C5 haloalkyl wherein the alkyl may be folly or partially halogenated, Ci- C galkoxy, C Ce deuteroalkoxy wherein the C -( alkyoxy chain may be folly or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Cs alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cg alkyl wherein the Ci-Cb alkyl chain may be folly or partially deuterated, cyano, S(O)qRb, -NRbNR?, -(CH2)nS(O)2NR R7, -(CH2)nC(O) NR5R7, -NHS(0)2Ro, -C(===NR6a)NRbR7, -C(O)NRbR7, -NHC(===O)-alkyl -NH(C=O)N SR7, -SO(=NH)R5, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C’i4alkyl, -C(R5)(R7)-cycioalkyl, substituted or unsubstituted C?-Cs cy cloalkyl, C?,-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S. and N, and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R-; substituents maybe further optionally substituted with one or more hydroxy, alkoxy or C:-C4alkyl substituents;Rs and Rga are individually and independently7selected from the group consisting of H, Ci-Cs alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs folly or partially fluorinated fluoroalkyl;R? is H, Ci-Cs alkyl, deuterated Ct-C4alkyl wherein C1-C4 alkyl is folly or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or Ci-Cs fully or partially fluorinated fluoroalkyl;Ri2is selected from the group consisting of hydrogen, OH, -OC -Chalky 1. -OCi-Cealkoxyl, Ci-Cealkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;Patent Application LTGO-019 / 01WO 36088 / 124 Ri2a is selected from the group consisting of hydrogen, Cj-Cealkyl, deuterated C1-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially deuterated. Ci-Cs fluoroalkyl wherein the Ci-Cs fluoroalkyl is partially or folly fluormated, substituted or unsubstituted 3 -8 membered cycloalkyl:RB, RM. R15. and Rie are independently selected from hydrogen, deuterium, hydroxy, oxo, -C(O)NR6R7, -(CH2)„S(O)2NR6R7, -(CH2)nC(O)NR6R7, cyano, halo, Ci-C6alkyl, deuterated Ci-C6alkyl wherein the C -C alkyl chain may be fully or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloCi-C4 alkyl wherein the C1-C4 alkyl chain may be fully or partially halogenated, C -C: fluoroalkyl wherein the C1-C4 fluoroalkyl is partially or fully fluorinated, Ci- ialkoxy, C1-C4 deuteroalkoxy wherein the C1-C4 alky oxy chain may be fully or partially deuterated, cycloalkoxy -S(0)qR7, -NR^NR?, -NHS(O)2R6. -C(=NR6a)NR R7, -NHC(=O)-Ci-C4-alkyl, -NH(C=O)NR6R7, -SO(=NH)Re, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C;.4 alkyl, -C(R6)(R7)-cycIoalkyl, substituted or unsubstituted CB-CS cycloalkyl, Cj-Cg cycloalkenyl, substituted or unsubstituted C0-C10 aryl, substituted or unsubstituted Cs-Cg heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R substituents may be farther optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents; m is 1-5;n is 0-3;q is 0-2.

12. The compound of claim 11, wherein the compound is a compound of Formula (II):R2aV-XyI A \f pwT )<Kn\AJ3a / AR3b H V.7rRj ^44a \ ’1,7. X3Z1'Z2(II)or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinZi is CR4b orN:Z2is CR4C orN;Z3 is CRBJ or;Z4 is CR+e or N;Patent Application LTGO-019 / 01WO 36088 / 124 R4a, Rib, R d, and R 4e are individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted Cri-Ce alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Ce deuteroalkoxy wherein the C -( alkyoxy chain may be fully or partially deuterated, Ci-Cs-fluoroalkoxy wherein the C1-C0 alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C.5 alkyl wherein the Ci-Ce alkyl chain may be Hilly or partially deuterated, cyano, -S(O)qR<,, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R:, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)Rb, -O-CCHzlmCt^JNRsR?, -O-(CH2)m-O-Ci-4alkyl, - C(R6)(R7)-cycloalkyl, substituted or unsubstituted Cs-Cg cycloalkyl, Cs-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rs substituents; wherein Rg is H. Ci-Cs alkyl, deuterated C1-C4 alkyl wherein C1-C4 alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxy! alkyl, or Ci-Cs fully or partially fluorinated fluoroalkyl:wherein each R and Rio are independently selected from the group comprising H, Ci-Cg alkyl, C 1 -Cg cycloalkyl, C2-Ce alkenyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, or Ci-Cs haloalkoxy.

13. Hie compound of claim 11, wherein the compound is a compound of Formula (III):or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinZ] is C ib or N:Z2is C ic or N;Z. is CR4d orN;Z^ is CR4e orN;...;b. k, ia, and R.icare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Coalkyi, Ci-Cs fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fullyPatent Application LTGO-019 / 01WO 36088 / 124 fluorinated, branched alkyl, substituted or un substituted C?-Cs alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Csalkoxy, Ci-Cs deuteroalkoxy wherein the C-Ce alkyoxy chain may be folly or partially deuterated, Ci-Cg- fluoroalkoxy wherein the Ci-Cs alkoxy may be folly orpartially fluorinated, cycloalkoxy, deuterated Ci-Cs alkyl wherein the Ci-Ce alkyl chain may be folly or partially deuterated, cyano, -S(O)qRe, -P(O)(C;- C4alkyl), -NRCNR7, -(CH2)nS(O)2R5R7, -(CH2)nC(O)NR6R7, -NHS(O)2R, CO^RbalNRRr, -C(0)NR?R-, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R )(R7)-cycloalkyl, substituted or unsubstituted C2,-Cg cycloalkyl. Ca-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rssubstituents;wherein each Ry and Rm are independently selected from the group comprising H, Ci-Cs alkyl, Ci-Cs cycloalkyl, C2-Ce alkenyl, Ci-Cs haloalkyl, Ci-Cs alkoxy, or Ci-Cg haloalkoxy.

14. The compound of claim 11, wherein the compound is a compound of Formula (IV):or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinZi is C ib or N:Z2is C ic or N;Z. is CR4d or N:Z.: is CR4e or N;R. Rb, ic- Rid, and Reare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Coalkyl, Ci-Ce fluoroalkyl wherein the C1-C0 fluoroalkyl is partially or folly fluorinated, branched alkyl, substituted or unsubstituted Cz-Ce alkenyl, substituted or unsubstituted C2-C4 alkynyl, Ci-Cg haloalkyl wherein the alkyl may be folly or partially halogenated, hydroxy, Ci-Cealkoxy, Ci-Ce deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Cs-fluoroalkoxy wherein the Ci-Cs alkoxy may be folly orpartially fluorinated, cycloalkoxy, deuterated Ci-C’oPatent Application LTGO-019 / 01WO 36088 / 124 alkyl wherein the Ci-Cg alkyl chain may be fully or partially deuterated, cyano, -S(O)qRs, -P(O)(Ci-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NR6a)NR6R7, -C(O)NRcR7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R„ -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, - C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, Ci-C4alkvl, or Rs substituents;wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy; p is 0-3;Y1is C(R8a)(R8b), O or N (R6);Y2= C(R8a)(R8b), O or N (R6);each Y3is independently C(R8a)(R8b), O or N (R6); and with the proviso that only one of Y1, Y2, and Y3, can be N;each R8aand R8bare independently: hydrogen, -OH, deuterium, halo, cyano, C1-C6alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, C1-C6alkoxy, cycloalkoxy, haloalkoxy, deuterated C1-C4alkyl wherein the C1-C4alkyl may be fully or partially deuterated, or C1-C8fully or partially fluorinated fluoroalkyl.

