KIF18A INHIBITORS

Abstract

Amide compounds of formula (I): (see Formula) (I), and compositions containing them, as well as processes for preparing such compounds. Also provided herein are methods for treating disorders or diseases that can be treated by inhibiting the motor protein kinesin KIF18A, such as cancer, psoriasis, atopic dermatitis, an autoimmune disorder, inflammatory bowel disease, and the like.

Description

KIF18A INHIBITORS The invention relates to the field of pharmaceutical agents and, more specifically, is directed to compounds and compositions useful for modulating KIF18A, and to uses and methods for controlling cell proliferation and for treating cancer. BACKGROUND OF THE INVENTION Cancer is one of the most widespread diseases affecting humanity and the main cause of death in the world. In an effort to find an effective treatment or cure for one or several of the many different cancers over the last couple of decades, numerous groups have invested a tremendous amount of time, effort, and financial resources. However, to date, of the cancer treatments and therapies available, only a few offer any considerable degree of success. Cancer is usually characterized by unregulated cell proliferation. Damage to one or more genes responsible for cellular pathways that control the progression of proliferation through the cell cycle and centrosome cycle can result in loss of normal regulation of cell proliferation. These unregulated genes may encode various tumor suppressors or oncogenic proteins that participate in a cascade of events, leading to uncontrolled cell cycle progression and cell proliferation. Various kinase and kinesin proteins have been identified that play key roles in cell cycle and mitotic regulation, as well as the progression of normal dividing cells and cancer cells. Kinesins are molecular motors that play important roles in cell division, and in the transport of intracellular organelles and vesicles. Mitotic kinesin plays roles in several aspects of mitotic spindle assembly, chromosome segregation, separation, and centrosome dynamics (reviewed in O. Rath and F. Kozielski, Nature Review Cancer, 12:527-39, 2012). Human kinesins are classified into 14 subfamilies based on sequential homology within the so-called motor domain; the ATPase activity of this domain drives unidirectional movement along Microtubules (MT). The nonmotor domain of these proteins is responsible for cargo fixation; A cargo may include any one of a variety of different membranous organelles, signal transduction scaffold systems and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Therefore, kinesins are often called plus-end or minus-end directed motors. The KIF18A gene belongs to the Kinesin 8 subfamily and is a plus end-directed motor. KIF18A is thought to influence dynamics at the plus end of kinetochore microtubules to control correct chromosome positioning and mitotic ίηη / ζζηζ / Ε / γίΛΐ spindle tension. Depletion of human KIF18A leads to longer mitotic spindles, increased metaphase chromosome wobble, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology 17, 488-98, 2007). KIF18A appears to be a viable target for cancer treatment. KIF18A is overexpressed in various types of cancers, including, but not limited to, colon, breast, lung, pancreas, prostate, bladder, head, neck, cervical, and ovarian cancers. Furthermore, genetic deletion or gene attenuation, or inhibition of KIF18A affects the mitotic spindle apparatus in cancer cell lines. Particularly, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that may promote cell death in mitosis through apoptosis, mitotic catastrophe, or multipolarity-driven lethality or death following mitotic dephase in interface. Therefore, there is great interest in finding inhibitors of KIF18A proteins. Therefore, inhibition of the ATPase activity of KIF18A is a promising approach for the development of novel antineoplastic agents. SUMMARY OF THE INVENTION One aspect of the present invention is a new class of compounds useful for modulating the KIF18A protein alone or in a microtubule-bound complex to treat KIF18A-mediated conditions and / or diseases, including cancer, inflammation or ciliopathologies. The compounds provided by the invention have MTy-based KIF18A modulating activity, in particular, KIF18A inhibitory activity. To this end, the invention also provides the use of these compounds, as well as pharmaceutically acceptable salts thereof, in the preparation and manufacture of a pharmaceutical composition or medicament for the therapeutic, prophylactic, acute or chronic treatment of diseases and disorders. mediated by KIF18A, including without limitation, cancer. Therefore, the compounds of the invention are useful in the manufacture of antineoplastic drugs. The invention also provides processes for preparing compounds of Formula I, as well as intermediates useful in such processes. In embodiment 1, the present invention provides a compound of formula R6 Lnn / zznz / E / YiAi or any pharmaceutically acceptable salt thereof, wherein: caz ίηη / ζζηζ / Ε / γίΛΐ each of RXa, RXb, RXc, RXd, RXe, RXf, RXg, RXh, RXi, Rx\ RXky RXIes H, halo, RXmo RXn; or, alternatively, each of the pair RXay RXb, pair RXcy RXd, pair RXey Rxf, pair RXgy RXb, pair RXiy RXj, and pair RXky RXI, independently, can combine with the carbon atom attached to each of them to form a 3, 4, 5, 6-membered saturated or partially saturated monocyclic spiro ring with the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepanyl ring; wherein said 3, 4, 5, 6-membered monocyclic ring contains 0 atoms of N, O and S, and further wherein said 3, 4, 5, 6-membered monocyclic ring is substituted with 0, 1,2 or 3 group(s) selected from F, Cl, Br, Ci-6 alkyl, C1.4 haloalkyl, ORa, -O-haloalkyl Cm, CN, -NRaRau oxo; or even, alternatively, each of the pair RXa and RXb, pair RXc and RXd, pair RXe and RXf, pair RXg and Rxq parrxí and RXj, and pairRXk and rxi, independently, can be combined to form a double bond; R1 is a group -Z-R12; where Z is absent, or is -alkyl Co-4-S-alkyl Co^i-, alkyl Co4-S(=O)-alkyl Co-4-, -alkyl Co-4-S02-alkyl Co-4-, -alkyl Co-4-NR1'-alkyl Co-4-, -alkyl Co-4-NR11S02-alkyl Co-4, -alkyl Co-4-S02NR11- alkyl C0-4-, - alkyl Co-4-NR11S02NR11-alkyl C0-4-, -alkyl Co-4-O-alkyl C0-4-, -alkyl Co-4-C(=0)-alkyl C0.4-, -alkyl Co- 4-C(=0)-0-alkyl Cm-, - alkyl Co-4-(C=0)NR11-alkyl C0-4-, -alkyl Co-4-NR11(C=0)-alkyl Co-4-, -alkyl C0-4S(=O)(=NH )-, -N=S(=O)<, -(C=O)- or -C(=N-OH)-; R2 is a -Y-R13 group, where Y is -alkyl Co-4-S-alkyl Co-4-, alkyl Co-4-S(=0)-alkyl Co-4-, - alkyl Co-4-SC2-alkyl C0-4-, -alkyl Co-4-NR13c-alkyl C0-4-, -alkyl Co-4-SC2NR13c-alkyl Co4-, -alkyl Co-4- NR13cS02-alkyl C0-4-, - alkyl Co-4-S(=0)(=NH)-, -alkyl Co-4-O-alkyl Co-4-, -alkyl Co-4-C(=0)-alkyl Co-4-, - alkyl Co-4-C(=0)-0-alkyl Co-4-, -alkyl Co-4-(C=0)NR13c-alkyl Co-4-, -alkyl C0-4-NR13c(C=O)-alkyl Co-4- or -N=S(=O)<; R3 is H, halo, Cm alkyl or Cm haloalkyl; R4 is H, halo, C1-4 alkyl or C1-4 haloalkyl; R5 is H, halo, C1-8 alkyl or Cim haloalkyl; R6 is H, halo, C1-8 alkyl or Cm haloalkyl; R7is H, halo, Cm alkyl or Cm haloalkyl; R8 is H, halo, C1-8 alkyl or Cm haloalkyl; or, alternatively, R2 and R8 may combine with the carbon atoms attached to each of them to form a saturated or partially saturated 5- or 6-membered monocyclic ring fused to the phenyl ring; wherein said 5- or 6-membered monocyclic ring contains 0, 1.2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein said 5- or 6-membered monocyclic ring is substituted with 0.1 , 2 or 3 group(s) selected from F, Cl, Br, Cm alkyl, Cm haloalkyl, -ORa, -O-Cm haloalkyl, CN, NRaRau oxo; R9 is H, halo, Cm alkyl or Cm haloalkyl; L is -(C=O)-NR10- or -NR10-(C=O)-; R10is H or Cm alkyl; R11esHo alkyl Cm; R12is H, halo, OH, CN, R12a or R12b; R13es halo, R13aor R13b; R13ces H or Cm alkyl; R12a and Ri3ase are independently selected, in each case, from the group consisting of a saturated, partially saturated or unsaturated monocyclic ring of 3,4, 5,6 or 7 members caz ίηη / ζζηζ / Ε / γίΛΐ bicyclic ring of 8, 9, 10, 11 or 12 members containing 0, 1,2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted with 0, 1,2 or 3 group(s) selected from the group consisting in F, Cl, Br, Ci-6 alkyl, C1-4 haloalkyl, -ORa, -O-C1.4 haloalkyl, CN, -C(=O)Rb, -C(=O)ORa, -C(= O)NRaRa, -C(=NRa)NRaRa, - OC(=O)Rb, -OC(=O)NRaRa, -O-C2.6-alkyl-NRaRa, -O-C2.6-alkyl-ORa, -SRa, -S(=O)Rb, S(= O)2Rb, -S(=O)2NRaRa, -NRaRa, -N(Ra)C(=O)Rb, -N(Ra)C(=O)ORb, -N(Ra)C(=O)NRaRa , N(Ra)C(=NRa)NRaRa, -N(Ra)S(=O)2Rb, - N(Ra)S(=O)2NRaRa, -NRa-C2-6-alkyl-NRaRa, -NRa-C2.6-alkyl-ORa, -Ci-6-alkyl-NRaRa, -Ci-6-alkyl-ORa, - alkyl Ci-6-N(Ra)C(=O)Rb, -alkyl Ci-6-OC(=O)Rb, -alkyl Ci-6-C(=O)NRaRa, -alkyl Ci-6C(= O)ORa, a saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic ring and oxo; R12b and R13b are independently selected, in each case, from the group consisting of C1.6 alkyl substituted with 0, 1.2, 3, 4 or 5 group(s) selected from the group consisting of F, Cl, Br, - CH2F, -CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl Cu, CN, NH2, NH(CH3), N(CH3)2, and a monocyclic ring of 3, 4, 5 or 6 members saturated, partially saturated or unsaturated; Raes independently, in each case, H or Rb; and Rbes independently, in each case, C1-6 alkyl, phenyl or benzyl, wherein the C1-6 alkyl is being substituted with 0, 1,2 or 3 substituents selected from halo, - OH, -O-Cm alkyl, -NH2, -NH-Cm alkyl, -OC(=O)Cm alkyl or -N(Ci-4 alkyl)C1.4 alkyl; and the phenyl or benzyl is being substituted with 0, 1,2 or 3 substituents selected from halo, C1-4 alkyl, Ci-3 haloalkyl, - OH, -O-C-m alkyl, -NH2, -NH-Cm alkyl, -OC(=O)Cm alkyl or -N(Ci 4 alkyl)C1-4 alkyl. In embodiment 2, the present invention provides compounds wherein Rx is selected from H, caz ίηη / ζζηζ / Ε / γίΛΐ where each of RXa, RXb, RXc and RXdes H, halo, RXmo RXn; or, alternatively, each of the RXa pair RXa and RXb, and the RXc and RXd pair, independently, can combine with the carbon atom attached to each of them to form a 3, 4, 5, 6 monocyclic spiro ring κ c N N saturated or partially saturated members with the pyrrolidinyl, piperidinyl or morpholinyl ring; wherein said 3, 4, 5, 6-membered monocyclic ring contains 0 atoms of N, O and S, and further wherein said 3, 4, 5, 6-membered monocyclic ring is substituted with 0, 1,2 or 3 group(s) selected from F, Cl, Br, Ci-6 alkyl, C-m haloalkyl, -ORa, -O-C-m haloalkyl, CN, -NRaRau oxo; or even, alternatively, each of the pair RXa and RXb or pair RXc and RXdin independently, can combine to form a double bond. In subembodiment 2a, the present invention provides compounds where Rxes RXcRXd In subembodiment 2b, the present invention provides compounds where Rxes Rxb^RXc In subembodiment 2c, the present invention provides compounds where Rxes In embodiment 3, the present invention provides compounds wherein each of RXa, RXb, RXc and RXd is selected from a) H, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3 or cyclopropyl; either b) alternatively, each of the pair RXa and RXb, and pair RXc and RXd, independently, can combine with the carbon atom attached to each of them to form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring, in where each ring is spiro with the pyrrolidinyl, piperidinyl or morpholinyl ring; and wherein each of said rings is substituted with 0, 1,2 or 3 group(s) selected from F, Cl, Br, C1-6 alkyl, C1-4 haloalkyl or methoxy; either c) alternatively, each of the pair RXa and RXb or pair RXc and RXd, independently, can be combined to form a >C=CH or >C=CH-CH3; and where each of RXe, Rxf, RXg, RXh, RXi, RXj, RXk and RXI is H, F or methyl. In embodiment 4, the present invention provides compounds wherein L is -NR10(C=O)-. In embodiment 5, the present invention provides compounds wherein L is (C-O)-NR10-. In embodiment 6, the present invention provides compounds wherein L is -NR10caz ίηη / ζζηζ / Ε / γίΛΐ (the); where Rxes In embodiment 7, the present invention provides compounds wherein L is (C=O)-NR10-; which have the formula (Ib): (Ib); where Rxes preferably In embodiment 8, the present invention provides compounds wherein Rxes caz ίηη / ζζηζ / Ε / γίΛΐ In embodiment 9, the present invention provides compounds wherein R10 is H or methyl. In embodiment 10, the present invention provides compounds wherein Z is absent, or is -SO2-, -CH2-SO2, -NH-, -NHSO2-, -SO2NH-, -SO2N(CH3)-, -O-, -(C=O)O-, (C=O)NH-, -(C=O)N(CH3)-, -S(=O)(=NH)-, -CH2-N(CH3)- or -C(=N-OH)-. In embodiment 11, the present invention provides compounds wherein R12 is selected from: a) H, F, Br, OH or CN; b) R12selected from a saturated, partially saturated or unsaturated 3, 4, 5, 6 or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, and 0 or 1 atom selected from O and S, which is substituted with 0, 1,2 or 3 group(s) selected from F, CI, Br, methyl, ethyl, -CF3, -CH2OH, -OH, -OCH3, -NH2u oxo; either c) R12b selected from Ci-6 alkyl substituted with 0, 1,2 or 3 group(s) selected from F, CI, Br, -CF3u -OH. In embodiment 12, the present invention provides compounds wherein R12 is R12 selected from cyclopropyl, oxetanyl, imidazolyl, isothiazolidinyl, azetidinyl, oxazolyl, pyrazolyl or diazirinyl; each of which is independently substituted with 0, 1,2 or 3 group(s) selected from methyl, ethyl, -CF3 or oxo; or R12b selected from methyl, ethyl, isopropyl, tert-butyl, -ethenyl, substituted with 0, 1, 2 or 3 group(s) selected from F, CI, Br, -CF3 or -OH. In embodiment 13, the present invention provides compounds wherein R1 is a -Z-R12 group, wherein Z is absent, or is -SO2-, -CH2SO2-, -(C=O)NH-, -NH-, - NHSO2- or SO2NH-; and R12 is cyclopropyl, oxetanyl, azetidinyl or imidazolyl ring, each of which is independently substituted with 0, 1 or 2 group(s) selected from methyl, -CF3 or oxo; or R12 is methyl, ethyl, isopropyl or tere-butyl, each of which is independently substituted with 0, 1.2 or 3 F, -CF3u OH group(s). In embodiment 14, the present invention provides compounds where R1 is a -Z-R12 group, where Z is -NHSO2- and R12 is -CH2-CH2-OH or -CH(CH3)CH2OH. In embodiment 15, the present invention provides compounds wherein Y is absent, or is -SO2NH-, -NH-, -SO2-, -S(=O)(=NH)- or -O-. In embodiment 16, the present invention provides compounds wherein R13 is H or F; R13ase is selected from morpholinyl, piperidinyl, cyclopentyl, cyclopropyl, azetidinyl or oxetanyl; wherein each of said rings is substituted with 0, 1, 2 or 3 OH group(s) selected from methyl or -OH; or R13b is selected from methyl, ethyl, propyl, isopropyl, ere-butyl or isopentyl; each of which is independently substituted with 0,1,2 or 3 OH group(s). In embodiment 17, the present invention provides compounds wherein R2 and R8 can combine with the carbon atoms attached to each of them to form a saturated or partially saturated 6-membered monocyclic ring fused with the phenyl ring; wherein said 6-membered monocyclic ring contains 0, 1.2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein said 6-membered monocyclic ring is substituted with 0, 1.2 or 3 group(s) selected from F, Cl, Br, C1.6 alkyl, C1.4 haloalkyl or oxo. In embodiment 18, the present invention provides compounds wherein R4 is H. In embodiment 19, the present invention provides compounds where R5 is H In embodiment 20, the present invention provides compounds wherein R6 is H or F. In embodiment 21, the present invention provides compounds wherein R7 is H or F. In embodiment 22, the present invention provides compounds wherein R8 is H, F or methyl; or, alternatively, R2 and R8 can combine with the carbon atoms attached to each of them to form a 6-membered saturated monocyclic ring fused to the phenyl ring; selected from the group: caz ίηη / ζζηζ / Ε / γίΛΐ In embodiment 23, the present invention provides compounds wherein R2 is: a) a group -Y-R13a, where Y is absent or is -S(=O)(=NH)-; and R13 is piperidinyl or azetidinyl; wherein each of said rings is independently substituted with 0, 1,2 or 3 F group(s); b) a group -Y-R13b, where Y is -SO2NH-, -O-. NH-; and wherein R13bes tert-butyl substituted with 0, 1.2 or 3 OH group(s); either c) alternatively, the carbon atoms attached to R2 and R8 combine to form a saturated 6-membered monocyclic ring fused to the phenyl ring; what is Lnn / zznz / E / YiAi ; wherein said 6-membered monocyclic ring is unsubstituted. In embodiment 24, the present invention provides compounds wherein R2 is -SOaNH-tert-butyl group or -NH-tert-butyl-OH group. In embodiment 25, the present invention provides compounds wherein R8 is H. In embodiment 26, the present invention provides compounds wherein R9 is H. In embodiment 27, the present invention provides compounds wherein R10 is H. In embodiment 28, the present invention provides a compound, or pharmaceutically acceptable salts thereof, selected from: In embodiment 29, the present invention provides a compound, or the pharmaceutically acceptable salt thereof, selected from the group consisting of: / V-(3-(W-(tert-butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide ; A / -(3-( / \ / -(tert-butíl)sulfamoyl)phenyl)-4-(methylsulfoníl)-2-(6-azaspiro[2.5]octan-6yl)benzamide; A / -(3-isopropylphenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; / V-(3-cyclopropylphenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-l)benzamide; A / -(3-(tert-butyl)phenyl)-4-(methylsulfoníl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; 4-(methylsulfonyl)- / \ / -(quinolin-8-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; A / -(4-methylquinol-8-l)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-l)benzamide; A / -(chroman-8-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; A / -(benzofuran-7-yl)-4-(methylsulfoníl)-2-(6-azaspiro[2.5]octan-6-íl)benzamide; A / -(benzo[b]thiophen-7-¡l)-4-(methylsulfon¡l)-2-(6-azaspiro[2.5]octan-6-¡l)benzamide; 4-(methylsulfon¡l)-A / -(3-morphol¡nophen¡l)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; A / -(3-(A / -(tert-but¡l)sulfamo¡l)phenyl)-4-((methylsulfon¡l)methyl)-2-(6-azaspiro[2.5]octan-6yl) benzamide; A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide; 4-(N-(tert-but¡l)sulfamo¡l)-N-(3-(M-(fert-but¡l)sulfamoyl)phen¡l)-2-(6-azaspiro[2.5] octan-6yl)benzamide; / V-(3-(W-(ert-butyl)sulfamoyl)pheníl)-4-(3-methyloxetan-3-íl)-2-(6-azaspyrO[2.5]octan-6yl)benzamide ; A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-4-(3-hydroxyoxetan-3-l)-2-(6-azaspiro[2.5] octan-6yl)benzamide; A / -(3-((1-hydroxy¡-2-methylpropan-2-yl)amino)phen¡l)-4-( / V-(3-methyloxetan-3-yl)sulfamoyl)-2-(6azaspiro [2.5]octan-6-yl)benzamide; A / -(2-fluoro-3-((1-hydroxy-2-ineethylpropan-2-yl)amino)phenyl)-4-( / \ / -(3-methyloxetan-3¡l )sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide; / \ / -(2-fluoro-3-((1-hydroxy¡-2-methylpropan-2-yl)amino)phen¡l)-4-((1-methylcyclopropane)-1sulfonamido) -2-(6-azaspiro[2.5]octan-6-yl)benzamide; A / -(3-(( 1 -hydroxy-2-methylpropan-24l)amino)phenyl)-4-((1 -methylcyclopropane)-1 -sulfonamido)2-(6-azaspiro[2.5]octane -6-yl)benzamide; A / -(3-(A / -(fert-butyl)sulfamo¡l)phen¡l)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6azaspiro[2.5]octane-6 -yl)benzamide; / V-(3-(W-(ferc-but¡l)sulfamo¡l)phen¡l)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6yl)benzamide; / V-(3-(N-(tert-butyl)sulfamoyl)pheníl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6yl)benzamide; / V-(3-(W-(tert-but¡l)sulfamoyl)phenyl)-4-((1-methyllet¡l)sulfonamido)-2-(6-azaspiro[2.5]octan6-¡ l)benzamide; A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-4-(cyclopropanesulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((1,1-dimethylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(W-(tert-butyl)sulfamoyl)phenyl)-4-(1,1-dioxidoisothiazolidin-24l)-2-(6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(W-(ert-butíl)sulfamoyl)pheníl)-4-((24iidroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(2-methylmorpholino)phenyl)-2-(6-azaspiro[2.5]octan6-yl)benzamide; ( / ?)-A / -(2-fluoro-3-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide; (R)-A / -(3-fluoro-5-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6- il)benzam¡da; caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi ( / ?)-A / -(4-fluoro-3-(2-methylmorpholino)pheníl)-4-((2-hydroxyethyl)sulfonamido)-2-( 6azaspiro[2.5]octan-6-yl)benzamide; A / -(3-(4,4-difluoropiperidin-1-¡l)-5-methylphenyl)-4-((2-hydroxy¡ethyl)sulfonamido)-2-(6azaspiro[ 2.5]octan-6-yl)benzamide; A / -(3-(4,4-difluoropiper¡din-1-¡l)phen¡l)-4-((2-hydroxy¡ethyl)sulfonamido)-2-(6azaspiro[2.5 ]octan-6-yl)benzamide; A / -(3-(4,4-difluoropiper¡din-1-yl)-2-fluorophen¡l)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-yl )benzamide; (S)-A / -(3-(N-(ferc-butyl)sulfamo¡l)phen¡l)-4-((2-hydroxy¡-1-methyllet¡l)sulfonam¡ c)-2-(6azaspiro[2.5]octan-6-yl)benzamide; (R)-A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-4-((2-hydroxyl-1-methylethyl)sulfonamido)- 2-(6azaspiro[2.5]octan-6-yl)benzamide; A / -(3-(2-hydroxy¡-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzam gives; 4-(azet¡din-1-¡lsulfonyl)-A / -(3-(A / -(fert-but¡l)sulfamo¡l)phen¡l)-2-(6-azaspiro[ 2.5]octan-6yl)benzamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phen¡l)-4-( / \ / -(1-hydroxy-2-methylpropan-2-¡l)sulfamo¡l )-2-(6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(W-(tert-butyl)sulfamoyl)pheníl)-4-(A / -(2-hydroxyethyl)sulfamoyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(W-(tert-but¡l)sulfamoyl)phenyl)-4-(M,W-dimethylsulfamo¡l)-2-(6-azaespiiO[2.5]octan-6yl)benzamide; / V-(3-(W-(íert-butíl)sulfamo¡l)pheníl)-4-(M-methylsulfamo¡l)-2-(6-azaspiro[2.5]octan-6yl) benzamide; / V-(3-(W-(tert-butyl)sulfamoyl)phen¡l)-4-(A / -(oxetan-3-yl)sulfamoyl)-2-(6-azaspircy[2.5]octan6-yl) benzamide; / V-(3-(W-(tert-but¡l)sulfamoyl)phenyl)-4-( / V-c¡clopiOpilsulfamoyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide; A / -(3-(A / -(ert-butyl)sulfamoyl)pheníl)-4-( / \ / -(1-methylcyclopropíl)sulfamoíl)-2-(6azaspiro[2.5]octan- 6-yl)benzamide; A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-4-sulfamoylbenzamide; ( / ?)