15. The compound of claim 12, wherein the compound is a compound of Formula (V):or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.16, The compound of claim 12, wherein the compound is a compound of Formula (VI):Patent Application LTGO-019 / 01WO 36088 / 124or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.

17. The compound of claim 12, wherein the compound is a compound of Formula (VII):or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.

18. The compound of claim 11, wherein the compound is a compound of Formula (VIII):Oor a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, whereinZ1is CR4bor N;Z2is CR4cor N;Z3is CR4dor N;Z4is CR4eor N;R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, Ci-Cealkoxy,Patent Application LTGO-019 / 01WO 36088 / 124 C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated C1-C6alkyl wherein the C1-C6alkyl chain may be fully or partially deuterated, cyano, -S(O)qR6, -P(O)(C1-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-Cs cycloalkyl, C3-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl. alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or Rssubstituents;wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy.

19. The compound of claim 18, wherein the compound is a compound of Formula (IX):Oor a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.

20. The compound of claim 11, wherein the compound is a compound of Formula (XI):Oor a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R1a, R1b, R2b, R2a, R3b, R3a, X2, X3, X4, X2a, X2b, X2c, and X2dare defined aboveZ1is CR4bor N;Patent Application LTGO-019 / 01WO 36088 / 124 Z2is CR4cor N;Z3is CR4dor N;Z4is CR4eor N;R4a, R4b, R4c, R4d, and R4eare individually and independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Cealkyl, Ci-Ce fluoroalkyl wherein the Ci-Cc fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C4alkynyl, Ci-Ce haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the C1-C6alkyoxy chain may be fully or partially deuterated, C1-C6-fluoroalkoxy wherein the C1-C6alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Cg alkyl chain may be fully or partially deuterated, cyano, -S(O)qR6, -P(O)(C1-C4alkyl), -NR6NR7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, -NHS(O)2R6, C(=NR6a)NR6R7, -C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl, -C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4alkyl, or R8substituents;wherein each R9and R10are independently selected from the group comprising H, C1-C8alkyl, C1-C8cycloalkyl, C2-C6alkenyl, C1-C8haloalkyl, C1-C8alkoxy, or C1-C8haloalkoxy.

21. A compound of Formula (XII):(XII)or a tautomer, a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein Ria, Rib, R2a, R2b, R7a. Rib are defined above, or R,a, Rib. R2a, R>b, R1a. Rsr are independently selected from the group consisting ofH, deuterium, halo, hydroxyl, Ci-Cs alkyl, C7-C. cycloalky], 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-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6alkenyl, C2-C6alkynyl, -[C(R6)(R7)]m-C3-C8-cycloalkoxy, cyano, -[C(R6)(R7)]m-C3-C8cycloalkyl, -[C(R6)(R7)]m-C3-C8Patent Application LTGO-019 / 01WO 36088 / 124 cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R6)(R7)]m-C3-C8heterocycloalkyl wherein the heterocycloalkyl comprises one or more heteroatoms independently selected from O, S, and N;wherein any of said alkyl or alkenyl moieties above may be further substituted with one, two, three or four R5substituents, where each R5is independently selected from halo, 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-C6alkoxy, C3-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, and m = 0 to 2;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 ring;wherein at least one of R1a, R2aand R3aare selected from the group comprising hydroxyl, C1-C6alkoxy, C1-C6deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C3-C8cycloalkoxy, C3-C8fluorocycloalkoxy wherein the cylcoalkoxy may be fully or partially fluorinated, and substituted or unsubstituted -O-[C(R6)(R7)]m-C6-C10-aryl;=^= represents a single or double bond;X2= CR12, N, or N+-O-;X3or X3= CR13, N, or N+-O-;X4= N, N+-O-, or CR14;X5= CR15; N or N+-O-;X6= CRib, N or N'-O";Ring B is selected from the group consisting of a C6-C10membered aryl ring, C5-C8membered heteroaryl ring; monocyclic, bicyclic, or spirocyclic cycloalkyl ring; or monocyclic, bicyclic, or spirocyclic cycloheteroalkyl ring, wherein the cycloheteroalkyl ring or the C₅-C₈ heteroaryl ring contain one or more heteroatoms independently selected from N, 0, and S, and wherein Ring B is substituted with one or more R4 substituents;Patent Application LTGO-019 / 01WO 36088 / 124 R.4 is hydrogen, deuterium, halo, Ci-Cgalkyl, Ci-Cg fluoroalkyl wherein the Ci-Cg fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Ci-C haloalkyl wherein the alkyl may be fully or partially halogenated, Ci- Cgalkoxy, Ci-Cg deuteroalkoxy wherein the Ci-Cg alkyoxy chain may be fully or partially deuterated, Ci-Cs-fluoroalkoxy wherein the Ci-Cg alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Cg alkyl wherein the Ci-Co alkyl chain may be fully or partially deuterated, cyano, S(O)qRg, -NRgNR7, -(CH2)nS(O)2NRgR7, -(CH2)nC(O) NR6R7, -NHS(O)2R6, -C(=NRga)NRgR7. - C(O)NR6R7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)Rg. -O-(CH2)mC(=O)NRgR7, -O-(CH2)ro- O-Ci-4 alkyl. -C(Rg)(R7)-cycloalkyl. substituted or unsubstituted Cs-Cs cycloalkyl. (ri-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from 0, S, and N; and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R_i substituents maybe further optionally substituted with one or more hydroxy, alkoxy or C1-C4 alkyl substituents;R6and R6aare individually and independently selected from the group consisting of H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;R7is H, C1-C8alkyl, deuterated C1-C4alkyl wherein C1-C4alkyl is fully or partially deuterated or halogenated, hydroxyalkyl, alkoxyl alkyl, or C1-C8fully or partially fluorinated fluoroalkyl;R12is selected from the group consisting of hydrogen, OH, -OC1-C6alkyl, -OC1-C6alkoxyl, C1-C6alkyl, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;R12ais selected from the group consisting of hydrogen, C1-C6alkyl, deuterated C1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially deuterated, C1-C8fluoroalkyl wherein the C1-C8fluoroalkyl is partially or fully fluorinated, substituted or unsubstituted 3-8 membered cycloalkyl;R13, R14, R15, and R16are independently selected from the group consisting of hydrogen, deuterium, hydroxy, oxo, -C(O)NR6R7, -(CH2)nS(O)2NR6R7, -(CH2)nC(O)NR6R7, cyano, halo, C1-C6alkyl, deuterated C1-C6alkyl wherein the C1-C6alkyl chain may be fully or partially deuterated, branched alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, haloC1-C4alkyl wherein the C1-C4alkyl chain may be fully or partially halogenated, C1-C4fluoroalkyl wherein the C1-C4fluoroalkyl is partially or fully fluorinated, C1-C4alkoxy, C1-C4deuteroalkoxy wherein the C1-C4alkyoxy chain may be fully or partially deuterated, cycloalkoxy, -S(O)qR6, -NR6NR7, -NHS(O)2R6, -C(=NR6a)NR6R7, -NHC(=O)-C1-C4-alkyl, -Patent Application LTGO-019 / 01WO 36088 / 124 NH(C=O)NR6R7, -SO(=NH)R6, -O-(CH2)mC(=O)NR6R7, -O-(CH2)m-O-C1-4alkyl,-C(R6)(R7)-cycloalkyl, substituted or unsubstituted C3-C8cycloalkyl, C3-C8cycloalkenyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C5-C8heteroaryl or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of R13, R14, R15, and R16substituents may be further optionally substituted with one or more hydroxy, alkoxy or C1-C4alkyl substituents;m is 1-5;n is 0-3; andq is 0-2.

22. The compound of claim 21, wherein — represents a single bond.

23. The compound of claim 14, wherein Yi and Y2are 0.24, The compound of claim 14, wherein Yi is N (Re).

25. The compound of claim 14, wherein m is 1-3 and Y2is 0 or N (Rr).Patent Application LTGO-019 / 01WO 36088 / 124Patent Application LTGO-019 / 01WO 36088 / 124 N~NH27. The compound of any one of claims 11 or 21. wherein Ring B is selected from the group consisting of:Patent Application LTGO-019 / 01WO 36088 / 12428. The compound of claim 11 or claim 21, wherein Ring B is a substituted or unsubstituted cyclohexyl.

29. The compound of claim 11, wherein Ring B is30. The compound of claim 22, wherein at least one of Ria, R2aand R2aare selected from the group consisting of substituted or unsubstituted Ci-Cg alkoxy.

31. The compound of any one of claims 11-13, wherein R2aand R2bare independently -CF3and -CH3.

32. The compound of any one of claims 11-13, wherein R2aand R2bare both -CH3,33. The compound of any one of claims 11-13, wherein R2ais CF3, and R2bis alkoxy.

34. The compound of any one of claims 11-13, wherein R2ais H and R2bis alkoxy or fluoroalkoxy,35. The compound of any one of claims 11-13, wherein R2ais H and R2bis alkyl, aryl or fluoroalkyl.

36. Tire compound of any one of claims 11-13, wherein R2ais aryl or heteroaryl and R2b is alkoxy.

37. The compound of any one of claims 11-13 or 18-20, wherein R2aand R2bcombine to form 3-6 membered substituted or unsubstituted spirocyclic cycloalkyl or heterocycloalkyl ring, wherein one or more hetero atoms in the spiro ring are O or N.Patent Application LTGO-019 / 01WO 36088 / 124 38. The compound of claim 37, wherein the spiro ring is substituted or unsubstituted cyclopropyl, cyclobutyl, or cyclopentyl.

39. The compound of any one of claims 12-20, whereina, b, R4c, R-M, and R4e are independently selected from the group consisting of hydrogen, deuterium, halo, Ci-Csalkyl, Ci-Ce fluoroalkyl wherein the Ci-Ce fluoroalkyl is partially or fully fluorinated, branched alkyl, substituted or unsubstituted C2-Ce alkenyl, substituted or unsubstituted ( -C; alkynyl, Ci-Ct, haloalkyl wherein the alkyl may be fully or partially halogenated, hydroxy, C -( alkoxy. Ci-Cg deuteroalkoxy wherein the Ci-Ce alkyoxy chain may be fully or partially deuterated, Ci-Ce-fluoroalkoxy wherein the Ci-Ce alkoxy may be fully or partially fluorinated, cycloalkoxy, deuterated Ci-Ce alkyl wherein the Ci-Ce alkyl chain may be folly or partially deuterated, cyano, -S(O)C1., - P(O)(Ci-C4alkyl), -NRsNR?, -(CH2)nS(O)2NRR?, -(CH2)nC(O)MR6R, -NHS(O)2R6, C(=NR6a)NRR7, -C(O)NRR7, -NHC(=O)-alkyl -NH(C=O)NR6R7, -SO(=NH)R6, -O- (CH2)mC(=O)NRR7, -O-(CH2) -O-Ci.4alkyl, -C(R)(R7)-cycloalkyI, substituted or unsubstituted C2-Cs cycloalkyl, G-Cs cycloalkenyl, or 3-7 membered heterocycloalkyl wherein the 3-7 membered heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N, and further wherein the haloalkyl, alkyl, alkoxy, cycloalkoxy, haloalkoxy fragments of the foregoing may be further optionally substituted with one or more substituents selected from halogen, hydroxy, alkoxy, -NR9R10, C1-C4 alkyl, or R8 substituents.

40. The compound of claim 39, wherein each R a, Rib, R,, Rd, and Reis independently selected from the group consisting of hydrogen, fluoro, chloro, -OCF3, -OCF2H, -OCH3, -O-CH -CH?,, - OCD3, and -CF,.

41. The compound of any one of claims 11-13 or 18-20, wherein Ria, Rib, R2a, R2b Ria, and Rb are independently selected from H, halo, hydroxyl, Ci-Cs alkyl. Cj-Cg cycloalkyl, deuterated Ci-Cg alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Ce alkoxy, C1-C5 deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be folly or partially halogenated, C2-C6 alkenyl, C2-Cb alkynyl, -[C( )(R7)]m-C3-Cs-cycloalkoxy, cyano, - [C(R)(R7)]m-C3-Cs cycloalkyl, -[C(Rb)(R7)]m-C3-Cg cycloalkenyl. -[C(R)(R7)]m-N(R)(R7), or - [C(R)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N.Patent Application LTGO-019 / 01WO 36088 / 124 42. The compound of claim 14, wherein Ra, Rn,, R3a, and R?b are independently selected from II, halo, hydroxyl, Ci-Cs alkyl, C3-Ce cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may¬ be folly or partially deuterated, Ci-Cs fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, C / -C, alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be folly or partially- deuterated, haloalkoxy wherein the alkoxy may be fully- or partially halogenated, C2-C6 alkenyl, C2-C6alkynyl, -[C(R6)(R7)]m-C3-Cs-cycloalkoxy, cyano, -[C / Rs RriJm-Cs-Cs cy cloalkyl, - [C(Rf,)(R7)]m-C3-C8cycloalkenyl, -[C(R6)(R- / )]m-N(R6)(R?), or -[C(R7.)(R7)]m-C3-C3heterocycloalkyl wherein the heterocycloal kyl comprises at least one heteroatom independently selected from O, S, and N.

43. The compound of claim 15, wherein R3aand R3t, are independently selected from H. halo, hydroxyl, Ci-Cs alkyl, C3-C& cycloalkyl, deuterated Ci-Cs alkyd wherein the alkyd chain may be folly or partially deuterated, Ci-Cs fluoroalkyl herein the alkyl chain may be fully or partially fluorinated, Ci-Ce alkoxy, Ci-Cs deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C6 alkenyl, Ck-Cs alkynyl, -[C(R6)(R7)]m-C3-Cs-cycloalkoxy, cyano, -[C(R3XR7)]m" C3-Cs cycloalkyl. - [C(R6)(R7)]m-C3-Cs cycloalkenyl, -[C(R6)(R7)]m-N(R6)(R7), or -[C(R3)(R7)]m-C3-C3heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N.