-A / -(3-(A / -(tert-butyl)sulfamo¡l)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6azaspiro[2.5]octan- 6-yl)benzamide; (S)-A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6azaspiro[2.5]octan-6-yl )benzamide; Lnn / zznz / E / YiAi / V-(3-(W-(tert-but¡l)sulfamo¡l)phenyl)-4-(1-methyl-1H-midazol-2-¡l)- 2-(6-azaspiro[2.5]octane6-l)benzamide; / V-(3-(W-(tert-butyl)sulfamoyl)phen¡l)-4-(1-methyl-1H-pyrazole-5-¡l)-2-(6-azaspiro[2.5]octan -6yl)benzamide; A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazol-4-l)-2-(6- azaspiro[2.5]octan-6yl)benzamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-4-(oxazol-2-yl)-2-(6-azaspiro[2.5]octan-6yl)benzamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-( 6azaspiro[2.5]octan-6-yl)benzamide; / V-(3-(N-(tert-but¡l)sulfamo¡l)phen¡l)-4-((2-hydroxy¡ethyl)amino)-2-(6-azaspiron [2.5]octan-6yl)benzamide; / V1-(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-A / 4-(2-hydroxyethyl)-2-(6-azaspiro[2.5]octan-6yl)terephthalamide ; / V^3-(N-(tert-butyl)sulfamo¡l)phen¡l)-W4-methyl-2-(6-azasp¡rc)[2.5]octan-6-¡l)terephthalamide; / VL(3-(N-(tert-but¡l)sulfamoyl)phen¡l)-N4-(2-hydroxyethyl)-A / 4-methyl-2-(6-azaspiro[2.5 ]octan6-yl)terephthalamide; / V%(3-(N-(tert-butyl)sulfamo¡l)phen¡l)-A / 4-(1-hydroxy-2-methylpropan-2-¡l)-2-(6azaspiro[2.5 ]octan-6-yl)terephthalamide; / Vú(3-(cyclopentylsulfonyl)phenyl)-N4-(2-hydroxyethyl)-2-(6-azaespiiO[2.5]octan-6yl)terephthalamide; (R)-A / -(3-(azetidin-1-sulfonim¡dol)phen¡l)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5] octan-6-yl)benzamide; (S)-A / -(3-(azetidin-1-sulfon¡m¡do¡l)phen¡l)-4-((2-hydroxy¡ethyl)sulfonannido)-2-(6azaspiro[2.5] octan-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(S-methylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(S-methylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide; (R)-4-((2-hydroxylethyl)sulfonamido)-W-(3-(2-methylpropan-2-lsulfonamidoyl)phenyl)-2 -(6azaspiro[2.5]octan-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6-yl )benzamide; or / V-(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1yl)benzamide. In embodiment 30, the present invention provides a compound, or the pharmaceutically acceptable salt thereof, selected from the group consisting of: caz ίηη / ζζηζ / Ε / γίΛΐ Example No. Chemical structure Chemical name 100 y- IZ o. / jW / ^o N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4-((3methyloxetan-3-yl)sulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 100-7 O 0 M -(Croman-8-yl)-4-(methylsulfon¡l)2-(6-azasp¡ ro[2,5]octan-6yljbenzamide 100-11 o. / O \ ° \ ZI Q Ο=ω=Ο IZ y- N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4((methylsulfonyl)methyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 100-13 y- TZ, <o c / o4o ZI c ωί IZ '° 4-(A / -(tert-Butyl)sulfamoyl)-N-(3( / V-(tert-butyl)sulfamoyl)phenyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 101 , Ί. ó i r il θ N ”... Zz x' O O\ / O A / -(3-((1-Hydroxy-2-methylpropan-2yl)amino)phenyl)-4-(M-(3methyloxetan- 3-yl)sulfamoyl)-2-(6azaspiro[2.5]octan-6yljbenzamide Example No. Chemical structure Chemical name 101-1 y n · í h í H Λ Lo A / -(2-Fluoro-3-((1-hydroxy¡-2methylpropan-2-yl)amino)phen¡l)-4 (W-(3-met¡loxetan-3-¡l)sulfamo¡l)2-(6-azaspiro[2.5]octan-6yl)benzamide 102 V .N^xk ii (j %> ° ^V / v N -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1 methylcyclopropane)-1 sulfonamido)-2-(6azaspiro[2.5]octan-6yl)benzamide 102-3 V ln^ / Ol aJL 1 δ H IAa% H N-(3-(N-(tertButyl)sulfamoyl)pheníl)-4-((1methylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yl)benzamide 102-4 ΖΞΕ Ο=ω=ο 0 xz \=° zz ω=ο 4'° N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4(cyclopropanesulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 103 V \ kk 0 -γ-ΝΗ L 111 H OH N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 104 V fS X [2.5]octan-6yl)benzamide c«z ίηη / ζζηζ / Ε / γίΛΐ Example No. Chemical structure Chemical name 104-1 n í: F pj hAíS v <^Axns'^^'oh F H Λ / -(3-(4,4-D ifl u oropi perid in-1 yl)phenyl) -4-((2hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 104-2 η. ·5 F n ηΛγ5 v F H W-(3-(4,4-Difluoropiperidín- 1-¡l)-2fluorophenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 105-1 V \ A'íí 0 -4— NH I II J Ϊ H 3 \ OH (S)-A / -(3-(A / -(tertButyl)sulfamoyl)phenyl)-4-((2-hydroxy¡1-methylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 105-2 V \ All ° / nhXA a a °7 “UA H / \ * OH (R)- / V-(3-( / V-(tert-Butyl)sulfamoyl)phen¡l)-4-((2 -hydroxy¡1-methylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 106 '5 AAaA 0 HO I H |l Ί ^'OH H O A / -(3-(2-Hydrox¡-2methylpropoxy)phenyl)- 4-((2hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 107 7 O<; <z>7 IZ A° ο.0Ο A O 4-(Azetidin-1-ylsulfonyl)-A / -(3-(A / (tert-butyl)sulfamoyl)pheníl)-2-(6azaspiro[2.5]octan-6yljbenzamide caz Lnn / zznz / Ε / γΐΛΐ Example No. Chemical structure Chemical name 108-1 s n -δ ΌΗ (R)-N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4-(1,2dihydroxypropan-2-¡l)- 2-(6azaspiro[2.5]octan-6yljbenzamide 108-2 ΓΌΗ ΌΗ (S)-N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4-(1,2dihydroxy¡propan-2-¡l)- 2-(6azaspiro[2.5]octan-6yl)benzamide 109 ^z^^ \=z ^z—<^2 o=( ZI 0. ωζ IZ ° ?v N-(3-(N-(tertButyl)sulfamoyl) phenyl)-4-(1 -methyl1H-imidazol-2-yl)-2-(6azaspiro[2.5]octan-6yljbenzamide 110 η ° δ H N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4- ((1 -hydroxy2-methylpropan-2-yl)amino)-2-(6azaspiro[2.5]octan-6yljbenzamide 111 .·,. δ 11 í| 0 N 0 Nñ(3-(N-(tertButyl)sulfamoyl )phenyl)- / \ / 4-(2hydroxyethyl )-2-(6azaspiro[2.5]octan-6yl)terephthalamide 112-1 zJ ,ω :p po> IZ ,o O o zc (R)- / V-(3 -(Azetidin-1sulfonimidoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide caz Lnn / zznz / Ε / γΐΛΐ or any pharmaceutically acceptable salt thereof. Another aspect of the present invention is a pharmaceutical composition comprising a new class of compounds useful for modulating the KIF18A protein alone or in a complex linked to microtubules or pharmaceutically acceptable salts thereof. In embodiment 31, the present invention provides pharmaceutical compositions comprising a compound, or pharmaceutically acceptable salts thereof, according to any one of embodiments 1-30, and a pharmaceutically acceptable diluent or carrier. Yet another aspect of the present invention is a method of treating a condition that can be treated with KIF18a inhibitors, the method comprising administering to a patient in need thereof a therapeutically effective amount of a new class of compounds useful for modulating the KIF18A protein alone or in a complex linked with microtubules or pharmaceutically acceptable salts thereof. In embodiment 32, the present invention provides a method of treating a condition that can be treated with KIF18a inhibitors, the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound according to embodiments 1-30 or composition according to embodiment 31. In embodiment 33, the present invention provides the method of claim 32, wherein said condition is cancer selected from the group consisting of (a) a solid or hematologically derived tumor selected from bladder, endometrial, squamous cell lung, breast cancer. , colon, kidney, liver, lung, small cell lung cancer, esophageal, gallbladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of selected lymphoid lineage among leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, tricholeukocyte lymphoma and Burkitt lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from myelogenous leukemias acute and chronic, myelodysplastic syndrome and promyelocytic leukemia, (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer or Kaposi's sarcoma. In sub-embodiment 33a, the present invention provides the method of embodiment 32, wherein said condition is cancer selected from the group consisting of melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma or leukemia . See: Zhang C. et al., Kif18A is involved in human breast carcinogenesis, Carcinogenesis, September 2010;31 (9):1676-84. doi: 10.1093 / carcin / bgq134. Epub dated July 1, 2010. See also: (1) https: / / www.proteinatlas.org / ENSG00000121621KIF18A / pathology; (2) Nagahara, M. et. al., Kinesin 18A expression: clinical relevance to colorectal cancer progression, Int. J. Cancer. 129, 2543-2552 (2011) VC 2011 UIC; and (3) Yu, Y. et al., The Role of Kinesin Family Proteins in Tumorigenesis and Progression - Potential Biomarkers and Molecular Targets for Cancer Therapy, Cancer 2010; 116:5150-60. VC 2010 American Cancer Society. In embodiment 34, the present invention provides a method of reducing the size of a solid tumor in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to embodiments 1-30 or the composition of according to embodiment 31. In embodiment 35, the present invention provides a method for treating a cell proliferation disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to embodiments 1-30 or the composition according to with realization 31. In embodiment 36, the present invention provides a method of inhibiting KIF18A in a cell, comprising contacting the cell with a compound, or pharmaceutically acceptable salts thereof, according to embodiments 1-30, or the composition according to with realization 31. Yet another aspect of the present invention is a method for preparing a new class of compounds useful for modulating the KIF18A protein alone or in a microtubule-bound complex or pharmaceutically acceptable salts thereof. In embodiment 37, the invention provides a method for preparing a compound of Formula (I) as described herein. caz ίηη / ζζηζ / Ε / γίΛΐ In embodiment 38, the invention provides an intermediate compound used in the method of preparing a compound of Formula (I) as described herein. DETAILED DESCRIPTION OF THE INVENTION The present invention includes all pharmaceutically acceptable isotope-labeled compounds of the present invention, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or number. mass that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 38CI, fluorine, such as 18F, iodine, such as 123L y125l, nitrogen, such as 13N and 15N, oxygen, such as 150,17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically labeled compounds of the present invention, for example, those that have a radioactive isotope incorporated, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and the means of detection available. Substitution with heavier isotopes such as deuterium, i.e.2H, may result in certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. . Substitution with positron-emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in positron emission tomography (PET) studies to examine receptor occupancy on the substrate. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using a suitable isotopically labeled reagent in place of the unlabeled reagent employed. previously. Pharmaceutically acceptable solvates according to the invention include those where the crystallization solvent may be isotopically substituted, for example, D2O, de-acetone, de-DMSO. Specific embodiments of the present invention include the compounds illustrated in the following examples and their salts, complexes, solvates, polymorphs, caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi stereoisomers, metabolites, prodrugs, and other pharmaceutically acceptable derivatives thereof. Unless otherwise specified, the following definitions apply to terms found in the specification and claims: alkyl Ca.p means an alkyl group comprising a minimum of a and a maximum of β carbon atoms in a linear or branched relationship or any combination of the three, where a and β represent integers. The alkyl groups described in this section may also contain one or two double or triple bonds. A Co alkyl designation indicates a direct bond. Examples of C1-6 alkyl include, but are not limited to, the following: Benzo group, alone or in combination, refers to the divalent radical C4H4=, a representation of which is -CH=CH-CH=CH-, which when attached vicinally to another ring forms a benzene-type ring, for example, tetrahydronaphthylene, indole and the like. The terms oxo and thioxo represent the groups =O (as in carbonyl) and =S (as in thiocarbonyl), respectively. Halo or halogen means a halogen atom selected from F, Cl, Br and I. Haloalkyl Ca.p means an alkyl group, as described above, wherein any number, at least one, of the hydrogen atoms attached to the alkyl chain is replaced by F, Cl, Br or I. The similar N(Ra)Ray group includes substituents where the two Ra groups together form a ring, which optionally includes an N, O or S atom, and include groups such as: The N(alkyl Ca.p)-alkyl Ca.p group, where a and β are as defined above, include substituents where the two alkyl Ca-p groups together form a ring, optionally including an N,O atom or S, and include groups such as: Bicyclic ring means a group that has two joined rings. A bicyclic ring can be carbocyclic (all ring atoms are carbon), or heterocyclic (ring atoms consist, for example, of 1,2, or 3 heteroatoms, such as N, O, or S, in addition to the carbon). The two rings can be aliphatic (e.g. decalin and norbornane) or they can be aromatic (e.g. naphthalene), or a combination of aliphatic and aromatic (e.g. tetralin). Bicyclic rings include: (a) spirocyclic compounds, where the two rings share a single atom, the spiro atom, which is usually a quaternary carbon. Examples of spirocyclic compounds include, but are not limited to: caz ίηη / ζζηζ / Ε / γίΛΐ (b) fused bicyclic compounds, where two rings share two adjacent atoms. In other words, the rings share a covalent bond, that is, bridgehead atoms (e.g., α-thujene and decalin) are directly connected. Examples of fused bicyclic rings include, but are not limited to: (c) bridged bicyclic compounds, where the two rings share three or more atoms, which separate the two bridgehead atoms by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings that each share three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to: Carbocycle or Carbocyclic means a ring comprising by itself or which, in combination with other terms, represents, unless otherwise indicated, a cyclic version of alkyl Ca.p. Examples of carbocycle include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene and the like. Heterocycle or Heterocyclic means a ring comprising at least one carbon atom and at least one different atom selected from N, O and S. Examples of heterocycles that can be found in the claims include, without limitation, the following: l\L / Ν Η. / Ν. IXL / Ν Lnn / zznz / E / YiAi Pharmaceutically acceptable salt means a salt prepared by conventional means, and is well known to those skilled in the art. Pharmacologically acceptable salts include basic salts of organic and inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, melic acid, acetic acid, oxalic acid, tartaric acid, acid citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When the compounds of the invention include an acid function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium, ammonium cations. quaternary and similar. For additional examples of pharmacologically acceptable salts, see above and Berge et al., J. Pharm. Sci. 66:1 (1977). Saturated, partially saturated or unsaturated includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens. Leaving group generally refers to groups that can be easily displaced by a nucleophile, such as an amine, a thiol, or an alcoholic nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate. Protecting group generally refers to groups well known in the art that are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing unwanted reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benchhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as ammonium salts. and phosphonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkyleneylalkyl radicals, preferably having 6-10 carbon atoms, include, but are not limited to, cyclohexenylmethyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, / so-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl and the like. It is possible to use a mixture of protecting groups to protect the same amino group, so that a primary amino group can be protected with either an aralkyl group or an aralkoxycarbonyl group. The amino protecting groups may also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups may further include aryl rings and adjacent cycloalkyl. Furthermore, the heterocyclic groups may be monosubstituted, disubstituted or trisubstituted, such as nitrophthalimidyl. The amino groups can also be protected against unwanted reactions, such as oxidation, by the formation of an addition salt, such as hydrochloride, with toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protection of carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable for the protection of hydroxy and mercapto groups, such as tere-butyl. Silyl-type protecting groups are silicon atoms optionally substituted with one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of amino groups provides monosilylamino or disilylamino groups. Silylation of aminoalcohol compounds can give rise to an N,N,O-trisilyl derivative. Removal of the silyl function from a silyl ether function is easily carried out by treatment with, for example, a metal hydroxide or ammonium fluoride type reagent, either in a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their products combined with imidazole or DMF. Methods for the silylation of amines and the removal of caz ίηη / ζζηζ / Ε / γίΛΐ silyl type protecting groups are well known to those skilled in the art. Methods of preparing these amine derivatives from the corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry and include amino acid / amino acid ester chemistry or amino acid ester chemistry. of amino alcohols. The protecting groups are removed under conditions that will not affect the remaining part of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves the removal of a protecting group, such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed with an organic or inorganic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can be easily neutralized to generate the free amine. The carboxy protecting group, such as methyl, ethyl, benclyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions that are well known to those skilled in the art. It should be noted that the compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic guanidine and amidine groups, heteroaryl groups substituted with heteroatoms (Y1 = O, S, NR), and the like, which are illustrated in the following examples: caz ίηη / ζζηζ / Ε / γίΛΐ and while a form is named, described, presented and / or claimed herein, all tautomeric forms are intended to be inherently included in said name, description, presentation and / or claim. Also contemplated in the present invention are prodrugs of the compounds of this invention. A prodrug is an active or inactive compound that is chemically modified by in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the present invention upon administration of the prodrug to a patient. The suitability and techniques involved in the preparation and use of prodrugs are known to those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include various esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). . Amines were masked as arylcarbonyloxymethyl-substituted derivatives that are cleaved by esterases in vivo that release free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Likewise, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with A / -acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxy groups have been masked as esters and ethers. EP 039 051 (Sloan and Little, 4 / 11 / 81) discloses hydroxamic acid-Mannich base prodrugs, their preparation and use. The specification and claims contain a list of species that use the expression selected from. .. and ... and it is . .. either . . . (sometimes referred to as Markush groups). When this expression is used in this application, unless otherwise indicated, it is understood to include the group as a whole, or any individual members thereof, or any subgroup thereof. The use of these expressions is merely for brevity, and is in no way intended to limit the removal of individual elements or subgroups as necessary. PHARMACEUTICAL COMPOSITIONS, DOSAGE AND ROUTES OF ADMINISTRATION Also provided herein are pharmaceutical compositions that include a compound as disclosed herein together with a pharmaceutically acceptable excipient such as, for example, a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those wherein the compound can be administered in an amount effective to achieve its desired purpose. Administration of the compound is described in more detail below. One skilled in the art can determine suitable pharmaceutical formulations according to the route of administration and the desired dosage. See, e.g., Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co., Easton, Pa., 1990). Formulations may alter the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered agents. Depending on the route of administration, an appropriate dose may be calculated based on body weight, body surface area, or organ size. Those skilled in the art routinely perform the further refinement of calculations necessary to determine the appropriate treatment dose without unnecessary experimentation and especially take into account the dosage information and assays disclosed herein, as well as the pharmacokinetic data reported herein. can be obtained through clinical trials in animals or humans. The terms pharmaceutically acceptable or pharmacologically acceptable refer to molecular entities and compositions that do not produce adverse, allergic, or other harmful reactions when administered to an animal or a human being. As used herein, pharmaceutically acceptable includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarding agents and the like. The use of such excipients for pharmaceutically active substances is known in the art. Except to the extent that any conventional agent or medium is incompatible with the therapeutic compositions, their use in the therapeutic compositions is contemplated. Complementary active ingredients can also be incorporated into the compositions. In exemplary embodiments, the formulation may comprise corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tribasic calcium phosphate, L-tyrosine, L-proline, L-acetate. lysine, DATEM (an emulsifier), L-glutamine, L-valine, dibasic potassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L -threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, α-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, cupric sulfate, thiamine chloride hydrochloride, calcium palmitate vitamin A, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, β-carotene potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3 and cyanocobalamin. The compound may be present in a pharmaceutical composition in the form of a pharmaceutically acceptable salt. As used herein, pharmaceutically acceptable salts include, for example, base addition salts and acid addition salts. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of the compounds can also be prepared with a pharmaceutically acceptable ίηη / ζζηζ / Ε / γίΛΐ cation. Suitable pharmaceutically acceptable cations are known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium or ferric and the like. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, Nmethylglucamine and procaine. Pharmaceutically acceptable acid addition salts include inorganic or organic acid addition salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are known to those skilled in the art, and these include, for example, formic, acetic, citric, oxalic, tartaric or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with phosphoacid, sulfoacid, sulfonic acid or organic carboxylic acid or N-substituted sulfamic acids, for example, acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid , melic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids such as the 20 α-amino acids involved in protein synthesis in nature, for example, glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane- 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, Ncyclohexylsulfamic acid (with formation of cyclamates) or with other acidic organic compounds, such as ascorbic acid. Pharmaceutical compositions containing the compounds disclosed herein can be produced in a conventional manner, e.g., by conventional mixing, dissolving, granulation, coating, levigation, emulsification, encapsulation, capture or lyophilization processes. The appropriate formulation depends on the chosen route of administration. In the case of oral administration, it is possible to formulate suitable compositions easily by combining a compound disclosed herein with pharmaceutically acceptable excipients, such as carriers known in the art. Said excipients and carriers make possible the formulation of the compounds herein as tablets, pills, dragees, capsules, liquids, gels, syrups, caz ίηη / ζζηζ / Ε / γίΛΐ suspensions and the like for oral ingestion by the patient leaving to treat. Pharmaceutical preparations for oral use can be obtained by adding a compound as disclosed herein with a solid excipient, optionally by grinding the resulting mixture and processing the granule mixture, after the addition of auxiliary agents. suitable, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, cellulose fillers and preparations. If desired, disintegrating agents can be added. Pharmaceutically acceptable ingredients for the various types of formulations are known and may be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweetening and flavoring agents, coating materials, preservatives, colorants, thickeners, adjuvants, antimicrobial agents, antioxidants and carriers for various types of formulations. When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is typically in the form of a solid formulation (e.g., tablet, capsule, pill, powder or troche) or a liquid formulation ( e.g., aqueous suspension, solution, elixir or syrup). When administered in tablet form, the composition may also contain a functional solid and / or a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule and powder may contain from about 1 to about 95% compound and preferably from about 15 to about 90% compound. When administered in liquid or suspension form, a functional liquid and / or a liquid carrier may be added, such as water, petroleum jelly, or oils of animal or plant origin. The liquid form of the composition may also contain physiological saline, solutions of sugar alcohols, dextrose or other solutions of saccharides or glycols. When administered in liquid or suspension form, the composition may contain from about 0.5 to about 90% by weight of a compound disclosed herein and preferably, from about 1 to about 50% of a compound disclosed in This document. In a contemplated embodiment, the liquid carrier is nonaqueous or substantially nonaqueous. For administration in liquid form, the composition may be supplied as a fast-dissolving solid formulation for dissolution or suspension immediately prior to administration. When a therapeutically effective amount of a compound disclosed herein is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking due account of pH, isotonicity, stability and the like, is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection typically contains, in addition to a compound disclosed herein, an isotonic carrier. Such compositions can be prepared for administration as free base solutions or pharmaceutically acceptable salts in water that are suitably mixed with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof and in oils. Under normal storage and use conditions, these preparations may optionally contain a preservative to prevent the growth of microorganisms. Injectable compositions may include sterile aqueous solutions, suspensions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions or dispersions. In all embodiments, the form must be sterile and must be fluid so that administration with a syringe is possible. It must be stable under manufacturing and storage conditions and must resist the contaminating action of microorganisms, such as bacteria and fungi, through the optional inclusion of a preservative. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol and the like), suitable mixtures thereof and vegetable oils. In a contemplated embodiment, the carrier is nonaqueous or substantially nonaqueous. It is possible to maintain adequate fluidity, for example, by the use of a coating, such as lecithin, by maintaining the required particle size of the compound in making the dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by means of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomersal and the like. In many embodiments, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be achieved by the use in the compositions of absorption retarding agents, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the necessary amount in the appropriate solvent with various of the other ingredients listed above, as necessary, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the various sterilized active ingredients in a sterile vehicle containing a basic dispersion medium and the other necessary ingredients from those mentioned above. In making sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and lyophilization techniques which produce a powder of the active ingredient plus any desired additional ingredients of a solution thereof previously sterilized by filtration. Slow release or sustained release formulations can also be prepared to achieve a controlled release of the active compound in contact with body fluids in the Gl tract and to provide a substantially constant and effective level of the compound in the blood plasma. For example, it is possible to control the release by one or more of dissolution, diffusion and ion exchange. Furthermore, the slow-release approach may enhance absorption through saturable or limiting pathways in the Gl tract. For example, the compound may be included for this purpose in a polymer matrix of a degradable biological polymer, a water-soluble polymer or a mixture of both and, optionally, suitable surfactants. In this context, inclusion can mean the incorporation of microparticles into a polymer matrix. Controlled release formulations are also obtained by encapsulation of dispersed microparticles or emulsified microdroplets using known emulsion or dispersion coating technologies. For administration by inhalation, the compounds of the present invention are conveniently administered in a spray form by aerosol in pressurized containers or a nebulizer with the use of a suitable propellant. In the embodiment of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Capsules and cartridges can be formulated from e.g. eg, gelatin, for use in an inhaler or insufflator containing a powder mixture of the compound and a suitable powder base, such as lactose or starch. The compounds disclosed herein may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage forms (e.g., in ampoules or multidose containers) with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the compounds in water-soluble form. Furthermore, suspensions of the compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic vehicles or solvents include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds and allow the preparation of highly concentrated solutions. Alternatively, the present Lnn / zznz / E / YiAi Lnn / zznz / E / YiAi composition may be in powder form to be reconstituted with a suitable vehicle (e.g. sterile pyrogen-free water) before use. The compounds disclosed herein may also be formulated into rectal compositions, such as suppositories or retention enemas (e.g., containing conventional suppository bases). In addition to the formulations described above, the compounds can also be formulated as a delayed release preparation. Such long-acting formulations can be administered by implant (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins or as poorly soluble derivatives, for example, as a poorly soluble salt. In particular, a compound disclosed herein can be administered orally, buccally or sublingually in the form of tablets containing excipients, such as starch or lactose or in capsules or suppositories, either alone or in premixture with excipients, or in form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents. A compound may also be injected parenterally, for example intravenously, intramuscularly, subcutaneously or intracoronally. For parenteral administration, it is best to use the compound in the form of a sterile aqueous solution that may contain other substances, for example, salts or sugar alcohols, such as mannitol or glucose, so that the solution is isotonic in blood. For veterinary use, a compound disclosed herein is administered as a suitable formulation acceptable in accordance with standard veterinary practice. The veterinarian can easily determine the most appropriate dosage regimen and route of administration for a specific animal. In some embodiments, all components necessary for the treatment of a KIF18A-related disorder can be packaged into a kit using a compound as disclosed herein either alone or in combination with another agent or intervention traditionally used for the treatment of such illness. Specifically, the present invention provides a kit for use in the therapeutic intervention of disease, comprising a packaged set of medications including the compound disclosed herein, as well as buffers and other components for preparing administerable forms of said medications, and / or devices for administering such medications, and / or any agent used in combination therapy with the compound disclosed herein, and / or instructions for the treatment of the disease included with the medications. Instructions may be found on any tangible medium, such as printed paper or a computer-readable magnetic or optical medium, or instructions that refer to a remote computer data source, such as a web page accessed over the Internet. . A therapeutically effective amount means an amount effective to treat or prevent the development, or to alleviate existing symptoms of the subject being treated. Determination of effective amounts is within the capabilities of those skilled in the art, especially in view of the detailed disclosure provided herein. In general, a therapeutically effective dose refers to that amount of the compound that produces the desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein decreases the activity of KIF18A by at least 5%, compared to the control, at least 10%, at least 15%, when at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90%. The amount of compound administered may depend on the subject being treated, the age, health status, sex and weight of the subject, the type of concomitant treatment (if any), the severity of the affliction, the nature of the desired effect, the form and frequency of treatment and the judgment of the doctor prescribing the treatment. Dosing frequency may also depend on pharmacodynamic effects on arterial oxygen pressures. While individual needs vary, determining optimal ranges of effective amounts of the compound is within the skill of the art. Such doses may be administered in a single dose or may be divided into multiple doses. The terms cancer and cancerous when used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers include, without limitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer, ovarian cancer, and cancer. of endometrium. Although the term cancer as used herein is not limited to any specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers that are found to be accompanied by uncontrolled levels of KIF18A or dependent on KIF18A for proper chromosome segregation and survival in the mammal. caz ίηη / ζζηζ / Ε / γίΛΐ The terms treat, treating, and treatment, as used herein, refer to therapy, including, but not limited to, curative therapy, prophylactic therapy, and preventive therapy. Prophylactic treatment generally constitutes both completely preventing the onset of disorders and delaying the onset of a preclinically evident stage of disorders in individuals. The term patient, subject or mammal as used herein refers to any patient, subject or mammal, including humans, cows, horses, dogs and cats. In one embodiment of the invention, the mammal is a human. The expression it comprises is intended to be open, and include the indicated component(s) but without excluding other elements. The terms Formula I include any subformula. METHODS OF USE OF KIF18A INHIBITORS The present disclosure provides compounds having MT-based KIF18A modeling activity in general, and inhibitory activity in particular. In one embodiment of the invention, a method is provided for modulating the KIF18A protein in a subject, the method comprising administering to the subject an effective dosage amount of a compound of Formulas I. As such, the compounds of the invention can be used to treat cell proliferation disorders, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and / or numerical, fragmentation). Other diseases or disorders associated with the accumulation of extra centrosomes (>2) include human papillomavirus (HPV) infection, including HPV-associated neoplasms. The compounds are also useful for cilia-related diseases, as well as ablation of the haploid germ cell population which could be used as a male contraceptive. Furthermore, the compounds of the invention are useful for, but not limited to, the prevention or treatment of cancer and other KIF18A-mediated diseases or disorders. For example, the compounds of the invention would be useful for the treatment of various solid and hematologically derived tumors, such as carcinomas, including, but not limited to, cancer of the bladder, breast, colon, kidney, liver, lung (including cancer of the squamous cell lung and small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, tricholeukocyte lymphoma, and Burkitt lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin caz ίηη / ζζηζ / Ε / γίΛΐ (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, for example, of soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, and Kaposi's sarcoma). The compounds of the invention are also useful in the treatment of cancer-related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, pericardial effusions. or tumor-induced pleural and malignant ascites. Based on the ability to modulate kinesin that affects angiogenesis, the compounds of the invention are also useful in the treatment and therapy of proliferative diseases. Specifically, these compounds can be used for the treatment of an inflammatory disease, especially manifestations in the musculoskeletal system, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis, including rheumatoid arthritis, juvenile arthritis or psoriatic arthropathy; paraneoplastic syndrome or inflammatory diseases induced by tumors, cloudy effusions, collagenoses, such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma, or mixed collagenoses; post-infectious arthritis, (when non-living pathogenic organisms can be found on or inside the affected part of the body), seronegative spondylarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis or osteoarthritis; or additionally any combination thereof. The compounds of the invention can also be used as active agents against pathologies such as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, angiogenesis of the ischemic limb, wound healing, Helicobacter-related diseases in peptic ulcer. , fractures, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy or macular degeneration. Furthermore, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid hyperplasia (especially Graves' disease) and cysts (such as ovarian stromal hypervascularity, characteristic of ovarian syndrome). polycystic (Stein-Leventhal syndrome)) because such diseases require a proliferation of blood vessel cells for growth and / or metastasis. In addition to being useful for treatment in humans, these compounds are useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs and cats can be treated with the compounds provided in the invention. COMBINATIONS Although the compounds of the invention can be dosed or administered as a single active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or in conjunction with other agents. When administered as a combination, the therapeutic agents may be formulated as separate compositions that are administered simultaneously or sequentially at different times, or the therapeutic agents may be administered as a single composition. The term simultaneous therapy (or combination therapy), in defining the use of a compound of the present invention and another pharmaceutical agent, is intended to encompass the administration of each agent sequentially in a schedule that will provide beneficial effects of the drug combination, and It is also intended to encompass the combined administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of these active agents or in multiple separate capsules for each agent. Specifically, administration of compounds of the present invention can be performed in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cancer, such as with radiotherapy, targeted agents that are low molecular weight molecules (e.g. e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies (e.g., pure and drug conjugated), antibodies for immunotherapy (checkpoint inhibitors, bispecific T cell couplers) with neoplastic or cytotoxic agents. If formulated as a fixed dose, such combination products employ the compounds of this invention within accepted dosage ranges. The compounds of Formula I can also be administered sequentially with known antineoplastic or cytotoxic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; The compounds of the invention can be administered before, simultaneously or after the administration of the known antineoplastic or cytotoxic agent. There are many antineoplastic agents available in commercial use, in clinical evaluation and in preclinical development, which would be selected for the treatment of neoplasms by combining pharmacological chemotherapy. These agents are included in several main categories, such as antibiotic-type agents, alkylating agents and alkylating analogs, antimyphotic agents, targeted ίηη / ζζηζ / Ε / γίΛΐ agents that are low molecular weight molecules, antimetabolite agents, hormonal agents, immunological agents, antiangiogenic agents, interferon-type agents, and a category of various agents. The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes is used in combination with a compound of the present disclosure or a salt. pharmaceutically acceptable thereof. In one aspect, such therapy includes, but is not limited to, combining one or more compounds of the invention with chemotherapeutic agents, therapeutic antibodies, agents that are low molecular weight targeted molecules, and radiation treatment to provide a synergistic or additive therapeutic effect. . Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents and low molecular weight non-peptide molecules such as Gleevec® (Imatinib Mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib). and Adriamycin, as well as a myriad of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylololamine; nitrogen mustards, such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembiquin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, caliceamicin, carabicin, carminomycin, carcinophylline, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-Lnorleucine, doxorubicin, epirubicin, esorubicin, ida rrubicin , marcelomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorrubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); caz ίηη / ζζηζ / Ε / γίΛΐ folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxyfluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glucoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomitin; elliptinium acetate; ethoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; fenamet; pirarubicin; podophylinic acid; 2-ethylhydrazide; procarbazine; PSK, razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2trichlorotriethylamine; urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobromano; gacitosin; arabinoside (Ara-C'j; cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel and docetaxel; Nab-paclitaxel; retinoic acid;esperamycins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included as suitable chemotherapeutic cell conditioners are antihormonal agents that act to regulate or inhibit hormonal action on tumors such as antiestrogens including, for example, tamoxifen, (NolvadexTM), raloxifene, 4(5)-midazoles inhibitors. aromatase, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin, oxaliplatin and carboplatin; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vinblastine, vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; Ibandronate; topotecan; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). When desired, the compounds or pharmaceutical composition of the present disclosure can be used in combination with commonly indicated antineoplastic drugs, such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Abraxane, Arimidex®, Taxotere®, ABVD , AVICINE, Abagovomab, acridine carboxamide, Adecatumumab, 17- / \ / -allylamino-17-desmethoxygeldanam¡cin, Alfaradine, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic agents, antitumorigenic herbs, apaziquone, Atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, non-cell cycle specific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi exatecan, exisulind, ferruginol, forodesin, phosphestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin , olaparib, talazoparib, niraparib, ortataxel, PAC-1, Pawpaw, pixantrone, proteasome inhibitor, rebecamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonin, talaporfin, tariquidar, tegafur-uracil, temodar , tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar, CDK4 / 6 inhibitors (Palbociclib, Ibrance; Ribociclib, Kisqali; Abemaciclib, Verzenio). This disclosure further relates to a method of using the compounds or pharmaceutical compositions provided herein, combined with radiotherapy to inhibit abnormal cell growth or treat hyperproliferative disorder in the mammal. Techniques for administering radiotherapy are known in the art, and these techniques may be used in the combination therapy described herein. Administration of the compound of the invention in this combination therapy can be determined as described herein. Radiation therapy may be administered through one of several methods or a combination of methods, including, without limitation, external radiation therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, permanent or temporary interstitial radiation therapy and brachytherapy. The term brachytherapy, as used herein, refers to radiation therapy administered using a spatially confined radioactive material introduced into the body at or near a tumor or other site with diseased tissue of a proliferative disease. The term is intended to include, without limitation, exposure to radioactive isotopes (e.g., At-211, 1-131, 1-125, Y-90, Re-186, Re188, Sm-153, Bi-212 , P-32 and radioactive isotopes of Lu). Radiation sources suitable for use as a cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source may be a radionuclide, such as 1-125,1-131, Yb-169, lr-192 as a solid source, 1-125 as a solid source, or other radionuclides that They emit photons, β particles, γ radiation or other therapeutic radiation. The radioactive material may also be a fluid of any solution of radionuclide(s), e.g. e.g., a solution of 1-125 or 1-131, or a radioactive fluid can be produced using a thick suspension of a suitable fluid containing small particles of solid radionuclides such as Au-198, Y-90. Likewise, the radionuclide(s) can be found in the form of a gel or radioactive microspheres. The compounds or pharmaceutical compositions of the invention can be used in combination with an amount of one or more substances selected from antiangiogenic agents, signal transduction inhibitors, antiproliferative agents, glycolysis inhibitors or autophagy inhibitors. Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors and COX-11 (cyclooxygenase 11) inhibitors can be used together with a compound of the disclosure and pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172, WO 96 / 27583, European Patent Publication EP0818442, European Patent Publication EP1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 07697. 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, European Patent Publication 606046, European Patent Publication 931 788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667 , WO1999007675, European Patent Publication EP1786785, European Patent Publication No. EP1181017, US Publication No. US20090012085, US Publication US5863 949, US Publication US5861 510 and Patent Publication European Union EP0780386, all of which are incorporated herein in their entirety by reference. Preferred MMP2 and MMP-9 inhibitors are those with little or no MMP-1 inhibition activity. More preferred are those that selectively inhibit MMP-2 and / or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP8, MMP-10, MMP-11, MMP-12 and MMP-13). AG-3340, RO 32-3555 and RS 13-0830 are some specific examples of MMP inhibitors useful in the disclosure. The present compounds can also be used in simultaneous therapies with other antineoplastic agents such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide , BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleucine, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon a, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitfur, epirubicin, epoetin β, etoposide phosphate, exemestane, exisuli nd, fadrozole, filgrastim , finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal fetoprotein a, caz acid ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi ibadronic, idarubicin, (imiquimod, interferon a, interferon a, natural, interferon a-2, interferon a-2a, interferon a-2b, interferon a-N1, interferon a-n3, interferon alfacon- 1, interferon a, natural, interferon β, interferon β-la, interferon β-1 b, interferon γ, interferon γ-la natural, interferon γ-1 b, interleukin-1 β, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult) wrong pairing , mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterfer on a- 2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit polyclonal antibody directed against thymocytes, polyethylene glycol interferon a-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium etidronate Re 186, retinamide Rll, rituximab, romurtide, samarlo (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tumbarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasine, thyrotropin a, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor a, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin estimalamer zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetane, ilomastat, IM 862 (Cytran), interleukin -2, iproxifen, LDI 200 (Milkhaus), leridistim, lintuzumab, monoclonal antibody against CA 125 (Biomira), monoclonal antibody against cancer (Japan Pharmaceutical Development), monoclonal antibody against HER-2 and Fe (Medarex), monoclonal antibody 105AD7 idiotypic (CRC Technology), Idiotypic CEA monoclonal antibody (Trilex), Iodine 131-labeled LYM-1 monoclonal antibody (Techniclone), Trio 90-conjugated polymorphic epithelial mucin monoclonal antibody (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, protein P 30, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), Tetrathiomolybdate, Taliblastin, Thrombopoietin, Tin Ethythiopurpurin, Tirapazamine, Cancer Vaccine (Biomira), Melanoma Vaccine (New York University), Melanoma Vaccine (Sloan Kettering Institute) , melanoma oncolysate vaccine (New York Medical College), melanoma cell viral vaccine (Royal Newcastle Hospital) or valspodar. The compounds of the invention can also be used with VEGFR inhibitors. It is possible to use in a combination therapy other compounds described in the following patents and patent applications: US 6 258 812, US 2003 / 0105091, WO 01 / 37820, US 6 235 764, WO 01 / 32651, US 6 630 500, US 6 515 004, US 6 713 485, US 5 521 184, US 5 770 599, US 5 747 498, WO 02 / 68406, WO 02 / 66470, WO 02 / 55501, WO 04 / 05279, WO 04 / 07481, WO 04 / 07458, WO 04 / 09784, WO 02 / 59110, WO 99 / 45009, WO 00 / 59509, WO 99 / 61422, US 5 990 141, WO 00 / 12089 and WO 00 / 02871. In some embodiments, the combination comprises a composition of the present invention together with at least one antiangiogenic agent. The agents include, but are not limited to, chemical compositions prepared synthetically in vitro, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An agent may be an agonist, antagonist, allosteric modulator, toxin, or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition) and thereby promote cell death or cell arrest. cell growth. Illustrative antiangiogenic agents include ERBITUX™ (IMC-C225), KDR (Kinase Domain Receptor) inhibition agents (e.g., antibodies and antigen binding regions that specifically bind to the receptor kinase domain), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind VEGF, or soluble VEGF receptors or a ligand binding region thereof) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to it), EGFR inhibition agents (e.g., antibodies or antigen-binding regions that specifically bind to the same) such as Vectibix (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind to it or its receptors, e.g., Tie2 / Tek), and Tie2 antikinase inhibition agents (e.g., Tie2 / Tek). e.g., antibodies or antigen-binding regions that specifically bind to it). The pharmaceutical compositions of the present invention may also include one or more agents (e.g., antibodies, antigen-binding regions or soluble receptors) that specifically bind to growth factors and inhibit their activity, such as growth factor antagonists. hepatocyte growth factor (HGF, also known as spreading factor), and antibodies or antigen-binding regions that specifically bind to its c-met receptor. caz ίηη / ζζηζ / Ε / γίΛΐ Other antiangiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003 / 0162712; US Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind, or antagonists of the soluble TWEAK receptor; see Wiley, US Patent No. 6,727,225), ADAM disintegrin domain for antagonize the binding of integrin to its ligands (Fanslow et al., US publication no. 2002 / 0042368), antibodies or anti-ephrin and / or anti-eph receptor antigen-binding regions that specifically bind ( US Patent Nos. 5,981,245, 5,728,813, 5,969,110, 6,596,852, 6,232,447, 6,057,124 and members of the patent family thereof), and anti-PDGF antagonists. BB (e.g., antibodies or antigen-binding regions that specifically bind), as well as antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands and PDGFR kinase inhibitors (e.g., PDGF-BB ligands). e.g., antibodies or antigen-binding regions that specifically bind to it). Additional antitumor / antiangiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO document 770622); pegaptanib octasodium (Gilead Sciences, USA); Alfastatin (BioActa, GB); M-PGA (Celgene, USA, document US 5712291); ilomastat (Arriva, USA, document US 5892112); emaxanib (Pfizer, USA, document US 5792783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); FTA ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); monoclonal antibody aD148 (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn monoclonal antibody (Crucell, Netherlands) DAC:antiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP79787 (Novartis, Switzerland, document EP 970070); ARGENT technology (Ariad, USA); YIGSR Stealth (Johnson & Johnson, USA); fibrinogen fragment E (BioActa, GB); angiogenesis inhibitor (Trigen, GB); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); angiogenesis inhibitor (Tripep, Sweden); maspina (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Benefina (Lañe Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142, (Fujisawa, Japan, document JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); monoclonal antibody, α5β3 integrin, second generation (Applied Molecular Evolution, USA and Medlmmune, USA); gene therapy, retinopathy (Oxford BioMedica, GB); enzastaurin hydrochloride (USAN) (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, caz ίηη / ζζηζ / Ε / γίΛΐ Italy); angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneren, USA); rBPI 21 and BPI-derived antiangiogenic agent (XOMA, USA); Pl 88 (Progen, Australia); cilengitide (pINN) (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); cetuximab (INN), (Aventis, France); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); ANGIOSTATIN (Boston Childrens Hospital, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474 (AstraZeneca, GB); ZD 6126 (Angiogene Pharmaceuticals, GB); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, GB); AZD 2171, (AstraZeneca, GB); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthorrhizol (Yonsei University, South Korea); gene-based vaccine, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California at San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidines (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, GB); atiprimod (pINN) (GlaxoSmithKIine, GB); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); vaccine, angiogenesis (EntreMed, USA); urokinase-type plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1a inhibitors (Xenova, GB); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKIine, GB); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKIine, GB); KRN 633 (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol (EntreMed, USA); anginex (Maastricht University, Netherlands and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor a inhibitors (National Institute on Aging, USA); SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); monoclonal antibody, KDR (ImClone Systems, USA); monoclonal antibody, α5β1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, GB and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG 13925 (Agouron, caz ίηη / ζζηζ / Ε / γίΛΐ USA.); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, GB); CKD 732 (Chong Kun Dang, South Korea); monoclonal antibody, vascular endothelial growth factor (Xenova, GB); irsogladin (INN) (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (pINN) (Genaera, USA); RPI 4610 (Sirna, USA); cancer therapy (Marinova, Australia); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VEGF receptor modulators (Pharmacopeia, USA); VE-cadherin-2 antagonists (ImClone Systems, USA); Vasostatin, (National Institutes of Health, USA); vaccine, Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneran, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that raise cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, siRNA or antisense can also be used that inhibits the expression of proteins including, but not limited to, ATG5 (involved in autophagy). Additional pharmaceutically active agents or compounds that can be used in the treatment of cancers and that can be used together with one or more compounds of the present invention include: epoetin a; darbepoetin a; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951 and AMG 706 or a pharmaceutically acceptable salt thereof. In certain embodiments, a composition provided herein is administered together with a chemotherapeutic agent. Suitable chemotherapeutic agents may include, natural products such as vinca alkaloids (e.g. vinblastine, vincristine and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g. etoposide and teniposide), antibiotics (e.g. dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., Lasparaginase which systemically metabolizes L-asparagine and causes starvation of cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, antimitotic / antiproliferative alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogues, melphalan and chlorambucil), ethyleneimines and caz ίηη / ζζηζ / Ε / γίΛΐ methylmelamines ( e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g. busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues, and streptozocin), trazenes-dacarbazinine (DTIC), antimitotic / antiproliferative antimetabolites such as folic acid analogues (e.g., methotrexate), pyrimidine analogues (e.g. fluorouracil, floxuridine and cytarabine), purine analogues and related inhibitors (e.g. mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g. anastrozole , exemestane and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, Histone DeACEtylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan ,suberoylanilidehydroxamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520 ), DNA binding agents (e.g. Zalypsis), PI3K δ inhibitor (e.g. e.g., GS-1101 and TGR-1202), PI3K δ and y inhibitor (e.g., CAL-130), multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goselerin, leuprolide, and triptorelin), BAFF-neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitor (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTI (e.g. Zarnestra™), anti-CD138 (eg, BT062), Torcí / 2-specific kinase inhibitor (eg, INK128), kinase inhibitor (eg. e.g., GS-1101), ER / UPR targeting agent (e.g., MKC-3946), cFMS inhibitor (e.g., ARRY382), JAK1 / 2 inhibitor (e.g., CYT387 ), PARP inhibitor (e.g., olaparib, talazoparib, niraparib veliparib (ABT-888)), BCL-2 antagonist. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analogue or variant derived from the above. The compounds of the present invention can also be used in conjunction with radiotherapy, hormonal therapy, surgery and immunotherapy, said therapies being well known to those skilled in the art. In certain embodiments, a pharmaceutical composition provided herein is administered together with a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoxymetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fluchloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortol one, fluorometholone , fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicar gown, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In a particular embodiment, the compounds of the present invention can also be used together with additional pharmaceutically active agents for the treatment of nausea. Examples of agents that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or a pharmaceutically acceptable salt thereof. The compounds or pharmaceutical compositions of the disclosure can also be used together with a quantity of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors and immunotherapies, including anti- PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40, GITR agonists, CAR-T cells and BiTE. EGFR inhibitors include, but are not limited to, antagonists that are low molecular weight molecules, antibody or siRNA inhibitors, or specific antisense nucleotides. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Low-molecular-weight EGFR antagonists include gefitinib, erlotinib (Tarceva), and, more recently, lapatinib (TykerB). See, p. e.g., Yan L, et. al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005; 39(4): 565-8, and Paez J G, et. al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304(5676): 1497-500). Non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European patent application EP 520722 published on 30 December 1992; European patent application EP 566226 published on October 20, 1993; PCT international publication WO 96 / 33980 published October 31, 1996; US Patent No. 5,747,498 issued January 5, 1998; PCT international publication WO 96 / 30347 published on October 3, nineteen ninety six; European patent application EP 787772 published on August 6, 1997; PCT international publication WO 97 / 30034 published August 21, 1997; PCT international publication WO 97 / 30044 published August 21, 1997; PCT international publication WO 97 / 38994 published October 23, 1997; PCT international publication WO 97 / 49688 published December 31, 1997; European patent application EP 837063 published on April 22, 1998; PCT international publication WO 98 / 02434 published January 22, 1998; PCT international publication WO 97 / 38983 published October 23, 1997; international publication PCTWO 95 / 19774 published July 27, 1995; PCT international publication WO 95 / 19970 published July 27, 1995; PCT international publication WO 97 / 13771 published April 17, 1997; PCT international publication WO 98 / 02437 published January 22, 1998; PCT international publication WO 98 / 02438 published January 22, 1998; PCT international publication WO 97 / 32881 published September 12, 1997; German application DE 19629652 published on January 29, 1998; PCT international publication WO 98 / 33798 published August 6, 1998; PCT international publication WO 97 / 32880 published September 12, 1997; PCT international publication WO 97 / 32880 published September 12, 1997; European patent application EP 682027 published on November 15, 1995; PCT international publication WO 97 / 02266 published January 23, 197; PCT international publication WO 97 / 27199 published July 31, 1997; PCT international publication WO 98 / 07726 published February 26, 1998; PCT international publication WO 97 / 34895 published September 25, 1997; PCT international publication WO 96 / 31510', published October 10, 1996; PCT international publication WO 98 / 14449 published April 9, 1998; PCT international publication WO 98 / 14450 published April 9, 1998; PCT international publication WO 98 / 14451 published April 9, 1998; international publication PCTWO 95 / 09847 published April 13, 1995; PCT international publication WO 97 / 19065 published May 29, 1997; PCT international publication WO 98 / 17662 published April 30, 1998; US Patent No. 5,789,427 issued August 4, 1998; US Patent No. 5,650,415 issued July 22, 1997; US Patent No. 5,656,643 issued August 12, 1997; PCT international publication WO 99 / 35146 published July 15, 1999; PCT international publication WO 99 / 35132 published July 15, 1999; PCT International Publication WO 99 / 07701 published February 18, 1999 and PCTWO International Publication 92 / 20642 published November 26, 1992. Additional non-limiting examples of low molecular weight EGFR inhibitors include any of the described EGFR inhibitors. in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625. Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block ίηη / ζζηζ / Ε / γίΛΐ caz activation of EGFR by its natural ligand. Some non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res 1:1311-1318; Huang, S. M„ etal., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., etal., 1999, Cancer Res. 59:1236-1243. Therefore, the EGFR inhibitor may be an E7.6.3 monoclonal antibody (Yang, 1999 mentioned above) or C225 monoclonal antibody (ATCC accession no. HB-8508), or an antibody or antibody fragment that has the specificity union of the same. MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901. PI3K inhibitors include, but are not limited to, wortmannin, 17hydroxywortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4(methylsulfon¡l )p¡peraz¡n-1-yl]met¡l]thieno[3,2-d]pyr¡midín-4-¡l]morphol¡ne (also known as GDC 0941 and described in the publications PCT No. WO 09 / 036 082 and WO 09 / 055 730), 2-methyl2-[4-[3-methyl-2-oxo-8-(quinolin-3-¡l)- 2,3-d¡hydro¡midazo[4,5-c]quinol¡n-1-¡l]phenyl]prop¡on¡trilo (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806), (S)-1-(4-((2-(2-am¡nop¡r¡m¡d¡n-5-¡l)-7 -met¡l-4-morphol¡not¡ene[3,2-d]p¡hm¡din-6¡l)methyl)piperaz¡n-1-¡l)-2-hydroxypropan-1-one (described in PCT Publication No. WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from Axon Medchem), Pl hydrochloride 103 (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2d]pyrimidin-2-yl]phenol hydrochloride available from Axon Medchem), PIK 75 (N'-[(1E)-(6bromoimidazo[1,2-a]pyridín-3-¡l)methylene hydrochloride]-N,2-dimethyl-5-nitrobenzenesulfone- hydrazída available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-ím¡dazo[1,2-c]quinazolin-5yl)-nicotinamide available from Axon Medchem ), GDC-0941 bismesylate (2-(1H¡ndazol-4-¡l)-6-(4-methanesulfonyl-p¡peraz¡n-1-ylmethyl)-4-morphol¡n-4-¡l-t bismesylate (eno[3,2-d]pyramidane available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan- 2-[l]-met-(Z)ylidene]-thiazolidine-2,4-dione available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)9-[1-(phenylamino) ethyl]-4H-pyr¡do-[1,2-a]pyr¡midin-4-one available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-11 5, CAL263, PI- 103, GNE-477, CUDC-907 and AEZS136. AKT inhibitors include, without limitation, Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (part 2), 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. 385 (part 2), 399-408); API-59CJ-Ome (e.g. Jin etal. (2004) Br. J. Cancer91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indol caz ίηη / ζζηζ / Ε / γίΛΐ 3-carbinol and derivatives thereof (e.g., US Patent No. 6,656,963; Sarkary L¡ (2004) J Nutr. 134(suppl. 12), 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (eg, Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9). TOR inhibitors include, but are not limited to, inhibitors including AP23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competing TORC1 / TORC2 inhibitors including PI-103, PP242, PP30, and Torina 1 Other TOR inhibitors include FKBP12 enhancer, rapamycins and derivatives thereof, including: CCI-779 (temsirolimus), RAD001 (Everolimus; WO 9409010) and AP23573; rapamycin analogues, e.g. e.g., as described in WO 98 / 02441 and WO 01 / 14387, p. e.g., AP23573, AP23464 or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also called CC1779), 40-epi(tetrazolite)-rapamycin (also called ABT578), 32-deoxorapamycin, 16- pentynyloxy32(S)-dihydrorrapanicin and other derivatives described in WO 05005434; derivatives described in US Patent No. 5,258,389, WO 94 / 090101, WO 92 / 05179, US Patent No. 5,118,677, US Pat. US Patent No. 5,118,678, US Patent No. 5,100,883, US Patent No. 5,151,413, US Patent No. 5,120,842 , WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and US Pat. #5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); derivatives of 4H-1-benzopyran-4-one (e.g., US provisional application no. 60 / 528 340). Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Examples of anti-PD-1 antibodies and methods for their use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (Publication No. WO 2006 / 121168 A1), each of which is incorporated expressly herein by reference and includes: Yervoy™ (ipilimumab) or Tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3475 (against PD -1), AMP224 (vs. B7DC), BMS-936559 (vs. B7-H1), MPDL3280A (vs. B7-H1), MEDI-570 (vs. ICOS), AMG557 (vs. B7H2), MGA271 (vs. B7H3), IMP321 (vs. against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (against OX40L), Atacicept (against TACI) , CP-870893 (against CD40), Lucatumumab (against CD40), Dacetuzumab (against CD40), Muromonab-CD3 (against CD3), Ipilumumab (against CTLAcaz ίηη / ζζηζ / Ε / γίΛΐ 4). Immunotherapies also include genetically modified T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE). GITR antagonists include, but are not limited to, GITR fusion proteins and antibodies directed against GITR (e.g., bivalent antibodies directed against GITR), such as a GITR fusion protein described in US Patent No. 6 111 090, box.c, European Patent No.: 090505B1, US Patent No. 8 586 023, PCT Publication Nos.: WO 2010 / 003118 and 2011 / 090754, or an anti-GITR antibody described, for example, in US Patent No. 7 025 962, European Patent No.: 1947183B1, US Patent No. 7 812 135, US Patent No. 8,388,967, US Patent No. 8,591,886, European Patent No.: EP 1866339, PCT Publication No.: WO 2011 / 028683, PCT Publication No.: WO 2013 / 039954, PCT Publication No: WO2005 / 007190, PCT Publication No: WO 2007 / 133822, PCT Publication No: WO2005 / 055808, PCT Publication No: WO 99 / 40196, PCT Publication No: No.: WO 2001 / 03720, PCT Publication No.: WO99 / 20758, PCT Publication No.: WO2006 / 083289, PCT Publication No.: WO 2005 / 115451, US Patent No. 7,618 632 and PCT Publication No: WO 2011 / 051726. The compounds described herein may be used in conjunction with the agents disclosed herein or other suitable agents, depending on the condition being treated. Accordingly, in some embodiments, the one or more compounds of the disclosure will be administered simultaneously with other agents as described above. When used in combination therapies, the compounds described herein are administered with the second agent simultaneously or separately. Combined administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the invention and any of the agents described above can be administered simultaneously, where both agents are present in separate formulations. In another alternative, a compound of the present disclosure may be administered followed by any of the agents described above or vice versa. In some embodiments of the separate administration protocol, a compound of the disclosure and any of the agents described above can be administered a few minutes apart, a few hours apart, or a few days apart. Since one aspect of the present invention contemplates the treatment of diseases / conditions with a combination of pharmaceutically active compounds that can be administered separately, the invention further relates to the combination in the form of ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi of separate pharmaceutical compositions kit. The kit comprises two separate pharmaceutical compositions; a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided aluminum container. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises instructions for use of the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral) are administered at different dosage intervals, or when the treating healthcare professional desires titration of the individual components of the combination. EXPERIMENTAL PART Abbreviations: The following abbreviations may be used in this document: AcOH acetic acid ac or ac. aqueous BOC or Boc tert-butyloxycarbonyl COMU hexafluorophosphate 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholinium Dppf, DPPF or dppf 1,1 '-bis(diphenylphosphino)ferrocene ESI or ES (ElectroSpray lonization ) ionization by electrospray Et ethyl Et2O diethyl ether EtOH ethyl alcohol EtOAc EtOAc g grams h hour HPLC IHigh Pressure Liquid Chromatography) high performance liquid chromatography ¡Pr isopropyl / Pr2NEt or DIPEA AZ-ethyl-diisopropylamine (Hünig base) KOAc potassium acetate LAH lithium aluminum hydride LDA lithium diisopropylamide LC MS, LCMS, LC-MS, or LC / MS (Liquid Chromatography Mass Spectroscopy) liquid chromatography with mass spectroscopy LG (Leaving Group) leaving group (e.g., halogen, mesylate, triflate) LiHMDS lithium bis(trimethylsilyl)amide m / z mass divided by charge Lnn / zznz / E / YiAi Memethyl MeCN / CAN acetonitrile MeOH methanol Met Metal species for cross-coupling (e.g., MgX, ZnX, SnR3, SiR3, B(OR)2) mg milligrams min minutes milliliters MS Mass Spectra MsCI methanesulfonyl chloride MTBE tert-butyl methyl ether NMP 1 -methyl-2-pyrrolidine n-BuL¡ n-butyl-lithium NMR Nuclear Magnetic Resonance Pd2(dba)3 tris(dibenzyldenacetone)d¡palladium (0) Pd(dppf)CI2DCM [1,r-bis(diphenylphosphine)phenocene]dichloropalladium (II), complex with DCM Pd(PPh3)4 tetrakis(triphenylphosphine)palladium (0) Ph phenyl PR or PG or Prot group. protective group MFR Round Bottom Flask RP-HPLC (Reverse Phase High Pressure Liquid Chromatography) RT or RT Room Temperature RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxy¡b Phenomenal sat. or satd. saturated SFC (Supercritical Fluid Chromatography) TBAB tetra-n-butylammonium bromide TBAF tetra-n-butylammonium fluoride TBDMS Cl tert-butyldimethylchlorosilane t-BuOH tert-butanol TEA or Et3N trimethylamine TFA trifluoroacetic acid THF tetrahydrofuran T3P 2, 2,4,6-tripropyl-1,3,5,2,4,6trioxatriphosphinane 4,6-trioxide TsCI p-toluenesulfonyl chloride Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated. All microwave-assisted reactions were performed with a Biotage™ Smith Synthesizer™. All compounds showed NMR spectra consistent with their assigned structures. Melting points were determined on a Buchi apparatus and are uncorrected. Mass spectral data were determined using the electrospray ionization technique. All examples were purified to >90% purity determined by high-performance liquid chromatography. Unless otherwise indicated, reactions were performed at room temperature. In the synthesis of the compounds of the present invention, it may be desirable to use certain leaving groups. The term leaving groups (LG) generally refers to groups that can be displaced by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH3), N -hydroxysuccinimide, Nhydroxybenzotriazole and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), and the like. The examples presented below illustrate specific embodiments of the present invention. These examples are intended to be representative and are not intended to limit the scope of the claims in any way. It should be noted that when a percentage (%) is used with respect to a liquid, it is a percentage by volume with respect to the solution. When used with a solid, it is the percentage with respect to the solid composition. Materials obtained from commercial suppliers will normally be used without additional purification. Reactions using moisture- or air-sensitive reagents were typically performed in a nitrogen or argon atmosphere. Purity was measured with a high-performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6 x 150 mm, 5 pm, 5 to 100% CH3CN in H2O with 0.1% TFA for 15 min at 1.5 ml / min; System B: Zorbax SB-C8, 4.6 x 75 mm, 10 to 90% CH3CN in H2O with 0.1% formic acid for 12 min at 1.0 ml / min ) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed with prefilled silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-lsco, Lincoln, NE). 1H NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a 400 MHz Vahan spectrometer (Agilent Technologies, Santa Clara, CA) at room temperature. All observed protons were reported as parts per million (ppm) downfield relative to tetramethysilane (TMS) or other internal reference in the appropriate solvent indicated. The data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, c = quadruplet, a = broad, m = multiplet), coupling constants and number of protons, spectral data Low-resolution mass measurements (MS) were determined on an Agilent 1100 series LC / MS (Agilent Technologies, Santa Clara, CA) with UV detection at 254 nm and 215 nm and a low-resonance electrospray (ESI) mode. caz ίηη / ζζηζ / Ε / γίΛΐ GENERAL SYNTHETIC SCHEME Unless otherwise stated, starting materials and reagents used in the preparation of these compounds can be purchased from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.) or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Reagents for Organic Synthesis by Fieser and Fieser, volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and the person skilled in the art after having read this disclosure will be able to make and will occur to him various modifications of these schemes. Starting materials and intermediates and end products of the reactions can be isolated and purified if desired using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless otherwise specified, the reactions described herein take place at atmospheric pressure in a temperature range of about -78°C to about 150°C, more preferably from about 0°C to about 125°C and most preferably at room (or ambient) temperature, for example, about 20°C. For the purpose of clarity, in this general synthesis section, the Compounds of Formula (I) can be represented schematically as containing Ring Ar1 and Ring Ar2 as follows: caz ίηη / ζζηζ / Ε / γίΛΐ R6 R4; wherein group L is a connector as defined in the summary of the inventions, that is, -NR3-(C=O)- or -NR3-(C=O)-; The Ar1 ring is located to the left of the connector, and the Ar2 ring is located to the right of the connector. Generally, compounds of Formula (I) can be synthesized by three general steps, as follows: Stage 1: preparation of Ar1 ring compound. Stage 2: preparation of Ar2 ring compound. Stage 3: coupling of the ring compound Ar1 with the ring compound Ar2. The following generic schemes are intended to serve as a guide to experienced synthetic chemists, who will readily see that it is possible to modify the solvent, concentration, reagent, protecting group, order of synthesis steps, time, temperature. and the like as necessary, which is within the judgment and discretion of the person skilled in the art. In one embodiment, a compound of Formula (I) having the following formula (la): R6caz ίηη / ζζηζ / Ε / γίΛΐ to); can be synthesized according to Schemes A and B. An example of a compound of formula (la) includes, but is not limited to: RXc^RXd SCHEME A: COMPOUND PREPARATION (la): Step A-1: ​​Preparation of Ar1 Ring Compound: According to Scheme A, in one embodiment, an Ar1se ring compound can be prepared as follows: R6 caz ίηη / ζζηζ / Ε / γίΛΐ Compound A-1, wherein the group W1 is a leaving group, for example, halo, such as fluorine, chlorine, bromine or iodine; which is commercially available or can be prepared according to methods and reagents known to those skilled in the art, can be reacted with an appropriate reagent R2, such as (1) (R)-2-methylmorpholine hydrochloride, (2 ) 4,4-difluoropiperidine, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethane-1-ol or (6) 2-amino3 -methylpropan-1-ol, in the presence of a base, such as diisopropylethylamine, potassium carbonate or sodium hydride, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, dioxane and the like, to form compound A- 2. Examples of compound A-1 include, but are not limited to, 1-fluoro-3-nitrobenzene, 1,3-difluoro-5-nitrobenzene, 1-fluoro-3-methylbenzene or 2-bromo-1-fluoro-4-nitrobenzene. Examples of compound A-2 include (R)-4-(3-fluoro-5-nitrophenyl)-2methylmorpholine, 4-(3-fluoro-5-nitrophenyl)morpholine, (R)-2-methyl-4 -(3-methyl-5-nitrophenyl)morpholine or 4,4-difluoro-1-(3-fluoro-5-nitrophenyl)piperidine. Compound A-2 can then be reacted with a reducing agent, such as hydrogen gas, in the presence of a suitable catalyst, such as Pd / C, in a suitable organic solvent such as MeOH, EtOH, THF and the like, to form compound A-3. Examples of compound A-3 include (R)-3-fluoro-5-(2-methylmorpholino)aniline, (R)-3-methyl-5-(2-methylmorpholino)aniline or 3- (4,4difluoropiper¡din-1-¡l)-5-fluoroaniline. Alternatively, Compound A-1 can be converted in a one-pot synthesis as described in Step 1a above into Compound A-3, without further purification of Compound A-2. R6R r / J^^r31. Reagent R2, metal catalyst and base r? r3 XX XX W1XX NO2 2. Reduction R2qx^NH2 R8R A-1 Even alternatively, Compound A-1 can be converted to compound A-2, as defined in Step 1a above, by metal catalyzed amination, where a suitable palladium or copper catalyst and a base are used. This step may be followed by a reduction with a suitable palladium catalyst and a hydrogen source, such as Pd / C in the presence of hydrogen gas, to form compound A-2. Even, as an alternative, Compound A-2 may be available on the market. An example of Compound A-2 available on the market is 3-amino-A / -(tert-butylbenzenesulfonamide. Step A-2: Preparation of Ar2 Ring Compound: Or W2 A-4 Rxbase Reagent A-5 fighter ίηη / ζζηζ / Ε / γίΛΐ In Step A-2, Compound A-4, where each of W2 and W3 is independently a halogen, for example, fluorine, chlorine, bromine or iodine, can be reacted with a reagent Rx, such as (1) hydrochloride of 6-azaspiro[2.5]octane, (2) 4,4-dimethylpipehdine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6azaspiro[2.5]octane hydrochloride or (5 ) 7-azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, DMSO and the like, to form compound A-5. Examples of compound A-4 that can be reacted in this manner include 4,6-dichloronicotinic acid, 2-fluoro-4-iodobenzoic acid or 4,6-difluoronicotinic acid. Alternatively, Compound A-4, as defined above, can be reacted with an appropriate carboxylic acid protecting group (reactive (PG1), such as PG1OH in the presence of SOCI2, or benzyl bromide in the presence of carbonate sodium, to form a methyl ester or benzyl ester, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like, followed by reaction with an Rx reagent, such as (1) 6-azaspiro[ 2.5]octane in the presence of DIPEA, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride or (5 ) 7-azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF and the like, to form compound A-4A, where W3 is as defined in compound A-4. Below , compound A-4A can be reacted with a deprotecting agent, which may be a base, such as lithium hydroxide, followed by neutralization with HCl, to form compound A-5, wherein W3 is as defined in the compound A-4. Step A-3: coupling of the ring compound Ar1 with the ring compound Ar2 followed by the introduction of R1: caz ίηη / ζζηζ / Ε / γίΛΐ A-6 In Step A-3, the compound A-5, which was obtained from Step A-2, can be reacted with an activating agent such as an acid chloride (COCl)2 or SOCI2, in a suitable organic solvent such as tetrahydrofuran, methylene chloride and the like, to form an acid chloride derivative, which can then be reacted with a compound A-2 to form compound A-6. Alternatively, compound A-2 can be reacted directly with compound A-5, which was obtained in Step A-2, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like, in presence of a coupling reagent, such as Ν,Ν'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl hexafluorophosphate )-N,N,N',N'-tetramethyluronium, thionyl chloride, carbonyldiimidazole and polyphosphonic anhydride. Those skilled in chemical synthesis will readily understand that other known coupling agents may be used. Compound A-6 can then be converted to Compound (la) by transformation reactions such as sulfoamidation, sulfinization or metal-catalyzed sulfonylation, in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like. , in the presence of a metal catalyst and a reagent R1, such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) 3-mercaptoazetidine-1-carboxylate tert-butyl, (4 ) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto- 2-methylpropan-1-ol, (10) 2-aminoethane-1-ol or (11) cyclopropanethiol. Those skilled in the art will readily understand that the coupling reaction, as shown in Step A-3a, can be carried out under various known conditions. SCHEME B: ALTERNATIVE PREPARATION OF THE COMPOUND (la): According to Scheme B, in another embodiment of the invention, the preparation of the Ar1se Ring compound can be carried out as described in Step A-1 of SCHEME A above. Step B-2: Preparation of Ar2 Ring Compound: Scheme B provides an alternative method for the formation of compounds of Formula (I), as disclosed herein. Following Step A-1 as described in Scheme A, the R1 group can alternatively be introduced into the Ar2 Ring in Step B-2 instead of in Step A-3 as in Scheme A. According to Step B-2, compound B-1, where each of W4 and W5 is independently a halogen, for example fluorine, chlorine, bromine, or iodine, can be reacted with a suitable carboxylic acid protecting group (PGi reagent) , such as methyl iodide in the presence of a base such as potassium carbonate to form a methyl ester, or other suitable protecting group, to form another ester such as a benzyl ester, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran , DMF, methylene chloride and the like, to form compound B2, where each of W4 and W5 are as defined in compound B-1. Compound B-2 can then be reacted with an Rx reagent, such as 6azaspiro[2.5]octane, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO and the like, to form the compound B-3, where W5 is as defined in compound B-1. Compound B-3 can then be reacted with a reagent R1 by a transformation reaction such as a sulfoamidation, sulfination, or metal-catalyzed sulfonylation, in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF, methylene chloride and similar, in the presence of a metal catalyst, such as copper iodide, Pd2(dba)3 to form compound B-4, which can subsequently be reacted with a suitable carboxylic acid deprotecting agent to form compound B-5. Suitable carboxylic acid protecting groups and deprotecting agents, e.g., are known to those skilled in the art. e.g., as discussed in Greene's Protective Groups in Organic Synthesis. Step B-3: coupling of the ring compound Ar1 with the ring compound Ar2: caz ίηη / ζζηζ / Ε / γίΛΐ In Step B-3, compound B-5, which was obtained from Step B-2, can be reacted with an activating agent such as an acid chloride (COCl)2 or SOCI2, in a suitable organic solvent such as such as tetrahydrofuran, methylene chloride and the like, to form an acid chloride derivative, which can then be reacted with a compound A-2 to form the compound (la). DIAGRAM In another embodiment, a compound of formula (I) having a general formula (Ib): R6 R4(Ib); as defined herein can be synthesized according to scheme C. An example of a compound of formula (Ib) includes, but is not limited to: Lnn / zznz / E / YiAi Step C-1: Preparation of Ar1 Ring Compound: In Step C-1, the compound C-1, where W4 is a halogen, for example, fluorine or chlorine, can be reacted with a reagent R2 in the presence of a suitable base, in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like, to form compound C-2. Examples of compound C1 include, but are not limited to, 3-fluorobenzoic acid or 3-fluoro-3-methylbenzoic acid. Examples of R2 reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazetidine hydrochloride. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate. Step C-2: Preparation of Ar2 Ring Compound: C-3 C-4 C-5 In Step C-2, the compound C-3, where each of W5 and W6 is independently a halogen, for example, fluorine, chlorine, bromine or iodine, can be reacted with a reagent Rx, such as (1) hydrochloride of 6-azaspiro[2.5]octane, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6azaspiro[2.5]octane hydrochloride or (5 ) 7-azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO and the like, forming compound C-4. Examples of compound C-3 include, but are not limited to, (1) 4-bromo-2-fluoro-1-nitrobenzene, (2) 4-iodo-2-fluoro-1-nitrobenzene or (3) 6-bromo -2-fluoro-3-nitropyridine. The nitro group of compound C-4 can then be converted to an amino group by reacting with a reducing agent, including, but not limited to, palladium on carbon and a hydrogen source, such as hydrogen gas, forming the compound. C-5. caz ίηη / ζζηζ / Ε / γίΛΐ Step C-3: coupling of the ring compound Ar1 with the ring compound Ar2: In Step C-3, compound C-2, which was obtained in Step C-1, can be reacted with compound C-5, which was obtained in Step C-2, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like, in the presence of a coupling agent, such as N, N'-diisopropylcarbodiimide, N-(3d¡methyllaminopropyl)-N'-ethylcarbodiimide, benzotriazole hexafluorophosphate- 1-yloxytripyrrolidinophosphonium, O-(benzotriazol-1-¡l)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyl-diimidazole or polyphosphonic anhydride, forming a C-6 compound. Those skilled in the art will readily understand that other coupling agents may be used. Further manipulation of the halogen group W6 can then be carried out by transformation reactions such as sulfoamidation, sulfination or metal-catalyzed sulfonylation, SNAr, in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF and the like, in the presence of a metal catalyst and a reagent R1, such as (1) oxetane-3-amine, (2) 2-amino-2-methylpropan-1-ol, (3) (3-aminooxetan-3-yl)methanol, (4) Ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-165 sulfonamide, (7) 2-mercaptopropan-1-ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethane-1-ol or (10) cyclopropanethiol, forming compound (Ib). Those skilled in the art will readily understand that the coupling reaction, as shown in Step C-3, can be carried out under various known conditions. One skilled in the art will recognize that the above transformations could also be carried out at earlier stages of the synthesis process based on the feasibility of the transformations. PREPARATION OF SYNTHETIC INTERMEDIATE COMPOUNDS Ar1 Ring Intermediates: Intermediate compound 1: (R)-3-fluoro-5-(2-methylmorpholine)aniline. '[^NH.HCI either. JvF F DIPEA, dioxane Ά, Pd-C,H2 ^96 5 kPaI14 psiD microwave, 100 °C í| | MeOH / THF, 16 h Stage 1 ΆΐN°2Stage 2 T0 Intermediate compound 1 Step 1: A mixture of 1,3-difluoro-5-nitrobenzene (3.0 g, 18.86 mmol, Apollo Scientific), (R)-2-methylmorpholine (2.29 g, 22.63 mmol, Arbor Chemicals) and DIPEA (6.59 ml) was stirred. , 37.7 mmol) in 1,4-dioxane (30 ml) in microwave at 100 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with a gradient of 0-40% EtOAc in petroleum ether to provide (R)-4-(3-fluoro-5-nitrophenyl)2. -methylmorpholine (1.5 g, 6.24 mmol, 33% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-cfe): δ ppm 7.54 (d, J = 2.3 Hz, 1 H), 7.38 (dt, J = 8.4, 2.1 Hz, 1 H), 7.27 (dt, J = 12.3, 2.3 Hz, 1 H), 3.92 (ddd, J = 11.5, 3.7, 1.4 Hz, 1 H), 3.80 (dt, J = 12.2, 2.2 Hz, 1 H), 3.68 (ddt, J = 12.2, 3.1, 1.6 Hz , 1 H), 3.53-3.67 (m, 2 H), 2.79 (td, J = 11.9, 3.6 Hz, 1 H), 2.41 -2.49 (m, 1 H), 1.16 (d, J= 6.2 Hz, 3 H). m / z (ESI): 241.1 (M+H)+. Step 2: to a solution of (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.8 g, 7.49 mmol) in MeOH (10 ml) and THF (10 ml), was added Pd on carbon (0.5 g, 4.70 mmol, Hindustan platinum) and stirred under H2 pressure (27.5 kPa [14 psi]) for 16 h. The reaction mixture was filtered through a bed of CELITE®, washed with MeOH and the filtrate was concentrated, obtaining (R)-3-fluoro-5-(2-methylmorpholino)anilina (1.1 g, 5.23 mmol , 70% yield) in the form of a beige solid. 1H NMR (400 MHz, DMSO-cfe): δ ppm 5.90 (d, J = 12.5 Hz, 2 H), 5.78 (d, J = 11.0 Hz, 1 H), 5.19 (d, J = 7.9 Hz, 2 H ), 3.86 (dd, J= 11.2, 3.4 Hz, 1 H), 3.57 (dtd, J = 14.7, 11.5, 10.0, 4.3 Hz, 2 H), 3.43 (d, J= 11.6 Hz, 1 H), 3.33 (m, 1 H), 2.58 (td, J= 11.7, 3.3 Hz, 1 H), 2.27 (c, J = 10.9, 10.3 Hz, 1 H), 1.13 (dd, J = 9.6, 5.7 Hz, 3 H ). m / z (ESI): 211.2 (M+H)+. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 2: (F?)-4-fluoro-3-(2-methylmorpholine)aníline. Intermediate compound 2 Step 1: A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Scientific), (R)-2-methyl-morpholine (1.94 g, 19.23 mmol, Arbor Chemicals), Pd(OAc)2 (0.36 g, 1.63 mmol), CS2CO3 (8.89 g, 27.3 mmol) in dioxane (15 ml) at 100 °C for 16 h. The reaction mixture was filtered through a pad of CELITE® and washed with EtOAc. The filtrate was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in hexanes, providing (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol, 21% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-cfa): δ ppm 7.89 (ddd, J = 8.9, 3.9, 2.8 Hz, 1 H), 7.79 (dd, J = 7.6, 2.8 Hz, 1 H), 7.46 (dd, J =12.2, 8.9 Hz, 1 H), 3.90 (ddd, J = 11.5, 3.2, 1.5 Hz, 1 H), 3.68 - 3.77 (m, 2 H), 3.27 - 3.40 (m, 2 H), 2.85 (td , J = 11.6,3.2 Hz, 1 H), 2.56 (dd, J= 11.6, 10.0 Hz, 1 H), 1.15 (d, J = 6.3 Hz, 3 H). m / z (ESI): 241.1 (M+H)+. Step 2: to a solution of (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol) in MeOH (10 mi) and THF (10 mi), Pd on carbon (0.35 g, 3.29 mmol, Hindustan Platinum) was added, and the reaction mixture was stirred under H2 pressure (27.5 kPa [14psi]) for 16 h. The reaction mixture was filtered through a bed of CELITE®, washed with MeOH and concentrated, obtaining (R)-4-fluoro-3-(2-methylmorpholino)aniline as a beige solid that was used directly for the next step without purification. 1H NMR (400 MHz, DMSO-cfe): δ ppm 6.75 (dd, J = 12.9, 8.5 Hz, 1 H), 6.22 (dd, J = 7.7, 2.6 Hz, 1 H), 6.10 (dt, J = 8.6 , 3.1 Hz, 1 H), 4.84 (s, 2 H), 3.79 - 3.87 (m, 1 H), 3.58-3.72 (m, 2 H), 3.07-3.20 (m, 2 H), 2.61 (td, J = 11.5, 3.2 Hz, 1 H), 2.32 (t, J = 10.7 Hz, 1 H), 1.10 (d, J = 6.3 Hz, 3 H). m / z (ESI): 211.2 (M+H)+. Table 1: Intermediates 2-1 and 2-2 were prepared analogously to the preparation of intermediate 2: Comp. int. No. Chemical structure LRMS name: (ESI, positive ion) m / z caz ίηη / ζζηζ / Ε / γίΛΐ Step 1: A mixture of 1-bromo-3-methyl-5-nitrobenzene (5 g, 23.14 mmol), 4,4-difluoropiperidine (4.21 g, 34.7 mmol), sodium tert-butoxide (6.67 g, 69.4 mmol) was stirred. , Pd2(dba)s (2.12 g, 2.31 mmol) and xanthphos (1.34 g, 2.31 mmol) in toluene (50 ml) at 100 °C for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel using 10% EtOAc in petroleum ether, yielding 4,4-difluoro-1 -(3-methyl-5-nitrophenyl)piperidine (3.70 g, 14.44 mmol, 62% yield) as a gray solid. 1H NMR (400 MHz, DMSO-cfe): δ ppm 7.55 (t, J = 2.3 Hz, 1 H), 7.45 (s, 1 H), 7.32 (d, J = 2.3 Hz, 1 H), 3.46 (t , J = 5.8 Hz, 4 H), 2.38 (s, 3 H), 1.96-2. 04 (m, 4 H). m / z (ESI): 257.1 (M+H)+. Step 2: A mixture of 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine (3.7 g, 14.44 mmol), iron powder (8.06 g, 144 mmol) and ammonium chloride was stirred. (7.72 g, 144 mmol) in EtOH (30 ml) and water (7 ml) was stirred at 75 °C for 16 h. The reaction mixture was filtered through a pad of CELITE®, washed with methanol, and the filtrate was concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography eluting with 30-40% EtOAc in petroleum ether, yielding 3-(4.4 -difluoropiperidin1 -yl)-5-methylaniline (2.6 g, 11.49 mmol, 80% yield) as a brown solid. 1H NMR (400 MHz, DMSO-c / 6): δ ppm 6.00 (s, 2 H), 5.89 (s, 1 H), 4.81 (s, 2 H), 3.16 - 3.22 (m, 4 H), 2.09 (s, 3 H), 1.94 - 2.04 (m, 4 H). m / z (ESI): 227.1 (M+H)+. Table 2: Intermediate Compound 3-1 was prepared analogously to the preparation of Intermediate compound 3: caz ίηη / ζζηζ / Ε / γίΛΐ Comp. int. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 3-1 ri F 3-(4,4difluoropiperidin-1yl)aniline 213.1 Intermediate compound 4: 3-(4l4-difluoropiper¡din-1-¡l)-2-fluoroan¡line. Intermediate compound 4 To a solution of 4,4-difluoropiperidine hydrochloride (0.91 g, 5.79 mmol) and lithium bis(trimethylsilyl)amide (1.0 M in THF, 11.84 ml, 11.84 mmol) in THF (50 ml), a solution of 3-bromo-2-fluoroaniline (0.5 g, 2.63 mmol) in THF (20 ml) and Ruphos Pd G-3 (0.13 g, 0.16 mmol, Strem chemicals). The reaction mixture was stirred at 60 °C for 6 h before diluting with water and extracting with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 5-10% EtOAc in petroleum ether, providing 3-(4,4-difluoropiperidin-1-yl)-2-fluoroaniline (0.45 g, 1.96 mmol , 74% yield) in the form of a black oil. 1H NMR (400 MHz, DMSO-cfe): δ ppm 6.75 (td, J = 8.0, 1.4 Hz, 1 H), 6.43 (td, J = 8.1, 1.5 Hz, 1 H), 6.25 (td, J= 7.9 , 1.6 Hz, 1 H), 5.01 (s, 2 H), 3.033.10 (m, 4 H), 2.02 - 2.17 (m, 4 H). m / z (ESI): 231.1 (M+H)+. Intermediate compound 5: 2-((3-amino-2-fluorophenyl)amino)-2-methylpropan-1-ol. Nal, Cul Cul, NaOH Γ jl | |l Dioxane, 120 °C JL JI ¡PrOH, 90 °C Βγ'Ύ'νη,---------* i^Y^nh2H I F Stage 1 F Stage 2 _ . . . .. _r r KIntermediate compound 5 Step 1: A pressure relief vial was charged with copper(I) iodide (0.025 g, 0.132 mmol) and sodium iodide (0.789 g, 5.26 mmol). The vial was emptied / refilled with nitrogen 3 times. Dioxane (5 ml) was added followed by 3-bromo-2-fluoroaniline (0.50 ml, 2.63 mmol, Oakwood Inc., Estill, SC, USA) and trans-N, / \f-dimethylcyclohexane-1,2-diamine (0.041 ml, 0.263 mmol). The lid was replaced and the reaction was stirred in an oil bath previously heated to 120 °C for 24 h. The reaction was partitioned between NH4CI satd. NH4OH satd. at 9:1 and EtOAc. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to provide 2-fluoro-3-iodoaniline (0.63 g, 2.66 mmol, 100% yield) as a dark brown oil. which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08 (ddd, J = 7.52, 5.55, 1.87 Hz, 1 H) 6.63 - 6.76 (m, 2 H) 3.78 (s a, 2 H). m / z (ESI, positive ion): 238.1 (M+H)+. Step 2: A pressure relief vial was charged with copper(I) iodide (0.024 g, 0.127 mmol) and sodium hydroxide (0.101 g, 2.53 mmol). The vial was sealed and emptied / refilled with nitrogen 3 times. Isopropanol (6 ml) was added followed by 2-fluoro-3-iodoaniline (0.30 g, 1.27 mmol) and 2-amino-2-methyl-1-propanol (0.13 ml, 1.52 mmol, Combi-Blocks Inc.). The lid was replaced and the reaction was stirred in an oil bath previously heated to 90 °C for 16 h. The reaction was partitioned between NH4CI:NH4OH satd. (9:1) and EtOAc. The organic phase was separated, washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (eluent: 50100% EtOAc:heptane), providing 2-((3-amino-2-fluorophenyl)amino)-2-methylpropan-1-ol (0.123 g, 0.620 mmol, 49% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (td, J = 8.03, 1.14 Hz, 1 H) 6.20 (td, J = 7.88, 1.24 Hz, 1 H) 6.10 (td, J = 8.09, 1.24 Hz , 1 H) 5.03 (t, J= 5.49 Hz, 1 H)4.80 (s, 2 H)4.31 (d a, J = 3.94 Hz, 1 H) 3.33 (s, 1 H) 1.19 (s, 6 H). m / z (ESI, positive ion): 199.2 (M+H)+. Intermediate compound 6: ((tert-butyldimethyls¡l¡l)¡m¡no)-sulfanone (3-aminophenyl)(fercbutyl). caz ίηη / ζζηζ / Ε / γίΛΐ CHCI3 Stage 3 AcCI, Et3N (NH4)2CO3, Phl(OAc)2 Methanol, RT, 1 h Step 4 caz ίηη / ζζηζ / Ε / γίΛΐ TBS-Cl, Imidazole DMAP.DCM, 2 hours Stage 5 NaOH aq. Methanol, 70 °C, 16 h Stage Intermediate compound 6 Step 1: to a solution of 3-bromoaniline (5 g, 29.1 mmol) in dioxane (30 ml), 2-methylpropane-2-thiol (2.88 g, 32.0 mmol), K2CO3 (4.02 g, 29.1 mmol), Pd2(dba)3 (26.6 g, 29.1 mmol) followed by Xantphos (16.82 g, 29.1 mmol), and the reaction mixture was heated at 100 °C for 14 h. The reaction mixture was filtered through a short pad of CELITE® and washed with EtOAc. The filtrate was taken and washed with brine, dried over Na2SÜ4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 10% EtOAc in petroleum ether, giving 3-(ert-butylthio)aniline (3.5 g, 19.31 mmol, 66% yield). 1H NMR (400 MHz, Chloroform-d): δ ppm 7.17 (t, J = 7.8 Hz, 1 H), 6.97 - 7.06 (m, 2 H), 6.81 (ddd, J = 7.9, 2.4, 1.0 Hz, 1 H), 4.34 (s, 2 H), 1.32 (d, J = 3.1 Hz, 9 H). Step 2: To a solution of 3-(tert-butylthio)anline (3.5 g, 19.31 mmol) in DCM (100 ml), 3-chlorobenzoperoxoic acid (3.33 g, 19.31 mmol) was added to 0 °C and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with 100 ml of NaHCO3satd solution. and extracted with DCM (2 times). The combined organic extracts were dried over Na2SO4 and concentrated, obtaining the crude product which was purified by silica gel column chromatography using 60% EtOAc in petroleum ether, giving 3-(ert-butylsulfinyl)aniline (2.8 g, 14.19 mmol, 73% yield). m / z (ESI): 198.2 (M+H)+. Step 3: To a solution of 3-(tert-butylsulfinyl)aniline (2.8 g, 14.19 mmol) in chloroform (20 ml), Et3N (2.87 g, 28.4 mmol) was added followed by acetyl chloride (1.67 g, 21.29 mmol) at 0 °C, and stirred for 3 h at rt. The reaction mixture was quenched with ice water and extracted with chloroform (2 times). The combined organic extracts were dried over Na2SO4 and concentrated, obtaining the crude material. Purification by silica gel column chromatography using 50% EtOAc in petroleum ether gave A / -(3-(3-butylsulfinyl)phenyl)acetamide (3.0 g, 12.53 mmol, 88% yield). ). 1H NMR (300 MHz, DMSO-de): δ ppm 10.18 (s, 1 H), 7.84 (t, J = 1.9 Hz, 1 H), 7.63 - 7.73 (m, 1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7.19 (dt, J= 7.8, 1.2 Hz, 1 H), 2.04 (s, 3 H), 1.05 (s, 9 H). m / z (ESI): 240.1 (M+H)+. Step 4: To a solution of A / -(3-(tert-butylsulfinyl)phenyl)acetamide (3.0 g, 12.53 mmol) in methanol (60 ml), phenyl-Á3-iodanodiyl diacetate (10.1 g, 31.3 mmol) followed by ammonium carbonate (4.19 g, 62.7 mmol) in portions, and the reaction mixture was stirred for 1 h at rt. The reaction mixture was quenched with water and extracted with EtOAc (2 times). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography using 90% EtOAc in petroleum ether, giving / V-(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)acetamide (2.4 g, 75% yield). %) in the form of a whitish solid. 1H NMR (300 MHz, DMSO-de): δ ppm 10.26 (s, 1 H), 8.09 (d,J = 2.1 Hz, 1 H), 7.89 (dt, J= 7.1,2.2 Hz, 1 H), 7.48 -7.53 (m, 2 H), 4.03 (s, 1 H), 2.06 (s, 3 H), 1.21 (s, 9 H). m / z (ESI): 255.1 (M+H)+. Step 5: To a solution of A / -(3-(2-methylpropan-2-ylsulfonamidoyl)phenyl)acetamide (2.4 g, 9.44 mmol) in DCM (48 ml), imidazole was added. (1.28g, 18.87 mmol), DMAP (0.57 g, 4.72 mmol) followed by TBS-CI (1.7 g, 11.32 mmol) at 0 °C, and the reaction mixture was stirred for 2 h at rt. The reaction mass was quenched with water followed by a 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc (2 times) and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography eluting with a gradient of 50-60% EtOAc in petroleum ether, providing N-(3-(N-(tert-butyldimethyls¡l¡l)-2 -met¡lpropan-2-ylsulfon¡m¡do¡l)phenyl)acetam¡de (3.2 g, 92% yield) as a light yellow liquid. 1H NMR (300 MHz, DMSO-de): δ ppm 10.24 (s, 1 H), 8.13 (t, J= 1.9 Hz, 1 H), 7.82 (d, J = 2.0 Hz, 1 H), 7.34-7.58 (m, 2 H), 2.06 (s, 3 H), 1.18 (s, 9 H), 0.87 (s, 9 H), -0.06 (s, 3 H), -0.07 (s, 3 H). m / z (ESI): 369.2 (M+H)+. Step 6: to a solution of A / -(3-(A / -(tert-butyldimethylsilyl)-2-methylpropan-2ylsulfonimidoyl)phenyl)acetamide (3.2 g, 8.68 mmol) in methanol ( 32 ml), a 2.5 M sodium hydroxide solution (64 ml) was added, and the reaction mixture was stirred for 16 h at 70 °C. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography using 20% ​​EtOAc in petroleum ether, yielding ((tert-butyldimethylsilyl)imino)-A6-sulfanone (tert-butyl)(3-aminophenyl) (2.1 g, 6.43 mmol, 74% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-c / 6): δ ppm 7.18 (t, J = 7.9 Hz, 1 H), 6.99 (t, J = 2.1 Hz, 1 H), 6.87 (ddd, J = 7.7, 1.8 , 1.0 Hz, 1 H), 6.75 (ddd, J = 8.0, 2.4, 1.0 Hz, 1 H), 5.51 (s, 2 H), 1.17 (d, J = 2.3 Hz, 9 H), 0.87 (d, J = 2.5 Hz, 9 H), -0.06 (s, 3 H), -0.07 (s, 3 H). m / z (ESI): 327.2 (M+H). Table 3: Intermediate Compound 6-1 was prepared analogously to the preparation of Intermediate Compound 6: caz ίηη / ζζηζ / Ε / γίΛΐ Comp. int. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 6-1 TBSN, 's; nh2 7 '0 ((tert-butyldimethylsilyl)imino)(methyl)-X6-sulfanone (3-aminophenyl) 285.2 Intermediate compound 7: 3-(A / -(tert-butyldimethylsilyl)azetidin-1-sulfonimidoyl)aniline. NH32M in MeOH THF, ta, 24 h Stage 1 TBSCI, DIPEA CH2CI2, ta, 16 h Stage 2 perchloroethane PPh3, DIPEA Stage 3 Fe / NH4CI EtOH / H2O 60 °C, 4 h Stage 4 Intermediate compound 7 Lnn / zznz / E / YiAi Step 1: A solution of 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol, Combi-blocks) in THF (10 ml) was treated with ammonia (20 ml, 40.0 mmol, 2 M in methanol) and stirred at room temperature. for 24 hours. The solvent was evaporated under reduced pressure and the residue was diluted with water, providing a solid material that was filtered and dried, producing 3-nitrobenzenesulfonamide (1.3 g, 6.43 mmol, 71% yield) as an off-white solid. Ή NMR (400 MHz, DMSO-d6): δ ppm 8.59 (t, J = 2.0 Hz, 1 H), 8.45 (dd, J = 8.3, 2.3 Hz, 1 H), 8.24 (dd, J = 7.9, 1.6 Hz, 1 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.71 (s, 2 H). m / z (ESI): 201.0 (M-H). Step 2: To a solution of 3-nitrobenzenesulfonamide (1.3 g, 6.43 mmol) in CH2CI2 (26 ml), EtaN (2.69 ml, 19.29 mmol) was added followed by TBS-CI (1.45 g, 9.64 mmol) at 0 °C . The reaction mixture was stirred at rt for 16 h before being quenched with cold water and extracted with CH2Cl2. The CH2CI2 layer was washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to give the crude product which was purified by silica gel column chromatography using a gradient of 0-10% EtOAc in ether. petroleum, providing A / -(tert-butyldimethylsilyl)-3-nitrobenzenesulfonamide (1.0 g, 3.16 mmol, 49% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-c / β): δ ppm 8.57 (t, J = 2.0 Hz, 1 H), 8.44 (ddd, J = 8.2, 2.4, 1.1 Hz, 1 H), 8.22 (dt, J = 7.9, 1.4 Hz, 1 H), 7.96 (s, 1 H), 7.89 (td, J = 8.0, 1.6 Hz, 1 H), 0.87 (d, J = 1.7 Hz, 9 H), 0.11 (s, 3H), 0.12 (s, 3H). m / z (ESI): 315.1 (M-H)-. Step 3: To a solution of PhsP (0.91 g, 3.48 mmol) in chloroform (10 ml), perchloroethane (0.82 g, 3.48 mmol, Aldrich) was added, and the reaction mixture was heated to 70 °C for Lnn / zznz / E / YiAi h. The solution was cooled to 0 °C and treated with Et3N (0.66 ml, 4.74 mmol) followed by N-(tert-butyldimethylsilyl)-3-nitrobenzenesulfonamide (1.0 g, 3.16 mmol) in chloroform (5 ml) and stirred for 30 minutes. Finally, azetidine (0.361 g, 6.32 mmol, Chempure) in chloroform (1.5 ml) was added dropwise at 0 °C and the reaction mixture was stirred for 16 h at rt. The reaction mixture was quenched with cold water, extracted with CH2CI2, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0-20% EtOAc in petroleum ether, providing 1-(A / -(ferc-butyldimethylsilyl)-3nitrophenylsulfonímídol) Azetidine (0.85 g, 2.39 mmol, 76% yield) in the form of a clear syrup. 1H NMR (400 MHz, DMSO-de): δ ppm 8.51 (ddd, J = 8.2, 2.4, 1.0 Hz, 1 H), 8.46 (t, J = 2.0 Hz, 1 H), 8.19 (dt, J = 7.8 , 1.4 Hz, 1 H), 7.95 (t, J = 8.0 Hz, 1 H), 3.57 (de, J = 20.9, 7.7 Hz, 4 H), 1.89 (pent, J = 7.6 Hz, 2 H), 0.90 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H). Step 4: to a mixture of 1-(A / -(te / 'c-butíldimethylsilyl)-3-nitrophenylsulfonímídol)azetídine (0.85 g, 2.39 mmol) in ethanol (7 mi) and water (3 mi), iron powder (1.33g, 23.91 mmol) and ammonium chloride (1.28 g, 23.91 mmol) were added. The reaction mixture was heated at 60 °C for 4 h before being filtered through a pad of CELITE® and washed with EtOAc. The filtrate was washed with water, 10% NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0-35% EtOAc in petroleum ether, yielding 3-(A / -(tert-butyld¡methylsilyl)azet¡din-1-sulfonimidoyl) aniline (0.54 g, 1.66 mmol, 69% yield) in the form of a transparent syrup m / z (ESI): 326.2 (M+H)+. PREPARATION OF AR2 RING INTERMEDIATE COMPOUNDS: Intermediate compound 8: 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid. Intermediate compound 8 To a solution of 2-fluoro-4-iodobenzoic acid (300 g, 1.13 mol, Combi-Blocks) in DMSO (2.10 I), 6-azaspiro[2.5]octane hydrochloride (216 g, 1.47 mol, Wuxi AppTec) was added. ) at 20 °C. Then, K2CO3 (468 g, 3.38 mol) was added and the reaction mixture was stirred at 140 °C for 48 h under N2. The reaction solution was poured slowly into ice water (4.20 I) and then extracted with hexanes (2 I x 3). The aqueous phase was separated and adjusted to ρΗ = 6 with HCl (2 M). The solid was precipitated and collected. The solid was washed with water (700 ml x 3) and filtered. The wet solid was spread on a large watch glass and air-dried at 25 °C for 72 h. 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (280 g, 777 mmol, 69% yield) was obtained as a light yellow solid. 400 MHz DMSO-δ ppm 8.07 (s, 1H), 7.76-7.66 (m, 2H), 3.10 (t, J = 5.2 Hz, 4H), 1.55 (s a,4H), 0.41 (s, 4H). Table 4: Intermediate Compounds 8-1 to 8-4 were prepared analogously to the ίηη / ζζηζ / Ε / γίΛΐ preparation of Intermediate Compound 8: Comp. int. No. Chemical structure LRMS name: (ESI, positive ion) m / z 8-1 HO^ 1 L 4-bromo-2-(6azaspiro[2.5]octan-6yl)benzoic acid 310.2 / 312.2 8-2 O MeO^ ^ δ or k 4-bromo-2-(6azaspiro[2.5]octan-6yl)methyl benzoate 324.0 / 326.0 8-3 O MeO^ c 4-iodo-2-(6azaspiro[2.5]octan-6yl)methyl benzoate 372.1 8 -4 O BnO^\ X XX J -yl)benzoic. BnBr, Na2CO3, DMF. 0 °C-rt, 12 h Stage 1 DIPEA, DMSO 100 °C, 24 h Stage 2 Lnn / zznz / E / YiAi Intermediate compound 9 Step 1: To a solution of 2-fluoro-4-(methylsulfonyl)benzoic acid (90.0 g, 412.1 mmol) in A / ,A / -dimethylformamide (1.0 1), benzyl bromide (78.1 g, 454.0 mmol) was added. and sodium carbonate (52.5 g, 495 mmol) at 0 °C. The reaction mixture was stirred for 12 h at RT. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 x 1 L). The combined organic extracts were washed with brine (1 I), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 0-30% EtOAc in hexanes, giving benzyl 2-fluoro-4(methylsulfonyl)benzoate (100 g, 79% yield) as a white solid. 