44. The compound of claims 16 or 17, wherein Ria, Rib, R2a, R3b R3a, R3b are independently selected from H, halo, hydroxyl, Ci-Cs alkyl, C3-Cs cycloalkyl, deuterated Ci-Cs alkyl wherein the alkyl chain may be folly or partially deuterated, Ci-Cg fluoroalkyl wherein the alkyl chain may be fully or partially fluorinated, Ci-Cs alkoxy, Ci -Co deuteroalkoxy wherein the alkoxy may be fully or partially deuterated, haloalkoxy wherein the alkoxy may be fully or partially halogenated, C2-C0 alkenyl. Cd-Ce alkynyl, -[C ReXRr^-.-Cj-Cs-cycloalkoxy, cyano, -[CfRbXRyilm-G-Cs cycloalkyl, -[C(R6)(R7)lm-C3-C8cycloalkenyl, -[C(Rb)(R7)]m-N(R6)(R7). or -[C(R6)(R7)]m-C3-Cs heterocycloalkyl wherein the heterocycloalkyl comprises at least one heteroatom independently selected from O, S, and N.

45. The compound of any one of claims 11-14, wherein R1aand Rib are both hydrogen.

46. The compound of any one of claims 11-16, wherein R3aand R3b are both hydrogen.Patent Application LTGO-019 / 01WO 36088 / 124 47. The compound of any of claims 11-16, wherein X is -C(Ria) (Ri b).

48. The compound of any of one preceding claims, wherein the compound is selected from the group consisting of:0 O „ o<.., NH O °YNH20 z-2Ar- AO-NCoHF5COW A |HU / Y __ Z'~~i / . Y i N A HF2CO y | H F3CO — <_ H F3CO \ H MeO^ J 'P MeO X YIFMeOxM "eO X yX F F F F F0 O*AH2O^NH o Y2o A 0 A A^ANAo if ])NMeO D3CO Xo D3COXF3CHXHX X 1C y3H3HF3A A F C F cYAZY A'AjAF■AjAp F F F FrdI / <3 >,■■■ NH2o o O^NH2o / \ ) (T A ° — 0 Y 0 _ O^ 3^NH2\ O zxcLL= — zAf NH2( o \ — / \ 0> I JD3CO, MeO N'ZL^'' MeO. jL XA Ph--,.X IHF3C XHO Y l3X 1F3C o A / K F CHH QxoAy MeoAjAp uZ5" FY i 'FF F1 F ' Foo^. MH2„ O,^NHoO^NH20 VZzAA l| l| „ r k JN / Ap-\ j N H '-xe- TZ\ / ° H 0 — < 1 H n ' iAMeoXA 0 AX F"! MeoAyAFF F F FFJTl Patent Application ® wo o LTGO-019 / 01 WO 36088 / 124 Z\ S / \ 0\ I O. _O^NH2O^NHJ 4zx° ■n iz-- V / / J \ o_01 0 4 c < Z V _T N> MeOx1 AX MeOsF3C XHXF3CHN «T HO. J! ^ X ''FSy 11.ZF F / \X \ ■7 / 0"(A o zx ALLz— - O~._ xNHS O^NHJ 0 0 X x.XYX 0EtOKZ^1X' N'Z^ZXLLo c 0 HOF3c X X-A.H. F3C XH? fl0 04 '^ Y^F F FQ^, NH2o 'V O^NH2C°= / cz / "\o_ o ~ NH 0 x 0xz / ° o \vNH220 x l OX \ ' 22Ji J v z n—4 w -.Me(3 z~~-X'''N'Z''''''Xn ilNMeO Zx-^ NX H 2 O - MeO / XxHp C " \ HF3C CMr X IF C '^HX H3Y<5X F3C ^X^XX □ 'Y" C X / L y ( X LLf—< FSC-' X'^-F XXs^FF ) \ ° F) OXC ZI u_= — '? ( o —<4 s O^NH2OO< V, NH2„ (X 0 X„NH2o | 0XX A-^ MeC) jf^XJ MeO. / — A A> Fjco-^y' H ‘ ‘XHXHMFe3OCx^X'N^ F3C X-A^. FgCAAp 1 FF MeO rO > Fr O^NH,0 y Q °<y-NH2 0 °YNH2 0 VH2A!X JINF3C X JL X MeO X f 1 ¥ J 1 MeO A x XZl XX X¥ \Z r N F3CO-- / J N MeO VJ F,c<r «' ~ FscVtHFX'XX X XI F / / F1FPatent Application LTGO-019 / 01WO 36088 / 124or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.