1H NMR (300 MHz, DMSO-c / 6) or ppm 8.16 (dd, J = 8.2, 6.9 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.48 - 7.31 (m, 5H), 5.40 (s, 2H), 3.33 (s, 3H). Step 2: To a solution of benzyl 2-fluoro-4-(methylsulfonyl)benzoate (55 g, 178 mmol) in DMSO (550 ml), DIPEA (57.6 g, 446 mmol) was added followed by 6-azaspiro[2.5 ]octane (29.8 g, 268 mmol) and the reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 x 1 L). The combined organic layer was washed with brine solution (1 L), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) using 0-10% EtOAc in hexanes, giving 4-(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl) Benzyl benzoate (55 g, 77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 4H), 7.43 - 7.35 (m, 3H), 5.35 (s, 2H), 3.25 (s, 3H), 3.05 (t, J = 5.3 Hz, 4H), 1.36 (t, J = 5.3 Hz, 4H), 0.30 (s, 4H). m / z (ESI): 400.1 (M+H)+. Step 3: to a solution of benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (65 g, 163 mmol) in tetrahydrofuran (108 ml) and methanol (36 ml) , a 1 N aqueous sodium hydroxide solution (407 ml, 407 mmol) was added and the reaction mixture was stirred for 12 h at 60 °C. The reaction mixture was concentrated under reduced pressure, removing THE and methanol. The remaining aqueous solution was acidified to pH ~2 with a 1.5 N HCl solution. The solid precipitate was filtered, washed with water (200 ml) followed by hexanes (200 ml), dried under vacuum for 12 h, giving the 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (42 g, 83% yield) as an off-white solid. 1H NMR (400 MHz, DMSOde) δ ppm 16.13 (s, 1H), 8.04 (d, J =8.0 Hz, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 3.29 ( s, 3H), 3.17 (s a, 4H), 1.55 (s a, 4H), 0.41 (s, 4H). m / z (ESI): 308.1 (M-H)+. Intermediate compound 10: 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6azaspirof2.51octan-6-yl)benzoic acid. Intermediate compound 10 Step 1: To a 250 ml sealed tube, benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6yl)benzoate (9 g, 22.48 mmol, Intermediate 8-4), 1-met was added. lcyclopropane-1sulfonamide (3.95 g, 29.2 mmol, Combi-Blocks) and K2CO3 (6.21 g, 45.0 mmol) in dioxane (90 ml), and the reaction mixture was degassed and purged with nitrogen for 5 min. To this reaction mixture, Xantphos (1.30 g, 2.25 mmol) was added, followed by Pd2(dba)s (1.03 g, 1.12 mmol), and the tube was sealed and stirred at 110 °C for 18 h. The reaction mixture was quenched with water (250 ml) and extracted with EtOAc (2 x 150 ml). The combined organic extracts were washed with water (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0-15% EtOAc in hexanes, giving 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaespi). Benzyl ro[2.5]octane-6-l)benzoate (6.1 g, 59% yield) as an orange oil. 1H NMR (400 MHz, DMSO-de) δ ppm 10.06 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.48 - 7.31 (m, 5H), 6.98 (s, 1H), 6.81 (d , J = 8.5 Hz, 1H), 5.27 (s, 2H), 2.92 (t, J = 4.96 Hz, 4H), 1.40 - 1.30 (m, 7H), 1.16 (dd, J = 6.4, 4.7 Hz, 2H) , 0.81 (dd, J = 6.4, 4.7 Hz, 2H), 0.28 (s, 4H). m / z (ESI): 455.2 (M+H)+. Step 2: to a solution of benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzoate (2.1 g, 4.62 mmol) in MeOH (20 mi) and EtOAc (10 mi), 10% Pd-C (1.05 g, 50% w / w) was added in a nitrogen atmosphere. The reaction mixture was degassed and stirred under hydrogen pressure (101.3 kPa [1 atm], balloon pressure) for 4 h. The reaction mixture was filtered through a pad of CELITE® and washed with MeOH (20 ml). The filtrate was concentrated under reduced pressure. The residue was triturated with EÍ2Ü (50 ml), giving 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-íl)benzoic acid (1.2 g, yield of 71%) in the form of an off-white solid. 1H NMR (400 MHz, DMSOd6)oppm 13.20 (s, 1H), 10.33 (s, 1H), 7.95 (d, J =8.6 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J =8.6 Hz , 1H), 2.99 (s, 4H), 1.56 (s, 4H), 1.39 (s, 3H), 1.18 (t, J = 4.8 Hz, 2H), 0.83 (t, J = 4.7 Hz, 2H), 0.42 (s, 4H). m / z (ESI): 363.2 (M-H). Intermediate compound 11: 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.51octan-6¡Dbenzoic acid. caz ίηη / ζζηζ / Ε / γίΛΐ either Intermediate compound 11 Step 1: To a solution of methyl 2-fluoro-4-methylbenzoate (10.0 g, 59.5 mmol) in carbon tetrachloride (200 ml), NBS (11.6 g, 65.4 mmol) and AIBN (0.98 g, 5.95 mmol) were added. ) to TA. The reaction mixture was stirred at 70 °C for 3 h before being quenched with water (250 ml) and extracted with DCM (2 x 200 ml). The combined organic extracts were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give methyl 2-fluoro-4-methylbenzoate (14.0 g, crude) as a yellow oil. pale. 1H NMR (400 MHz, Chloroform-d): 58.04 - 7.88 (m, 1H), 7.27 - 7.13 (m, 2H), 4.46 (s, 2H), 3.96 (s, 3H). Step 2: A mixture of methyl 2-fluoro-4-methylbenzoate (14.0 g, 56.7 mmol) and sodium methanesulfinate (12.15 g, 119 mmol) in DMF (42 ml) was irradiated in a microwave oven (Biotage+ initiator) at 120 °C for 30 min. The reaction mixture was quenched with water (150 ml) and extracted with EtOAc (2 x 200 ml). The combined organic extracts were washed with a satd brine solution. (150 ml), dried with Na2SO4, filtered and concentrated under reduced pressure, giving methyl 2-fluoro-4-((methylsulfonyl)methyl)benzoate (6 g, crude) as an off-white solid. Step 3: A mixture of methyl 2-fluoro-4((methylsulfonyl)methyl)benzoate (6.0 g, 24 mmol) and 6-azaspiro[2.5]octane (2.71 g, 24.4 mmol) in DMSO was irradiated in a microwave oven. (30 mi) at 150 °C for 1 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried with Na2SO4, filtered and concentrated under reduced pressure to give 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6- Methyl yl)benzoate (4.0 g, crude) as an off-white solid. The material as such was taken to the next stage without further purification. 1H NMR (400 MHz, Chloroform-c / ) δ 7.72 (d, J= 7.8 Hz, 1H), 7.11 (s, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 4.24 (s, 2H ), 3.93 (s, 3H), 3.12 (t, J = 5.4 Hz, 4H), 2.78 (s, 3H), 1.55 (t, J = 5.5 Hz, 4H), 0.37 (s, 4H). m / z (ESI): 338.1 (M-H)+. Step 4: To a solution of methyl 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.0 g, 3.0 mmol) in THF (15 ml), added sodium hydroxide (0.474 g, 11.8 mmol) in water (7 ml) and stirred at RT for 12 h. The reaction mixture was acidified with a 1.5 N HCl solution to pH ~3 and extracted with EtOAc (5 x 20 ml). The combined organic extracts were washed with brine solution (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5] acid. ]octan6-¡l)benzoic acid (1.0 g, 10% yield in 3 steps) as a white solid, m / z (ESI): 324.1 (M-H)+. Intermediate compound 12: 4-(A / -(3-methyloxetan-3-yl)sulfamo¡l)-2-(6azaspiro[2.5]octan-6-yl)benzo¡c acid. caz ίηη / ζζηζ / Ε / γίΛΐ LiOH, H2O MeOH-THF Stage 3 Intermediate compound 12 Step 1: to a solution of 3-methyl-3-oxetanamine hydrochloride (5.50 g, 44.5 mmol) and DIPEA (23.26 ml, 134 mmol) in DCM (200 ml) at 0 °C, methyl 4-(chlorosulfonyl)-279 fluorobenzoate (12.37 g, 49.0 mmol) was added, and the mixture was stirred from 0 °C to RT for 1 hour. The mixture was diluted with 1.0 N HCl (200 ml) and extracted with DCM (150 ml x 2). The combined organic extracts were washed with brine, dried with anhydrous Na2SÜ4, filtered and concentrated under reduced pressure to provide a crude product. The crude product was purified with a 100 g Biotage SNAP column eluting with 0-30% EtOAc-EtOH (3:1) in heptane, providing 2-fluoro-4-(A / -(3-methyloxetan-3- Methyl il)sulfamoyl)benzoate (13.59g, 44.8 mmol, 100% yield) as a white solid. 1H NMR (500 MHz, DMSO-de) δ ppm 8.67 (s, 1H), 8.11 (t, J =7.37 Hz, 1H), 7.76-7.82 (m, 1H), 7.69-7.76 (m, 1H), 4.56 (d, J = 6.23 Hz, 2H), 4.18 (d, J = 6.75 Hz, 2H), 3.90 (s, 3H), 1.42 (s, 3H). Step 2: A mixture of N, AZ-diisopropylethylamine (16.23 ml, 93 mmol), 6azaspiro[2.5]octane (6.22 g, 55.9 mmol), and 2-fluoro-4-(A / -(3-methyloxetan-) was stirred. Methyl 3-yl)sulfamoyl)benzoate (14.13 g, 46.6 mmol) in anhydrous dioxane at 100 °C for 20 h. The mixture was cooled to RT, quenched with water and extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried and evaporated to dryness under reduced pressure. The crude product was purified using the 340 g Biotage SNAP column eluting with 0-40% EtOAc-EtOH 3:1 in heptane, providing 4-(A / -(3-methyloxetan-3yl)sulfamoyl)-2- Methyl (6-azaspiro[2.5]octan-6-¡l)benzoate (14.15 g, 35.9 mmol, 77% yield) as an off-white solid. 1H NMR (500 MHz, DMSO-cfe) δ ppm 8.42 (s, 1H), 7.72 (d, J =8.04 Hz, 1H), 7.47 (d, J =1.56 Hz, 1H), 7.36 (dd, J = 1.82 , 8.04 Hz, 1H), 4.55 (d, J = 5.97 Hz, 2H), 4.14 (d, J = 6.49 Hz, 2H), 3.85 (s, 3H), 3.02-3.09 (m, 4H), 1.44-1.50 (m, 4H), 1.42 (s, 3H), 0.35 (s, 4H). Step 3: A mixture of methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6azaspiro[2.5]octan-6-yl)benzoate (14.15 g, 35.9 mmol) was stirred. and lithium hydroxide monohydrate (22.58 g, 538 mmol) in THF-water-MeOH (1:1:1,300 ml) at RT overnight. The mixture was concentrated under reduced pressure to partially remove the organic solvent. The solution was acidified with 2 N HCl until reaching a pH < 3. The precipitated solid was filtered and dried in air, giving 4-(A / -(3-methyloxetan-3-yl)sulfamoyl)-2-(6) -azaspiro[2.5]octan-6yl)benzoic acid (9.94 g, 26.1 mmol, 73% yield) as a white solid. 1H NMR (500 MHz, DMSO-cfe) δ ppm 8.51 (s, 1H), 8.04 (d, J = 8.04 Hz, 1H), 7.89 (d, J = 1.30 Hz, 1H), 7.66 (dd, J = 1.69 , 8.17 Hz, 1H), 4.55 (d, J = 6.23 Hz, 2H), 4.09-4.17 (m, 2H), 3.063.19 (m, 4H), 1.56 (t, J= 5.19 Hz, 4H), 1.40 (s, 3H), 0.40 (s, 4H). Intermediate compound 13: 4-( / \ / -(tert-Butyl)sulfamoyl)-2-(6-azaspiro[2.51octan-6¡Dbenzoic acid. caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi Stage 1 Intermediate compound 13 Step 1: A solution of benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (25 g, 62 mmol, intermediate 8-4), DIPEA (21.8 ml, 125 mmol) was degassed. mmol), xantphos (1.81 g, 3.12 mmol), Pd2(dba)3 (1.14 g, 1.25 mmol) and benzyl mercaptan (10 g, 81 mmol) in dioxane (250 ml) and purged with nitrogen for 15 min. The reaction mixture was heated at 100 °C for 16 h in a sealed pressure-resistant container and then quenched with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (60-120 mesh) using 5-10% EtOAc in hexanes, giving 4-(benzylthio)-2-(6-azaspiro[2.5]octan-6yl )benzyl benzoate (20 g, 72% yield) as a pale yellow liquid. 1H NMR (400 MHz, DMSO-c / 6): δ 7.57 - 7.53 (m, 1H), 7.48 - 7.26 (m, 10H), 6.93 - 6.87 (m, 2H), 5.27 (s, 2H), 4.32 ( s, 2H), 2.95 - 2.87 (m, 4H), 1.35 (t, J = 5.3 Hz, 4H), 0.28 (s, 4H). m / z (ESI): 442.2 (M-H)+. Steps 2 and 3: to a solution of benzyl 4-(benzylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (20 g, 45 mmol) in DCM (160 ml) and water (40 ml), sulfuryl chloride (18.3 ml, 225 mmol) was added at 0 °C. The reaction mixture was stirred for 1 h before diluting with water (200 mL) and extracting with DCM (200 mL). The organic extract was dried with anhydrous Na2SO4, filtered and cooled to 0 °C. tert-butylamine (47.8 ml, 451 mmol) was added to the above solution. The reaction mixture was stirred at RT for 1 h before being quenched with water (200 ml) and extracted with DCM (2 x 100 ml). The combined organic extracts were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (60-120 mesh) using 15% EtOAc in hexanes, giving 4-(A / -(tert-butyl)sulfamo¡l)-2-(6 -azaspiro[2.5]octan-6-yl)benzyl benzoate (12 g, 61% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-c / 6): δ 7.71 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.55- 7.46 (m, 3H), 7.45- 7.33 (m, 4H) , 5.33 (s, 2H), 3.01 (s a, 4H), 1.38 (s a, 4H), 1.10 (s, 9H), 0.31 (2, 4H). m / z (ESI): 457.2 (M-H)+. Step 4: to a solution of 4-(A / -(ferc-butyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6 caz ίηη / ζζηζ / Ε / γίΛΐ il)benzyl benzoate (10 g, 21.9 mmol) in ethanol (50 ml) and EtOAc (50 ml), 10% palladium on carbon (4.66 g, 4.38 mmol) was added at RT under a nitrogen atmosphere. The reaction mixture was degassed and stirred under a hydrogen atmosphere (101.3 kPa [1 atm]) at RT for 16 h. The reaction mixture was filtered through a pad of CELITE® and the filter pad was washed with EtOAc (200 ml). The filtrate was concentrated under reduced pressure. The crude residue was purified with diethyl ether (200 ml) to give the title compound (6.0 g, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=8.2 Hz, 1H), 7.98 (s, 1H), 7.73-7.68 (m, 2H), 3.12 (t, J = 5.3 Hz, 4H ), 1.57 (t, J = 5.3 Hz, 4H), 1.10 (s, 9H), 0.43 (s, 4H). m / z (ESI): 365.2 (M-H)+. Intermediate compound 14: 4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6azaspiroí2.51octan-6-yl)benzoic acid. O F O F HS^-°HO F ü 1 NBS, AIBN,CCI41„ II I . JJ i °C, 4 h DMF, 120 °C Stage 1 Stage 2 mCPBA, DCM Stage 3 LiOH, THF, MeOH, H2O Stage 5 Intermediate compound 14 Step 1: To a stirred solution of methyl 2-fluoro-4-methylbenzoate (7.5 g, 44.6 mmol) in carbon tetrachloride (75 ml), NBS (7.94 g, 44.6 mmol) and AIBN (0.366 g, 2.23 mmol), and stirred at 70 °C for 4 h. The reaction mixture was quenched with water (200 ml) and extracted with DCM (2 x 200 ml). The combined organic extracts were washed with brine solution (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, giving methyl 4-(bromomethyl)-2-fluorobenzoate (8.5 g, crude) as of a rubbery solid. The crude material showed a mixture of monobromo and dibromo compounds and was therefore taken to the next stage without any purification, m / z (ESI): 247.1 [M+1 ] Step 2: a mixture of methyl 4-(bromomethyl)-2-fluorobenzoate (7 g, 28.3 mmol) and 2-mercaptoethane-1-ol (2.214 g, 28.3 mmol) was taken in / V, / V-dimethylformamide ( 25.0 mi) to a microwave-safe vial. The vial was sealed and irradiated in a microwave reactor at 120 °C for 1 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine solution (100 ml), dried with Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 50% EtOAc in hexane to give methyl 2-fluoro-4-(((2-hydroxyethyl)thio)methyl)benzoate. (2 g, 29% yield) as a viscous oil. 1H NMR (300 MHz, Chloroform-d): or 8.06 - 7.86 (m, 1H), 7.17 (td, J= 10.5, 3.8 Hz, 2H), 3.90 (s, 3H), 3.85-3.67 (m, 4H) , 2.65 (td, J = 6.0, 1.4 Hz, 2H), 1.42-1.18 (m, 1H). m / z (ESI): 245.1 [M+1], Step 3: To a stirred solution of methyl 2-fluoro-4-(((2-hydroxyethyl)thio)methyl)benzoate (2 g, 8.19 mmol) in DCM (20 ml), mCPBA (2.826 g, 16.38 mmol) at 0°Cyse stirred at RT for 1 h. The reaction mixture was quenched with satd aqueous solution. of NaHCOs (25 ml) and extracted with DCM (2 x 25 ml). The organic layer was washed with brine solution (25 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give a gummy solid. The crude residue was triturated with diethyl ether (40 ml), giving methyl 2-fluoro-4-(((2hydroxyethyl)sulfonyl)methyl)benzoate (1.0 g, 44% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-d6): δ 8.07 - 7.78 (m, 1H), 7.50 - 7.23 (m, 2H), 5.29 (s a, 1H), 4.62 (s, 2H), 3.87 (s, 3H) , 3.85 - 3.79 (m, 2H), 3.21 (t, J = 5.8 Hz, 2H). m / z (ESI): 277.1 [M+1], Step 4: A glass tube was charged with methyl 2-fluoro-4-(((2-hydroxyethyl)sulfonyl)methyl)benzoate (1.0 g, 3.62 mmol), 6-azaspiro[2.5]octane (0.48 g , 4.34 mmol), DIPEA (0.76 ml, 4.34 mmol) and DMSO (10 ml). The tube was sealed and heated at 100 °C for 72 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine solution (50 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated with diethyl ether (100 ml), giving 4-(((2-hydroxy¡ethyl)sulfon¡l)methyl)-2-(6-azaspiro[2.5]octan-6- Methyl yl)benzoate (900 mg, 67% yield) as a gummy solid. 1H NMR (300 MHz, DMSOd6): δ 7.55 (d, J = 7.6 Hz, 1H), 7.13 - 7.01 (m, 2H), 5.24 (s, 1H), 4.48 (s, 2H), 3.88 - 3.72 (m , 5H), 3.31 (s a, 2H), 3.16 (s a, 4H), 1.43 (t, J = 6.5 Hz, 4H), 0.31 (s, 4H). m / z (ESI): 368.1 [M+1], Step 5: to a stirred solution of methyl 4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6azaspiro[2.5]octan-6-yl)benzoate (0.9 g, 2.45 mmol) in THF (6 ml ) and methanol (4 ml), sodium hydroxide (98 mg, 2.45 mmol) in water (4 ml) was added and stirred at RT for 2 h. caz ίηη / ζζηζ / Ε / γίΛΐ The reaction mixture was concentrated under reduced pressure, removing the solvents. The resulting aqueous layer was acidified with a 6 N aqueous HCl solution to pH ~2 and extracted with 10% methanol in DCM (3 x 50 ml). The organic layer was washed with brine solution (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was triturated with diethyl ether (50 ml) to give 4-(((2-hydroxyethyl)sulfon¡l)methyl)-2-(6-azaspiro[2.5]octan6-¡acid). l)benzoic acid (0.6 g, 69% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe): δ 8.03 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 5.28 (t, J = 4.9 Hz, 1H), 4.60 (s, 2H), 3.88 - 3.80 (m, 2H), 3.22 (t, J = 5.8 Hz, 2H), 3.09 (t, J = 5.4 Hz, 4H ), 1.72 - 1.47 (m, 4H), 0.44 (s, 4H). m / z (ESI): 352.1 [M-1], [Note: COOH proton was not observed], Intermediate compound 15: 4-((3-methyloxetan-3-¡l)sulfon¡l)-2-(6azaspiroí2.51octan-6-yl)benzo¡ic acid. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 15 Step 1: In a glass microwave-safe reaction vessel (20 ml), to a solution of methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.0 g, 5.39 mmol , Intermediate 8-3) in DMSO (15.0 ml), potassium metabisulfite (2.40 g, 10.78 mmol), TBAB (1.91 g, 5.93 mmol), sodium formate (0.81 g, 11.85 mmol), triphenylphosphine (0.212 g, 0.81 mmol), 1,10-phenanthroline (0.146 g, 0.81 mmol) and palladium acetate (0.060 g, 0.27 mmol) in a nitrogen atmosphere. The reaction mixture was degassed and purged with nitrogen for 10 min. The reaction vessel was sealed and heated at 70 °C for 3 h. The reaction mixture was cooled to RT, 3-iodooxetane (2.39 g, 12.97 mmol) was added and stirred at 120 °C for 4 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography through a Redi-Sep prepacked silica gel column (40 g), eluting with a gradient. of 1-40% EtOAc in hexanes, giving methyl 4-(oxetan-3-ylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzoate (360 mg, 15% yield) as a yellow solid. 1H NMR (400 MHz, Chloroform-d): or 7.79 (dd, J = 8.1, 1.6 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.8 Hz, 1H ), 4.98 (dd, J= 7.4, 6.2 Hz, 2H), 4.80 (dd, J = 8.4, 7.1 Hz, 2H), 4.45 (tt, J = 8.4, 6.2 Hz, 1H), 3.94 (s, 3H) , 3.22-3.10 (m, 4H), 1.52 (t, J = 5.2 Hz, 4H), 0.38 (s, 4H). m / z (ESI): 366.1 [M+1]. Step 2: To a solution of methyl 4-(oxetan-3-ylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (350 mg, 0.96 mmol) in THF (5 ml), LÍHMDS (1.0 M solution in hexanes, 1.92 ml, 1.91 mmol) was added at -78 °C in a nitrogen atmosphere and stirred for 1 h. Iodomethane (71.9 μΙ, 1.15 mmol) was slowly added to the reaction mixture and slowly warmed to RT. The reaction mixture was quenched with a sat. aqueous solution. of NH4Cl (25 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography through a Redi-Sep prepacked silica gel column (12 g), eluting with a gradient. 1-50% EtOAc in hexanes, giving methyl 4-((3-methyloxetan-3¡l)sulfonyl)-2-(6-azaspiro[2.5]octan-6-¡l)benzoate (260 mg, yield 72%) as a pale yellow solid. 1H NMR (400 MHz, Chloroform-d): δ 7.82 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 5.20 (d, J = 6.9 Hz, 2H), 4.43 (d, J = 6.9 Hz, 2H), 3.97 (s, 3H), 3.24-3.12 (m, 4H), 1.70 (s, 3H), 1.58 (t , J = 5.4 Hz, 4H), 0.40 (s, 4H). m / z (ESI): 380.2 [M+1], Step 3: to a solution of methyl 4-((3-methyloxetan-3-yl)sulfoníl)-2-(6-azaspiro[2.5]octan-6yl)benzoate (250 mg, 0.66 mmol) in THF (5 ml), water (5 ml) and methanol (1 ml), lithium hydroxide (63 mg, 2.64 mmol) was added and stirred at RT for 5 h. The reaction mixture was acidified with 1.5 N HCl to pH ~4. The aqueous layer was extracted with EtOAc (3 x 50 ml), washed with brine (25 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure to give 4-((3-methyloxetan-3-yl acid )sulfoníl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 83% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-de): δ 16.01 (s, 1H), 8.05 (d, J= 8.1 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.0 , 1.8 Hz, 1H), 5.01 (d, J = 7.4 Hz, 2H), 4.48 (d, J = 7.4 Hz, 2H), 3.19 (t, J = 5.2 Hz, 4H), 1.60 - 1.52 (m, 7H ), 0.41 (s, 4H). m / z (ESI): 366.2 [M+1], Intermediate compound 16: 4-(3-methyloxetan-3-¡l)-2-(6-azaspiro[2.51octan-6¡Dbenzoic acid. CAZ Lnn / Zznz / E / YIAI Lnn / zznz / E / YiAi Intermediate compound 16 Step 1: To a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (180 g, 772 mmol) in EtOH (1500 ml), thionyl chloride (92.1 g, 772 mmol) was added at 0 °C and heated at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted with EtOAc (3 x 1000 ml) and washed with satd solution. of baking soda (2 x 2000 mi). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 2-(4-bromo-3-fluorophenyl)acetate (155 g, 77% yield) as a colorless gum. 1H NMR (400 MHz, Chloroform-c / ): δ 7.54 - 7.48 (m, 1H), 7.11 (dd, J = 9.3, 2.1 Hz, 1H), 6.98 (ddt, J = 8.2, 2.0, 0.8 Hz, 1H ), 4.19 (c, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H). Step 2: To a solution of ethyl 2-(4-bromo-3-fluorophenyl)acetate (155 g, 594 mmol) in dry THF (1500 ml), LDA (2.0 M solution in THF, 297 ml, 594 ml) was added. mmol) at -78 °C and stirred at -78 °C for 1 h. Ethyl cyanoformate (64.7 g, 653 mmol) was added to the reaction mixture at -78 °C and the reaction mixture was stirred for 1 h at -78 °C. The mixture was quenched with a 1.5 N HCl solution (1 I) and extracted with EtOAc (3x2 I). The organic layer was washed with water (1 I), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60-120 mesh) using 10% EtOAc in hexanes, giving diethyl 2-(4-bromo-3-fluorophenyl)malonate (120.0 g, yield of 60%) in the form of a viscous oil. 1H NMR (400 MHz, Chloroform-d): δ 7.59 - 7.49 (m, 1H), 7.31 -7.25 (m, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 4.59 (s, 1H) , 4.37-4.14 (m, 4H), 1.36- 1.24 (m, 6H). Lnn / zznz / E / YiAi Step 3: To a solution of diethyl 2-(4-bromo-3-fluorophenyl)malonate (60.0 g, 180 mmol) in DMF (600 ml), sodium hydride (8.64 g, 360 mmol) was added at 0° C followed by the addition of methane iodine (30.7 g, 216 mmol), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice and extracted with EtOAc (3 x 1 I). The combined organic extracts were washed with water (1 I), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 10% EtOAc in hexanes, giving diethyl 2-(4-bromo-3-fluorophenyl)methylmalonate (45.0 g, 72% yield) as a gum. pale brown in color. 