49. The compound of any of one preceding claims, wherein the compound is selected from the group consisting of:Patent Application LTGO-019 / 01WO 36088 / 1240 o © O NC OX, NH2An b,._ ©o / A A o Y v '" Nx £ AZ » 1 Jz / N n ilN|| H x^AA xT'« " AJl Xx JL x0 y F X 0 X yX. F X'^Y^F F F F F0 O NC O^NH20o Y v r^ XjN1X / '-'Y' N 1A r F- XX 1Hx3CF3CXJX A PXAJI F3CAAXYYx jt X o Y ^O'^'Y^FX'^ y F? A'F FFF Fo NC OXZH20o Y0? AxX^nNn tT^NX H x x / Yr^N'X HZ<^ F3C / V\ X. F3C-X>\^X P\ Il H F3CXA XX'^' y^F XO^ Y^'F F Yr ^ r X'' Y^FF F FO 0 o „ CK, NH2X jj^N / A'Nfj Y N An F3C ZX^AF3C A \--A^HX X 1 H Y\ I HF3X^Y A CY yY Y\jAF\QJXX? X,FF / F FrX F0 0 O NC 0 MeO ZXNX jjNx Z"'< x / ^V^'N'^' JLSMNX x Z^V^N''^^X 1HH F3C^Y Y ^M F3c XK 1HAA0CF3X0JxyXxFMeO'^ Y^F F FFPatent Application LTGO-019 / 01WO 36088 / 124O^. NHZ0 0 Q o <!■ U 0 / JYit 1 A H 1T^N£ JM Z'A''x / '"r NN CiF3XCHJX ] H XJ ”-Al ''" O'^X^F X-A0CF3O X F FF<r NH20 CN O.^ / NH2O o V 0 YAA'N N || A A\ / Y N / ^ AF3CH3X H X IHF c-^vA -.AF■1 iAJA ^O'AAFF MeO'^^X^F ''O''i'''p>'' FF \z 0== F F C0”” — / ff0 OXH2 0 HO OH 0 1p ■"1 A1 Y Y X o1 AY zx. / ^> AN T F3C xp^ N - AY X H Z' 'Z^V N / F3C ^-' X^Y X 1 H XHF3C F3C A-'-A-X,MeoXjXp AF " AYxXsyxFF F F0 0 O „ O^NH200 x 11 'rr\ AP z- AYNfo N / XzzjYOr F3C IX V-X HF3C AViV%H3XF CHo< Xx ' J O TI F \ 0 A yi F Xy A^F X'A^F F F F FO^NH20 0 O O^NH20 Y 0 i 0 y 1 <±> 0 (Sf (f jT^NX'-'-AN x~'’llNTX i H XHzzAA \ / \ JHF3C 'X:'' X F3C A-A^X AHF3C -pAj U XACFO QXl X O Vx3J F F F F F■n TI w Patent Application W / / . A 5 z SJZ— z w— uzo / LTGO-019 / 01 WO 36088 / 124 / zX ) e o \ — y / CM \ — X / / X A o LLL ^ / ZT fi_— -- ~ / ) O — — / V3 / °ZT0.XNH;, 0 O^NH2r( b~- ya)~z x / 0 X YO= rz \\ / / / AA \ o_X / zX A yocx ■" < # o / z V — n t V i! Ji. J LL U.08-J p Z\HF3C F3C XXrj xXX Zw U-— xv ' XX r / / X ° Lx f X / OA o- CF 3 ji i F 1F / \Z _= z 0 V FX FX \ / oZTF Fjl X*X o / coIL cox. / ~~XAj '’'xX 1HF3C X / ^. a>{ Z- / / A SXXcF, \ / ° C / -~LLY y Q / il ZZ - —^\3X o=To— / X ) / o— 0 OxXNH2q \ I ® 0 A Z LL \ S: JL C! II 1xxx N it Z'XN ji ji o / x / "-A'A "' fl 1 X IL j LXr-A N" ■^ v-XH° X H I X 1 H FSCAXX XXoXX F1 F Fo o O NCXANXo / XX"''' X H X H z\ J.HF3C F3CO'' Y^F QJ\XCFV T^FX F IFI F FOx^^NH20^, NH20 % 9 T il IX-X^N / AX'hJ••x / X N X / "-< 'N'X ihF3C \--XAX PsAJyYIl 1 oX^F XX X F F FT1 “H Patent Application co <>*c\ O / / LTGO-019 / 01 WO 36088,4 / z~124) oA y4 _=u- / z > o Q u_ <- zx; A A — — XX / A ’, ) ( O XX \ / — / \ ® — £ Y O (X> = T] X / 2X° <mx X O 0 / V z M— LL CM X „ M C CMTi \ / \ z XA zz- ■~\ u.j _! ^Z- X i \ I ) —. / <. \=-AzH ■AV AXA \ o,o“-zr°> v% -.0 Vp^ V-XV° 'x? I i 0) — ' n 0 C tn en ( Y“ ■"_\ LL LL X z z—T \ / Ar 'N’'" CAOZvJLHT1 ■n G5 f Gi\ \) - 1 \! ' O / 0 / cF) / \ 7 < VJ0 — y)O- \(4 y IZ - < X, NH20 Y CyOo■"T" o o 9 0 y II. N^NH CH ■". K / X zx \ II X J V / y J6O ji JYx \ Z' r^ 'N- ''X i H V-XN^3C X 1H■n T! F3C w0 / \ / 'Y'F- X X 'O Y F F ( / / X F 02 — X y4 ■,i-— #A ■" / . Ck, NHZy0\= o A Qx - 4 ■" 1 A- Xzz- X / M / x >A P XL F3C - OMeQx,. NHS o°yNH* O AXXX N Xx^1''1I i1II A X. N ii XJ \ r~~y N X 1HPXX ~ F3C A--XYX AXXX J A V F O Y F F FPatent Applicatio Oi ■n LTGO-019 / 01 WO 36088 FA Z / 124 / A A / _ / _ / \ Xx / ' ) ( O — y^ \, x o-^ Xz / X0~VO-^ OXHo<-=^LkzTNx° 4 ° "nz x—ff / 209 Ox, NH2o Y JL A 9 XANH>: y 4X°A i y / X y ’zA y v i' i LL co I 0 / / "" Y NI T v X’Y1HFt-j.uXX > JYY] F, CVX^ N * exry >> XyFSZ-XDgCO / ( 0OC / X F Q / A < ix. —- F F \ O y, i r / / zp Q LL: / — - / / / A0\"^ \. s::: V (- yoxO NHZO O.x XNH201 JL / -^NHz O o 0 Y P XFX / -- Jl X O r> < 0 " 1o"xTV; A NXHLL LL / Xx F3C ^ yA \ / Y^NX^y^ F3C Yy -HYAA^O^ y^F F HOS JL X..F F FCk, MH2Ck. NH2Ho Y o Y O YOH11PjMyFv\iNA'Y'NX XX I Xx\ AAN ' \ Z^A-NX 1XH3XHF C Y-A / HS. F3CI 1Y'^ y^F yyyFFF F0- NHO °, NH2 2A AH2 0 '8 o Y 0 Y yyXNyyXN / y3XF CHF3C X'Y^H■ '1 X zA'YAp N^Fxpr-NH N-NH 0 N'Y (jA N1 / V 00 Y01 Ji X 1 A\ / -" Y^N 'F3C X ''-'A iH\AY ^N X FHF3C X3C YA -H.■A o YX F •^AyAf.F Y^yA'-f:F FJP Patent Application ° / LTGO-019 / 01 WO 36088 / 124 ) / O —^Oo=•HZ Z— ^ - X o X CK, NH20 Ji L, NH » L JL, NH?A X-'-A X^NIX Fl f jX6' z I \ / X^N XF3CH1FF3cCw '• ^xyy ' F3C -A I H F3C X A^YH^ J J ^O'^p 'F0 YF XOXAF F HO'X^ FFF FCk _NH2O 0 ci o yX N'X] Y A X0 / Oy jjN\ / jXANF A JHXH\ / AX AN XA3C \ / " A F3C XH / — \ JHF3c A> Y^ ■'FF F V yS F FO O YX / X* JI II X-> / NH2XvHi1 X 0 X H 0 \ Z^X^N'A^ \ XAX N \ Z> A'NF3C "' yA ) — \ 1HXF3CHF3C X A^YH^ ^A^yy2 Z X'X^F ''O^Y 'F F X"“F F Fj H Fy^y \Xo=z:£: / N N 0 XN' o VN, P / ( O — IL XX 0 X XXN"o / Xx / XX N \ / ^X'N' t£Z^'XHX 1H1 Iz F3C A-A^. F3C X'X:AXF X / y^XF F0 Y FF OX, NH20 Y O O< XXXNH2 OX XNH2o yx0-^XXrNII 1AAXNN / ^XJ^AAA 1FaC\ AHF3C— < I H F3C -- / 1 H ^O'XjA^F HF2COXAAFHF2CO'X#^F F F OMePatent Application LTGO-019 / 01WO 36088 / 124M C: X X iy i Z z—A 1\ / \ / Iv< O Zl) 1 LL\ y= — ' A O ZIvY rk U- 1=. — xx><0°i ( \? \ i / \ a>:'s 0 i Y- O - 'or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.00 O!1 U.1 <>* i Q50. The compound of any of one preceding claims, X wherein the compound is selected from the group consisting of:0o °VNH2oO.yNH2Ji l l HFjCO- / ^ H HF2CO-< 1 H HF2CO-< J H MeO'^'y^F MeO^^'F F F F1% i w -n CS O:p 0 O •,oOyNH, 0 X > i f s \ ® \ / ®:)0'; 0 — i — ■■ A l / \ i > / ==\ i / A4 VOz NF3C \°= ""2:2—z n:>=--, HF2CO" < 1 H CO — ( H V1 / Y / #0\ YYO-;_A iz / \ XQ Z 1 V!z zy -—_ MeO'^P^' I XF KJ MeO YF1 M F FO,., NH, „ cn. NH2Q O T 0 yA 1 < A^'NI O / ii MeO.■■''--■Y* ''N ™ / ' NFgCO1' / ! H F3CO" < i H X HF3C11 u A MeO y F MeO Y F MeO y FF F FPatent Application LTGO-019 / 01WO 36088 / 124 Igx < s\ / CD) / O — O^NH2^\° IZQ° I OO:=TZoD3CQ. (i MZ-X^L iZN> / s; H F3CoJ1o XyZ^FP o,FS< sg <) ( O - O^NH2^\ \o >o>==31O^ / NH2o o o y 0 \ iz~\ / O^NH2V / / \ o.__ y 0 X ilN>< X" NH yyA / XX2c £D3C \ZZL- 1 JL z^ MeO, X X O AX / X D3CQ. D3CO / 'XN / "'H / 3lX(s; i H Aw HF C' F3C N <X □ F3C' / y XyxF? O < \oZj yX o o. y / \FF?I F 1FF o?=LL' °” \ co / ) / O —o o £ o Yo= 'T|< iz—x 4) X o yNH2fl) w o X>'*MeCl " (i ll vNz— Ph-\1 H MeOl N -X / FjG N I jwy ] H °7s)\ JHZA 5- F3Cy c \ LL — MecX-j / X / O \ fiF( Qr (i! ZIE ~S- Y { FF?1} ( O — / \ ®jc c 0^, NH:0Oy NH5o R o y £ r°tx 1CMF3C— \ / ^< ^N t) JU ^O...<M yto0\ JHH MeO'X^^^F MeO'^^vF MBO'£^XF F F FO^NH2O^NH2 O^NH; F n L FXo y F. o y o..co v / ~F1 XA X,-RiZ'~~< 'N ° \ A.Ho y j H MeO'xlxYx'F MeO'^ yZs.pMeO'£y 'FF F FPatent Application z LTGO-019 / 01 WO 36088 / 124 W v J ( Z-Q' / LL° \ -xlH.7—X- MeO'^V^FF ^JEs _ 7 / T \— I / \ / \ f Oz> s j yo_7 0 \ / 4 j —7 *’’’■ LJ_ / \.?. ZZ -— °) o — ■■oVH2) \ o —4O= -n J } ZZ-. / \ ® / y y \ o_^ xOC^L'£ Y “P <. _X u_ l u / CM XMeO'^Y^F \, z2^ jm x^F y v4- _ / Q^V cry 23Cu. J zx / -- ^ -n XZCU. Jzz- ^ °~ X 2 <O^, NH2\ ) O < — ’ Q. NH2\ ®a ) ( O — O^NH2O | X / s o " V o Yf © / X £ fi 1 O°=’I2 / yoJ o o'' f! 7MeO.°' JW) H GH ■"\ JHzF3C' V>.„zx. wMeO'^^'F g - ^ x^x^Kp n^\ LT — p oF11- QFJfe s\S ® / r O^NH2O-^XNHZ\ O 1 -. Ox, NH- O T O ■*< o xM eO Y OCk / / x N i?vS jt x> Q)o="izy 'T1o\ / / \Y °\= A xG GMeO MeO. ZX(AN / X / MeO, C^ { ■" Z Y 7^ Z _. / x / Ss > T- - Twy H XRJ I H A X I -- _ _ F3C' V>..,ZX^ Fad FaC^ V-Ay^xH0\xAykFXX^^F F FO-O^o YMeO-yAyA^MeO.Twy HF3C'V' |YyApFPatent Application LTGO-019 / 01WO 36088 / 124O^, NH2O^NH2O^NH2OV^XNH2p A o A o A 0 AN( U f l J HO. HOZHO„o< T H AR> H As; H As; H F3C' F3C FjOV"J--.ZY^ " IX7F / Y ^F AsjAp F F F FO_NH, O- / NH2OO^NH2° 10101 XAf ^NX / l f ANHO. M MeOO, / — -.-•' N MeOvZ--~7A 1' N MeO.AR; H A»HAR; HF3C' F3CVv^, F3C' F3C' A^^''AYAHA^A U A xQ / '-FA AA' \A^ ''FFJC'^A^P F F F0AH2 o NH2O- AJ O^NHJ O Y o Y o A 0 n 1 L AAAX> YNF (i D j J II AJ MeO, / A^N7^ H J AF-H\fsyA^N'A^Z(sZA''kN'A''' / As; H ° \AH°' \ JH°!\AHF3CFsC / XX^p Ay^F -^Y^F AY^F F F F„ A<NH= O-., NH2O^.- O^NH o AN H22o A o A 0 A AX / ■'A' Nr-J 1 XX ( X J MeO, / -•~V-' OA u MeO. / bv MeO,As)I H AR) H A«) H FaCAAyyF F3C' AA,^Y" O-^Y'X’F AxcA-p: AAA-FAAAFFO^NH2O<> ZNH2O-AHJ o-. AH2o A o A01 0 A1 x ( (5u MeO / ~-A''N MeO N MeO. / T"''^-5hf v EtO, / "" A^N AR> H AR; H As; H As; H F3C' F3C' V-A, F3C F3CAA-pC|-A#AFci'''AAFxAjA'FF7' < Patent Applicati CMon n z g LTGO-019 / 01 WO 36088 \ z z / — 124 m ) IL 3 / 1 JH °( \Y\ O 23: / O^N ~ O-^NH, H2oO°VNH2V o Y / YzY'N rf yf^ N Y"'\x§t" W1 z z ' — Xo XY z: FjCOyX ' X^F3Xo °EtO. / ''VXRZ^N LL Tco^Y [) HF3C" VY TJ CM W EtO ' 'v?\ X EtO" XcA O / F A Z Z - AAFf F o F Fo >- F n u- \ / —£zy o_ \< O ZE / / \=A< k-v==O °yNH2 o °YNH2X \O / '12 / =. (OX -$ 0)A\ ■O O ® «F,cy. W YA A - A? 'iz Z-3\Z'> " 'N AY Yr N Tk. Qn, Y^ 1 H M MeO V- -X MeO ' — XM CM C X YA R / / Y X\ Z Z~ Z z.— / " XX 4-M MeO J F A YY I F F?x °„ 0-.., NH, O-^NH,O0<VNH2HA o 'Yzo Yi \ 9 V \ \" / X LU A A jzY N fi YiNAo 6 MeO y-^ A A A ® o “VANX^ o m |T s LL F3C'- \LJHF XXHeO \Y / ,N < \ JX T0Y=AA Z Z~ XO \ _ / / A / FX1F / \3 <^Z ZE O z S=„ 0., NH2o 'YO / A 0> O CO F3CO-< SA T 'H t!\ _J;r\ / Y°"\=AiFCY. NH;. 0 OyNH20OVNH2 oOyNA 0 yAXAi i F C (X F3C A AAXi N ^ •X«A \s) I HHO' HO'xZRT V-Y. T Y JTY MeO / / Y X F / A / F / / FFPatent Application LTGO-019 / 01WO 36088 / 124O^NH2„ o Y. NH2zOOVNH2A. A......66 J JiNA \ J 6 n F3COX? F3cOOMeO J J Med 6A Med T \F F^F 1XF F F0°^NH2 p 0 0^. NH Q V2J. X, iJo.. I JOv z..o A JoA z\. A.. Z AF0’0 / H v\S) / H3AOKHFA MeO V- AMeO / I " X 7 / AFAFA Cd*FF X?Z X"" Y\ / F x6F F % / A F<, / O 2X V / / = O-A °'o °VNH2^ Y_ZU-""0O^NH, „ O...,o Y. NH2P A A A fO AAoF,%ANA A6 HO A ZO Oj\R) I H A LL y-%> ] M 1O; / ^" CA « eO M 1XXPVOJfooA \ Z= Z / F I 'F AF F F / F F / \ ° '\p O ZI / / \A Au. / ■ '0oO^NH2o °yNH* 0 Of bO- A if [ANY- HQ. A A A OJ ~ A JA A AA VG< A tAJ°A \ HF- / VJ.HF—( \A,HF'XF 'AOQFFHOAo JAO OA / F. / I Fr6 AX F' \ F I i FF F F F00<^NH200< X. NH2„ 0;.. NH, o Y2I A J.- / ..66 / ■^O J^A 'tv NF3CO7S.\ J HF / T^Jo-OOi r OA C ■^A-. F F \6A^ 'C| iN « T Patent Applicati X ~n MX7 Z z—on o LTGO-019 / 01 WO 36088 / 124 o3 / rA y ( ° y\ Ov zz= \ 0\ r / ~) 4 >ozz=zW >< o= ooU.; esA v V z z— X °' vX ^CJS 1: T ■ AFY;= Z O J'AZ Ai / / F FJ i 3: / \ / i C j“ 1 B. "AZ I ■■■ (11 oZ XAT ii ( \ — • _ / LL \ \= / i“^CK. NH, „ O-., NH, O< V, NH, o y ^:=\ Q " Y'Z Z i0zzyz ■ XX ( O i 1A X / ix(AAA ''N\:=Z Z Z-^Z'N'AA JvNF3CO^Qr H X; M; LU F iA FA <)FQA Xk-°\XTxo V / i c\ HO / A / TF HO\ArX\ / F A Z Z - F< A. F F 4K\ 6 O< XX --- jSo°VNH2 / A “-A \= 0 °VNH2 AA ZAz > A° rV- V / - A A / F / °< J K' o / P-X"Li \ co \ o o L / r / \ J BHA'-" A.FZ / F H0U 7= A"% X S A 1 c h F FO.5.^ NH2 o°yNH* O^NHjA A I / AANZV’W ■ A N A ~ZA< X J F~( HF2COyY i HFH<\ j / AF / AS / ZyAFF F„ O^ ^NHs O^NH,o Y"o%AH27 V N Z~'~< Jt N AA ^ -WHFsCO^y^i H> aA\ J H.. J H JQ HOs J / / Xy%HO\AX XA F FFPatent Application LTGO-019 / 01WO 36088 / 124or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof51. The compound of any of one preceding claims, wherein the compound is selected from the group consisting of:Patent Applicat Xio CNn LTGO-019 / 01 WO 36088 Z / 124 / \ OLuAt OPzz=0 0f \j \21 —A Ct (f lA / TCNO' 'A® H LL 1] H F3c' F3C v-ypxM C\OA^AFXdZ \on -AxFF F / S\ y—- VZ / _ o= z—1"Q^ u_ zi 7 / --- 0 0 r / . V-U' \=y^7 \ o — 'p c / M / \ / ^O’■ '■MR) 1 H LLF3C Xznx- ’V J ' 'F / X yCU" ’F F^ / Q ‘"~£ —y — \O 0 MeO cob / A(XxA *^ / ■^-X^’NXXU "F’CXA. zn\ ± x z-—A. © ) IL. JQO X F MeO'^A^Fo= / f / X Oyu. / zi / - F F o 0X 7H2o OOz0 XAjl l, XyNH? An Z — yZ ' N Ci x fl ■x A\ JlH>\JLH° z\ JHX-AArF FO,- ®, O o yH2o °yNH2«. / '"< JU ''N OXH X15F>% / tfANF3C, A. A FaC' ^ y A JMV y ^OA^F HO, HO AF Xy% >F FPatent Applicat CMion LTGO-019 / 01 WO 36088 _ X / 124 ) / \ ) / O — y / o \0 CN O^. NH2C0A" "n12— # 0 A / ( o — \ / A^N'z^x6X I Q^H U. co >z\ JHMeO^^^'FA'^^XFFF0 0 O^NH2JL o A, / D«u. / ANTQsj H H ■K3FA3C' HF C' ' / % M C F3C' V-"A y S XZA _ X zZ" A'^A^'^FFF / X \LLF / / X O y3 / p g ( LL / ZZ — — / - \O XV=u-ZI- °~O HO / X O ) ( o — 0 HO o—O / \ / zAS / ''A N F3C^QJ^NA^AfS) H?<ysj i HF3C' F3Cv" Srx n Tl wO “T1 P, SfcA'V^A A" / A MeO'^^A^'FF F F db ( / / / X ( ) o —' ° Z k —S XA V 4o.= aZ T q q GV, HH2A ■” z iz—o A o A ■" " / \VO -n= (fSr^ / Ti NZJ1 S N t° ■"r vz— / X A I' A A ^Sl ^ / ■ v AV I T / A' N'^' >■ '' A A AX \ Vs; H As; H ZA^N F3C,,F3C F3C"V- V As; H / A N %?F3C'JJXSAHxO' 1 A F A'A^ Fxozys'FF A^' A^F F F FO;,_, HH2o AAA'AZ\ Z^< N< X JHF■n w Patent Applicatio con O / z x CM LL—LTGO-019 / 01 WO 3608 o e ) X8 / / v>32 / 124 yO-Z000o<=Zu. CO O 0 Z:i— ° °~y \ o —Ji l Zl) O / O O®Z v mNHW — w \IQS) LL co o / F3C % HF3C'I (f^J," CF3F / o y ——4 ) YO)= ■n TZ—, 0 / v o__< / y -n- VZ- X!)XX HF3C ^""rp^nm°'K ' / Z LL<)31 1Ffo=V:i J) TZ \\ / Ck Xz 7 \ O — Ox, NH2Y o A / # \ C oK-__, NHoz'!2° I JL C Aco o<Y o / / ' 5LZ ^ m_o ' -iw < -.x U.NNu1 z i o\ Z> ‘ N X. NC> YK / Xfs; HZ\ 1HO CM SJ T HF3C' W / M F3C'Q / ,ow r iJ\^>kFI ®L(s>LVO " CF3Jx. FocF F \ / / \ Ly=□_ / ZI__ C °f O o 0) w\z§ O NC Ox, NH2□ < o Y LL «if ilN Nz\HX. / xy^N'zil^ F3C ^"" PI jvsj H F3C'W'Yp ^ ^^'OCFa / XX'0CF3Ox X? 0 o 0 T1! JL|i II J<, NH2jf JI Jx^^FhN•x. Z> ’'^Nz^ x / ~xrX' N '“' ll j ' / - S xXT- X x ' A XH 0>< ]HO 1 X 1 HXy xX T xo-Z^XFZV^F F F1Fn ■n w Patent Applicati w Ton o / wO,, LTGO-019 / 01 WO 3608 z Jii V8 U / 124 yX, (? - 5 V / o ——oX u-y / 0 f / / y y y O-^ *J-' — zi_— ' / o? —0O4^H2N0PH2NO NC ■n Z iz—7 \ o z ( 0— — 4 "n TZ-_# 84 J jO? Z / / 6d (i llN0 / " < O / O -n / „ / " V' N VZ- c>* LL? JXW H A s} ] H LL XHF3C FgC F3CX'' ySTxo / y ^FF F • F0 o1 1 / J / "-< 'NA IHA 1HF3C T1 wo7< MeO'z><yXF 0 CF3 / J ( / F\770 — y 11 ft - )o= 7 ^\ \ 2( f O““ — 7 Q ( Y 0 \= ■,—- o S^ / / / / 'x (3U" 0 ymO / Z VH- co:i: LL J 1 J n ilNy / ^Z^N FgC. / ■'•'•>■''' NI H CM T1 X JHWO6>'XX YY''F / L y0 — F3C OMe IF / \ _OZ= U-zx' °( >< LL \==43> 'nA IZ~ A / y \ 0y_ LL UUO^9, NH2O-JC-NI"h Oit’" - £ v~v., _ 0 XJ C' ' 0 0 'S' co / LL / IJF3C<NH XR; j H cVS) | H F3C' ^’'yX, F3C'0XyA.FO'^xrXF o'' y?T A. F1F f-^ 'F!F0M^NH O °^NHii6S' AnjXfsj HF3C'w''yX F3C'o'^p 'F O'^X TI i 1 iPatent ApplicatioM Cn LTGO-019 / 01 WO 36088,^ z / z"124J H / y QX / V= LLz:c-0H 0 NCO >. A-- o V J 0 4T \0F3C. N3 / (X>HLL. C9JXOT; J H F C - ",,■nO / , MeO'>v'pxFF1 J Y / 0 ——4 ) yo 'n) xz — / X y 0 \ O—__ O^NH2O ^ WNHZ 00c ■” Xy^NH / 'X z’ vz-_ / Ji llNF3C — <f 1 HF3C X' X^-.,HXJLH-o.XxJI X.^ p FF MeO'^X^'FF FO^NH2O^NH2NC? N-^_ NC~N-^ 0 OO Y O j(| YjNXX^NN(f lJNF3C CM F3Q. / ~~~j ’'' N?<(s; H J! VRJ ] H J\S)HF3C Z Hw _— x — P<fR; 1 H F3C' XZJ-., / ^.W / QO^' y^F XX T Jx^JxF oXpXF1FF 1 4 Z XJ°2 X°1F) 0 4X \ O\^NH2O000 '' 0 yLi. m X^N^J^NH2n JL1 XJ(T ilNF3c rZ '^ J6HZ'V^N O I C\S) H \ / ^r N?\S) I H F3C'3A 1F CHX^Y^ F3C'o-J\-sJ^FOxAxr 'F1 F r EtO'X^F CF ''f ''F1FF1F0 O^. NHZO^^NH2O^NH2O 'W 0 X 0 (X^«. / "'< 'NFt‘ii3<\ / '■v'^N'''^^NTvs; HF3C' X->-„ ^ \LXhZ \ J.HF-0nMsO^r F 0'>''< Y '-FO'XXF1 £ i F F3C'^x<::::^OMePatent Applicationk_ X LTGO-019 / 01 WO 36088 / 124 yA / / - O € LL— V yO V< / _= zZo / ■ y \ Q u.1 > —- - - O^NH2flJ O o ^■ 1 ) V ( O1 f 0Tx / - A— 0 - — V — ’ '' ) ) — \ / \x O - o / o / if'’zX'?' Xz' z v N\ JHFgC' ^ ^ S s r i7 z X Zz ■-—^ ^ 'OMe\ ( O — X W\ / / V< / _z / _ / K o > zXOr V—ypo0X==:u. / # it zi f Z~ XX —~ '*0"lz^^o= izOX^NHQ 0o2- > VV o 0 VZ—— o\ / x o ' HX ' ■n_ E / \ 0A & W "7. / \Qx§ o><sM F3c 0 C>''7'* ' ‘ / ^.•''^N'^^pwy 1 HZ- z XZ HO'xyS^F= Li“ #4 ° C“P / HD0“• FQZ \,p- o 0O °^x- OX ZNH20 V V LL Xo / "' VO ^HF3C^ _ _ T 'O^X^F o. VXz1FO ^, NH2OX_, NH20 Z ou / 'r''. N F3c / —...•’' NXHpwy ] HFaCHCk JI ^ Xx,Q'^X^FF x-JF0? / / 'NH2F3tfnFPatent Applicati CM LLon _ \ T LTGO-019 / 01 WO 36088 / 124 7 C A 01 Y Q( V=rSX.- Q. _ NH2O^, NH20 'Y01 < O— - ‘ / O NF3G / o "Yv; J y H LL COs H w ]F3C'CM LLC' y S \ _ _ T1 J 1 F)t A b£O= AASJ-— °”0 0<^NH2O^ / NH20 Y X / ><NH20Z w—- 0 Y£ jf 0 § \'■■<, / " T" s / N cr xAfei 1 H J«R) H o cf ( b tf llNF3C' F3C LL(. AF3C -Z ] HY y AF F F F H O^. NH, O-^.XNH20 Y0O^N-^'OH 0 YNbbFgCF= ^£b Y J H / \ J.HAHM C^, zZQ-b.£x,FX u.O'^f 'F O^ Y^'F!F 1 1 F y Q_ Z3Z - y b f— — H O^ / NH20 ILX, O-ANH, _ O<5, N-^ / ~'-OHO-jixNH20 Y 0 Y 0 "'S O 'S Y'-VT^'N JL X bf llNA XCO x. Ar L 4^? VS) H?vs; H \ / "'i N3C' X ]HF3C' V>-.,, YY / X *HG> Y TO'^ T^F 1 JO'bA^'F!FF 1 FO^,. NH20 O^XN H2 OXNH2OJHXNH20 Y 0 Y O 'S(f jlNbvb n blNF3G'-. / 'V N XHz \ _JHXR; I H v?^NF3C- F3C'V--AY'Y FjCHO. JL bxFO'^A^F O'^ y^pF ® F 1Fn T] w Patent Applicati w 4Non O o LTGO-019 / 01 WO 36088 / 124 X) / \ / \ / oO — -- — / A \ Z —Q-. AH2O<^NH2CX0Xj ■"0“y ~ Z IZ o YV / ( °- / \ - g xxz Z \ z Aoz I co \> -c’ KJ T LL A JHF3C x' #T1 Ti C> w4Q O > X. O x'OOx''- 1xb d / / \ / ( ) O o — — AF4 )o= "F1 T2"" # / T - o rN' 0XNA\ jLn'~fl \ z z \ z z XA / 1 TN■X H '■. / >-•' il Nl F3C' 1HX 0 Q. F F Fn-NH N-NH N-NH oXN~A / / A / / A JL > U-NO1 ° O Xj Xsj H jbu (i X^N{f llNF3C' < N 1 X | HF3C ^\R> HXsj Hx1 zo / y^F FSC' ^-'AY^ F3C'F Xy ^^F XD''' Y^ r fZ XrC F F F: coO i <Z' O^NH2i LL.J X- ■ ■ F3C -< / ^XJ H6X'Jsy 'FF HoXji-F F0 o 0 H O H sV^"A 11 JL o.,. X T XR; H Xsj H Xs; H j HF3C F3C' F3Cr■. lbXD'^ Y^FXO^f^FF F F FPatent Application LTGO-019 / 01WO 36088 / 124Patent Application LTGO-019 / 01WO 36088 / 124or a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof.

52. 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 1-51.

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