1H NMR (400 MHz, Chloroform-d): 5 7.53 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 10.0,2.4 Hz, 1H), 7.11 7.05 (m, 1H), 4.25 (c, J=7.1 Hz, 4H), 1.85 (s,3H), 1.27 (t, J = 7A Hz, 6H). Step 4: To a solution of diethyl 2-(4-bromo-3-fluorophenyl)methylmalonate (45.0 g, 130 mmol) in dry THF (500 ml), lithium aluminum hydride (2.0 M solution in THF, 130 ml, 260 mmol) at 0 °C and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (40 ml) and then 1.5 N HCl (500 ml) was added. The mixture was extracted with EtOAc (3 x 500 ml). The combined organic extracts were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 20% ​​EtOAc in hexanes, giving 2-(4-bromo-3fluorophenyl)-2-methylpropane-1,3-diol (20 g, 59% yield). in the form of a rubber. Ή NMR (400 MHz, Chloroform-d): <5 7.53 (dd, J= 8.4, 7.5 Hz, 1H), 7.29-7.21 (m, 1H), 7.12 (dd, J = 8.4, 2.2 Hz, 1H) , 3.92 (d, J = 11.0 Hz, 2H), 3.77 (d, J = 11.0 Hz, 2H), 2.44 (s a, 2H), 1.25 (s, 3H). Step 5: To a solution of 2-(4-bromo-3-fluorophenyl)-2-methylpropane-1,3-diol (2.5 g, 9.50 mmol) in dry THF (30 ml), n-butyllithium was added (2.5 M solution in hexanes, 3.8 ml, 9.5 mmol) at 0°C and stirred for 30 min. Tosyl chloride (1.08 g, 5.70 mmol) was added to this reaction mixture at 0 °C and stirred at RT for 1 h. After cooling the reaction mixture to 0 °C, n-butyllithium (3.8 ml, 9.5 mmol) was added at 0 °C and slowly heated to 70 °C for 2 h. The reaction mixture was quenched with satd solution. of ammonium chloride (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 5% EtOAc in hexanes, giving 3-(4bromo-3-fluorophenyl)-3-methyloxetane (0.25 g, 11% yield) as a white solid. . Ή NMR (400 MHz, Chloroform-d): δ 7.54 (td, J = 7.6, 7.1 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.92 (dd, J = 8.2, 2.2 Hz, 1H), 4.89 (d, J = 5.7 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 1.72 (s, 3H). Step 6: To a solution of 3-(4-bromo-3-fluorophenyl)-3-methyloxetane (2.5 g, 10.20 mmol) in THF (50 ml), n-butyllithium (4.9 ml, 12.24 mmol) was added. at -78 °C and the reaction mixture was stirred for 15 min at -78 °C. To this, ethyl cyanoformate (1.21 g, 12.24 mmol) was added. Lnn / zznz / E / YiAi to -78 °C and the reaction mixture was heated slowly to 0 °C. The reaction mixture was quenched with a satd solution. of ammonium chloride (15 ml) and extracted with EtOAc (3 x 100 ml). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography using 10% EtOAc in hexanes, giving ethyl 2-fluoro-4-(3-methyloxetan-3-yl)benzoate (1.25g, 51% yield) as of a solid white. 1H NMR (400 MHz, Chloroform-d): δ 7.95 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 7.03-6.97 (m, 1H), 4.93 (d , J = 5.7 Hz, 2H), 4.67 (d, J = 5.7 Hz, 2H), 4.41 (c, J = 7.1 Hz, 2H), 1.74 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H ). m / z (ESI): 239.2 [M+1], Step 7: To a solution of ethyl 2-fluoro-4-(3-methyloxetan-3-yl)benzoate (0.5 g, 2.10 mmol) in DMSO (5 ml), azaspiro[2.5]octane (0.28 g, 2.52 mmol), and heated to 130 °C for 6 h in microwave. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3 x 50 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 10% EtOAc in hexanes, giving ethyl 4-(3-methyloxetan-3-yl)-2-(6azaspiro[2.5]octan-6-yl)benzoate. (0.4 g, 58% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d): or 7.70 (d, J = 8.0 Hz, 1H), 6.94 - 6.79 (m, 2H), 4.97 (d, J = 5.6 Hz, 2H), 4.64 (d, J = 5.6 Hz, 2H), 4.39 (c, J = 7.1 Hz, 2H), 3.12 (s, 4H), 1.74 (s, 3H), 1.55 (s a, 4H), 1.41 (t, J = 7.1 Hz, 3H ), 0.37 (s, 4H). m / z (ESI): 330.8 [M+1], Step 8: to a solution of ethyl 4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.8 g, 2.428 mmol) in THF (5 ml) , water (5 ml) and MeOH (3 ml), lithium hydroxide monohydrate (117 mg, 4.86 mmol) was added and stirred at RT for 12 h. The reaction mixture was diluted with water (30 ml) and neutralized with a 1.5 N HCl solution, obtaining a pH of ~7. The reaction mixture was extracted with EtOAc (3 x 70 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether (20 ml), filtered and dried in vacuo, giving 4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]octan-6yl)benzoic acid ( 0.45 g, 62% yield) as a white solid. 1H NMR (400 MHz, DMSO-c / 6): δ 8.01 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.30 (dd, J = 8.4, 1.6 Hz, 1H ), 4.85 (d, J = 5.6 Hz, 2H), 4.58 (d, J = 5.6 Hz, 2H), 3.13 (t, J = 5.4 Hz, 4H), 1.65 (s, 3H), 1.60 (dd, J = 8.7, 4.6 Hz, 4H), 0.44 (s, 4H). Note: the acidic proton was not visible, m / z (ESI): 302.2 [M+1], Intermediate compound 17: 4-(3-hydroxy¡oxetan-3-¡l)-2-(6-azaspiro[2.51octane-6¡Dbenzoic acid. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 17 Step 1: To a solution of 4-bromo-2-fluorobenzoic acid (10.0 g, 45.7 mmol) in THE (150 ml), n-butyllithium (2.5 M solution in hexanes, 36.5 ml, 91 mmol) was added to -78 °C and stirred for 30 min at -78 °C. Oxetan-3-one (6.5 g, 91.4 mmol) was added to this mixture at 78 °C and stirred for an additional 1 h. The reaction mixture was quenched with 2.0 M aqueous sodium hydroxide solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was discarded and the aqueous layer was cooled to 0 °C, and acidified with 2.0 N HCl to pH ~5 and extracted with EtOAc (3 x 300 ml). The combined organic extracts were washed with water (200 ml), dried with Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50% EtOAc in hexanes, giving 2-fluoro-4-(3-hydroxyoxetan-3-yl)benzoic acid (1.7 g, 17% yield). form of a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.92 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.45 (d, J= 12.3 Hz, 1H), 6.65 ( s, 1H), 4.78 (d, J = 6.6 Hz, 2H), 4.67 (d, J = 6.6 Hz, 2H). Note: the acidic proton was not visible, m / z (ESI): 211.1 [M-1 ]. Step 2: To a solution of 2-fluoro-4-(3-hydroxyoxetan-3-yl)benzoic acid (3.8 g, 17.91 mmol) in DMSO (40 ml), 6-azaspiro[2.5]octane (4.0 g) was added. , 35.8 mmol) and heated to 160 °C in microwave (Biotage+ Microwave Starter) for 4 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (3 x 100 ml). The organic layer was dried over Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase silica gel chromatography using 40% CH3CN in water, giving 4-(3-hydroxy¡oxetan-3-¡l)-2-(6-azaspiro[2.5] acid. octan-6-yl)benzoic acid (1.1 g, 20% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J = 8.2, 1.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.69 (dt, J = 8.3, 1.8 Hz, 1H ), 6.62 (d, J = 1.7 Hz, 1H), 4.79 (d, J = 6.4 Hz, 2H), 4.72 (d, J = 6.4 Hz, 2H), 3.14 - 3.08 (m, 4H), 1.59 (s a , 4H), 0.44 (s, 4H). Note: the acidic proton was not visible, m / z (ESI): 302.2 [M-1], Intermediate compound 18: 4-bromo-2-(6-azaspyro[2.51octan-6-yl)anilina. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 18 Step 1: a mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.4 mmol, Combi-Blocks), 6-azaspiro[2.5]octane hydrochloride (2.45 g, 16.57 mmol, AstaTech) and Potassium carbonate (5.97 g, 43.2 mmol, Sigma-Aldrich Corporation) in DMSO (12 mL) in an oil bath at 60 °C for 10 min, then heated to 90 °C for 1 h. The mixture was cooled to RT, treated with 20 ml of water and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with water (2x5 ml), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified on a silica gel column (15-45% EtOAc in heptane), giving 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (4.26 g, 13.7 mmol, yield 95%) as an orange solid, m / z (ESI): 311.0 / 313.0 (M+H)+. Step 2: to a mixture of 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (2.91 g, 9.35 mmol) and NH4CI (1.50 g, 28.1 mmol, Sigma-Aldrich Corporation) in EtOH (16 ml) and water (4 ml), powdered iron (3.13 g, 56.1 mmol, Sigma-Aldrich Corporation) was added. The heterogeneous mixture was heated in an oil bath at 85 °C for 2 h. The dark mixture was diluted with 50 ml of MeOH and filtered through a bed of CELITE®. The filter cake was rinsed with 2 x 5 ml of MeOH and the filtrate was concentrated in vacuo. The residue was distributed between 10 ml of water and 75 ml of EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated to provide 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)anilina (2.23 g, 7.95 mmol, 85% yield). form of a brown oil. 1H NMR (400 MHz, METHANOL-d4) δ 6.87 (d, J = 2.28 Hz, 1H), 6.77 (dd, J = 2.18, 8.40 Hz, 1H), 6.48 (d, J = 8.50 Hz, 1H), 4.65 (s, 4H), 1,231.50 (s a, 4H), 0.18 (s, 4H). m / z (ESI): 281.0 / 283.0 (M+H)+. AR1AND AR2 INTERMEDIATE COMPOUND COUPLING Intermediate compound 19:A / -(3-(A / -(terC-butyl)sulfamoyl)phenyl)-4-iodo-2-(6azaspiro[2.5]octan-6-¡l)benzamide. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 19 Step -1: To a solution of 2-fluoro-4-iodobenzoic acid (2.0 g, 7.52 mmol) in DMF (20 ml), 3-amino-A / -(tert-butyl)benzenesulfonamide (1.72 g) was added. 2.48 ml, 22.56 mmol) slowly at RT and stirred for 2 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep prepacked silica gel column, eluting with a gradient of 0-50% EtOAc in hexanes, giving A / -(3-( / V-(tert-butyl)sulfamoyl)pheníl)-2-fluoro-4-iodobenzamide (2.8 g, 78% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-cfe): δ 10.72 (s, 1H), 8.29 (s, 1H), 7.86-7.71 (m, 3H), 7.61 -7.51 (m, 3H), 7.48 (t, J= 7.83 Hz, 1H), 1.12 (s, 9H). m / z (ESI): 475.0 [M-1], Step -2: to a solution of M-(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-2-fluoro-4-iodobenzamide (8.0 g, 16.80 mmol) in dimethyl sulfoxide (50 ml), 6-azaspiro[2.5]octane (1.87 g, 16.80 mmol) and DIPEA (2.93 ml, 16.80 mmol) were added under a nitrogen atmosphere and stirred at 100 °C for 16 h. The reaction mixture was quenched with water (150 ml). The precipitated solid was filtered, washed with water (200 ml) and dried under vacuum. The solid cake was adsorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep prepacked silica gel column, eluting with a gradient of 0-30% EtOAc in hexanes, giving A / - (3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (6.0 g, 63% yield) in the form of a whitish foamy solid. 1H NMR (400 MHz, DMSO-c / 6): 5 11.37 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 7.59 - 7.54 (m, 5H), 7.47 7.44 (m, 1H), 3.35 (s, 4H), 1.41 (s, 4H), 1.18 (s, 9H), 0.28 (s, 4H). m / z (ESI): 568.1 [M+1], Table 5: Intermediate Compounds 19-1 and 19-2 were prepared analogously to the preparation of Intermediate Compound 19. caz ίηη / ζζηζ / Ε / γίΛΐ Comp. int. No. Chemical structure LRMS name: (ESI, positive ion) m / z 19-1 m [>θ^5 o=\ ωί ΙΖ ° / Γ 4-bromo-A / -(3-( / V(tert-butyl) sulfamoyl)phenyl) -2-(6azaspiro[2.5]octan -6-¡l)benzamide 520.2 / 522.2 19-2 .. n - OO H XX ,OMe O 4-((3-(N-(tert-butyl)sulfamoyl) phenyl)carbamoyl)-3-(6azaspiro[2.5]octan -6-yl)methylbenzoate 500.3 Intermediate compound 20: 4-Bromo- / \ / -(3-(4,4-difluoropiperidin-1-¡l)-5-methylphenyl)-2-(6azaspiro[2.5]octan-6-¡l )benzamide. Intermediate compound 20 A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.47 g, 7.96 mmol, Intermediate 8-1), A / -ethyl-A / -isopropylpropane- was stirred. 2-amine (2.57 g, 19.89 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorano-2,4,6-trioxide (50 % in EtOAc, 12.66 g, 19.89 mmol) and 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (1.5 g, 6.63 mmol, Intermediate 3) in DCM (15 ml) at RT for 6 hrs. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography using 6070% EtOAc in petroleum ether, yielding 4-bromo-M-(3- (4,4-difluoropíperídin-1-íl)-5methylphenyl)-2-(6-azaspiro[2.5]octan-6-íl)benzamide (1 g, 1.93 mmol, yield of 29%) in the form of a pale brown oil. 1H NMR (400 MHz, DMSO-de): δ ppm 11.19 (s, 1 H), 7.68 (d, J= 8.3 Hz, 1 H), 7.45 (d, J= 1.9 Hz, 1 H), 7.39 (dd , J = 8.3, 1.9 Hz, 1 H), 7.17 (s, 1 H), 7.14 (d, J = 2.4 Hz, 1 H), 6.61 (s, 1 H), 3.30 - 3.34 (m, 4 H) , 3.02 (t, J = 5.2 Hz, 4 H), 2.27 (s, 3 H), 1.97-2.13 (m, 4 H), 1.49 (t, J = 5.2 Hz, 4 H), 0.32 (s, 4 H). m / z (ESI): 518.1 (M+H)+. Intermediate compound 21: 4-Bromo- / V-(3-(4,4-d¡fluorop¡pendin-1-yl)-2-fluorophen¡l)-2-(6azaspiror2.51octan-6-yl)benzam¡ gives. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 21 A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.2 g, 0.64 mmol, Intermediate 8-1), oxalyl dichloride (0.123 g, 0.97 mmol) was stirred. and catalytic DMF in DCM (3 ml) at 0 °C for 30 min. The reaction mixture was concentrated and the residue was dissolved in dioxane (2 ml). This solution was treated with a solution of 3-(4,4-difluoropipendin1-yl)-2-fluoroaniline (0.15 g, 0.64 mmol, Intermediate 4) and EtaN (0.27 ml, 1.93 mmol) in dioxane (4 ml ). The reaction mixture was stirred at 100 °C for 16 h before diluting with water and extracting with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 10-20% EtOAc in petroleum ether, yielding 4-bromo-A / -(3(4,4-difluorop¡pendin-1-¡ l)-2-fluoropheníl)-2-(6-azaspiro[2.5]octan-6-íl)benzamide (0.160 g, 0.31 mmol, 48% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-cfe): δ ppm 11.86 (s, 1 H), 7.99 (t, J = 7.5 Hz, 1 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.60 (d , J = 1.9 Hz, 1 H), 7.49 (dd, J = 8.3, 1.8 Hz, 1 H), 7.13 (t, J = 8.2 Hz, 1 H), 6.92 (t, J = 8.2 Hz, 1 H) , 3.16 (t, J = 6.0 Hz, 4 H), 3.03 (t, J = 5.3 Hz, 4 H), 2.07 - 2.22 (m, 4 H), 1.53 (s, 4 H), 0.36 (s, 4 H). m / z (ESI): 524.1 (M+H)+. Table 6: Intermediate Compounds 22 to 26 were prepared analogously to the preparations of Intermediate Compound 20 or 21: Comp. int. No. Chemical structure LRMS name: (ESI, positive ion) m / z 22 P (R)-4-bromo-A / -(3-fluoro5-(2-methylmorpholino)phen¡l)2-(6-azaspiro [2.5]octane6-l)benzamide 502.1 / 504.1 23 6 . IZ (R)-4-bromo- / \ / -(4-fluoro3-(2-methylmorpholino)phenyl)2-(6-azaspiro[2.5]octan6-yl)benzamide 502.1 / 504.1 24 4-bromo- / V- (3-(A / -(fercbutyldimethylsilyl)-2methylpropan-2ylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 618.2 / 620.2 25 n '5 tbsn, 1 Λ 11 1 's; n q / z x° H [ | 1 ''Br 4-bromo-A / -(3-(N-(fercbutyldimethylsilyl)methylsulfonamido¡l)phen¡l)-2(6-azaspiro[2.5]octan-6yl)benzamide 576.2 / 578.2 26 Λ · $ TBSNX 11 ÓL U 1 N |— N o Η H J U ^^^Br 4-bromo-A / -(3-(A / -(fercbutyldimethylsilyl)azetidin-1 sulfonimidoyl)phen¡l)-2-(6azaspiro[ 2.5]octan-6yljbenzamide 617.2 / 619.2 Intermediate compound 27: 4-Bromo-A / -(3-(2-hydroxy-2-methylpropoxy)phenyl)-2-(6azaspiro[2.51octan-6-¡l)benzamide. caz ίηη / ζζηζ / Ε / γίΛΐ Stage 1 Boc2O, THF 70 °C, 24 h methyl ethyl ketone BrCH2CO2Et, K2CO3°C,4 h TFA, DCM from 0 °C to RT, 6 h Stage 3 EITHER Stage 2 Stage 4 Intermediate compound 27 Step 1: A mixture of 3-aminophenol (5 g, 45.8 mmol) and Boc-anhydride (9.0 g, 41.2 mmol) in THF (50 ml) was stirred at 70 °C for 24 h. The reaction mixture was diluted with EtOAc, washed with 1.5 N HCl. The organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 15-20% EtOAc in petroleum ether, providing tert-butyl (3hydroxyphenyl)carbamate (8.0 g, 38.2 mmol, 83% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-cfe): δ ppm 9.25 (d, J = 1.7 Hz, 1 H), 9.20 (s, 1 H), 6.90-7.13 (m, 2 H), 6.74-6.90 (m, 1 H), 6.35 (ddt, J = 1.3, 2.7, 8.1 Hz, 1 H), 1.47 (s, 9 H). Step 2: A mixture of (3-hydroxyphenyl)tert-butyl carbamate (3.0 g, 14.34 mmol), K2CO3 (5.94 g, 43.0 mmol) and ethyl 2-bromoacetate (2.39 ml, 21.51 mmol) was stirred in methyl ethyl ketone ( 40 mi) at 78 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 10-15% EtOAc in petroleum ether, providing ethyl 2-(3-((tert-butoxycarbonyl)amino)phenoxy¡)acetate (3.4 g, 11.51 mmol , 80% yield) in the form of a colorless oil. 1H NMR (300 MHz, DMSO-cfe): δ ppm 9.32 (s, 1 H), 6.98 - 7.14 (m, 3 Η), 6.49 (dd, J = 2.6, 8.0 Hz, 1 H), 4.67 (s, 2 H), 3.75 - 4.37 (m, 2 H), 1.45 (s, 9 H), 1.20 (t, J = 7.2Hz, 3H). m / z (ESI): 196.1 (M-Boc)+. Step 3: A solution of ethyl 2-(3-((tert-butoxycarbonyl)amino)phenoxy)acetate (1.0 g, 3.39 mmol) and TEA (1.30 ml, 16.93 mmol) in DCM (10 ml) was stirred. at RT for 6 h. The reaction was concentrated, neutralized with a satd aqueous solution. of sodium bicarbonate and extracted with DCM. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated to provide ethyl 2-(3-aminophenoxy)acetate (0.6 g, 3.07 mmol, 91% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-cfe): δ ppm 7.27 (t, J = 8.1 Hz, 2 H), 6.66 - 6.80 (m, 3 H), 4.77 (s, 2 H), 4.17 (c, J = 7.1 Hz, 2 H), 1.22 (t, J = 7.1 Hz, 3 H). m / z (ESI): 196.1 (M+H)+. Step 4: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.5 g, 1.61 mmol, Intermediate 8-1), 2-(3- ethyl aminophenoxy)acetate (0.47 g, 2.42 mmol), DIPEA (0.84 ml, 4.84 mmol) and T3P (50% in EtOAc, 2.05 g, 3.22 mmol) in DCM (10 ml) at rt for 48 h. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether, yielding 2-(3-(4-bromo-2-(6-azaspiro[2.5]octan-6yl)benzamido) Ethyl phenoxy)acetate (0.41 g, 0.84 mmol, 52% yield) as a light yellow oil. 1H NMR (300 MHz, DMSO-cfe): δ ppm 11.16 (s, 1 H), 7.65 (d, J = 8.2 Hz, 1 H), 7.48 (s, 1 H), 7.40 (dd, J = 1.8, 14.8 Hz, 1 H), 7.32 (d, J = 17.3 Hz, 1 H), 7.28 7.32 (m, 2 H), 6.64 - 6.70 (m, 1 H), 4.76 (s, 2 H), 4.18 (c , J = 7.1 Hz, 2 H), 3.03 (t, J = 6.4 Hz, 4 H), 1.46 (s a, 4 H), 1.21 (t, J = 7.4 Hz, 3 H), 0.32 (s, 4 H ). m / z (ESI): 487.1 (M+H)+. Step 5: to a solution of ethyl 2-(3-(4-bromo-2-(6-azaspiro[2.5]octan-6yl)benzamido)phenoxy¡) acetate (0.5 g, 1.03 mmol) in THF (15 ml ), methyl magnesium bromide (2.05 ml, 6.16 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with a satd aqueous solution. of NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 15% EtOAc in petroleum, providing 4-bromo-A / -(3-(2-hydroxy¡-2 methylpropoxy)phen¡l)-2-( 6-azaspiro[2.5]octan-6-l)benzamide (0.26 g, 0.55 mmol, 53% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-cfe): δ ppm 11.18 (s, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.56 (t, J = 2.2 Hz, 1 H), 7.29 - 7.48 (m, 2 H), 7.18 - 7.30 (m, 2 H), 6.66 - 6.70 (m, 1 H), 4.66 (s, 1 H), 3.70 (s, 2 H), 3.02 (t, J = 5.4 Hz, 4 H), 1.46 (s a, 4 H), 1.21 (s, 6 H), 0.32 (s, 4 H). m / z (ESI): 473.1 (M+H)+. caz ίηη / ζζηζ / Ε / γίΛΐ Intermediate compound 28: Ethyl 2-Sulfamoylpropanoate or ci O n-BuLi, THF,00 PMB. Λfrom-78° C to -20° C, 1 h π,Οιι TFA, Aniso!^Oll PMB Stage 1 PMB 'Stage 2' Intermediate compound 28 Step 1: To a solution of A / ,A / -bis(4-methoxybenzyl)ethanesulfonamide (200.0 g, 572.0 mmol) in THF (4000 ml), nBuLi (1.6 M in hexane, 608.0 ml, 973.0 mmol) was added to 78 °C slowly and stirred for 30 min. Ethyl carbonhydrochloride (92.0 ml, 973.0 mmol) in THF (50 ml) was added to the reaction mixture and stirred at -78 °C for 1 h. The reaction mixture was quenched with HCl (1.5 N, 3000 ml) and extracted with EtOAc (2 x 3000 ml). The organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure, giving the crude material of ethyl 2-(A / ,A / -bis(4-methoxybenzyl)sulfamoyl)propanoate (250.0 g, purity of 60%) in the form of a yellow oil, which was passed to the next stage without any purification. Step 2: To a solution of ethyl 2-(A / ,A / -bis(4-methoxybenzyl)sulfamo¡l)propanoate (600.0 g, 1.4 mol) in trifluoroacetic acid (2.50 I, 32.45 mol), anisole was added (500.0 ml, 4.57 mol) and stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure, quenched with cold aqueous 10% NaHCOs solution (3 I) and extracted with EtOAc (2 x 3 I). The combined organic extracts were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 25% EtOAc in hexanes to give a pale yellow solid (168 g) which was dissolved in DCM (1 I) and precipitated by the addition of hexanes. (3000 mi). The solid was filtered and dried under vacuum, yielding the title compound (109.0 g, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-ofe) δ ppm 7.14 (s, 2H), 4.15 (c, J= 7.1 Hz, 2H), 3.98 (c, J= 7.0 Hz, 1H), 1.45 (d, J= 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). m / z (ESI): 180.1 (M-H)+. EXAMPLES Example 100: A / -(3-(A / -(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)-2-(6azaspirof2.51octan-6-yl)benzamide caz Lnn / zznz / Ε / γΐΛΐ Lnn / zznz / E / YiAi To a solution of 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6yl)benzoic acid (120 mg, 0.33 mmol, Intermediate 15) in DMF (2 ml ), HATU (187 mg, 0.49 mmol) and DIPEA (143 μΙ, 0.821 mmol) were added to RT and stirred for 10 min. To this reaction mixture, 3-amino-A / -(tert-butyl)benzenesulfonamide (82 mg, 0.36 mmol) was added and stirred for 12 h at RT. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc (3 x 25 ml). The combined organic extracts were washed with brine solution (20 ml), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexanes to give the title compound (110 mg, 58% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-c / ): δ 12.33 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (t, J= 8.0 Hz, 1H), 5.19 (d, J = 7.0 Hz, 2H), 4.52 (s, 1H), 4.47 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 5.5 Hz, 4H), 1.73 (s, 3H), 1.70 - 1.60 (s a, 3H), 1.30 (s, 9H), 0.48 (s, 4H). m / z (ESI): 576.2 [M+1]. Table 7: Examples 100-1 to 100-15 were prepared analogously to the preparation of Example 100: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 100-1 V AA, O 0 N-(3-(N / tert-butyl)sulfamoyl)phenyl)-4(methylsulfonyl)-2-( 6azaspiro[2.5]octan-6yljbenzamide 520.1 100-2 = O 0 A / -(3-isopropylphenyl)-4(methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 427.2 100-3 νΑγχ / / C O O A / -(3 -cyclopropylphenyl)-4(methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 425.2 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 100-4 n - '5 0 0 A / -(3-(tert-butyl)pheníl)-4(methylsulfonyl)- 2-(éazaspiro[2.5]octan-6yljbenzamide 441.2 100-5 n.»5 0 0 4-(methylsulfonyl)- / \ / (quinolin-8-yl)-2-(6azaspiro[2.5]octan-6yljbenzamide 436.2 100- 6 n J Zz Λ 0 O A / -(4-methylquinol¡n-8-¡l)-4(methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 495.2 100-7 . δ Λ 0 0 A / -( croman-8-yl)-4- (methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 440.8 100-8 n · 5 á%ó,. % 0 0 / V-(benzofuran-7-yl)-4 (methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 425.1 100-9 0 0 A / -(benzo[b]thiophen-7-yl)-4(methylsulfonyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 441.2 caz Lnn / zznz / Ε / γΐΛΐ Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 100- 10 0 o. / O \ 4-(methylsulfonyl)- / \ / -(3morpholinophenyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 470.1 100- 11 Ox / JtZ) O \ o=\ ZT ϋ Ο=ω=Ο / ΣΖ _ N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4((methylsulfonyl)methyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 534.2 100- 12 \ ZI Ο=ω=ο P IZ ) =° χο \ .o ωζ c° N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4(((2hydroxyethyl)sulfonyl)methyl)2-(6-azaspiro[2.5]octan6-yl) benzamide 564.2 100- 13 V H A íí I \ Jk Jk / k H ^ll^l H loo H li J. n A 0 0 4-( / V-(tert-butyl)sulfamoyl)- N-(3-(N- (tert-butyl)sulfamoyl)phenyl)-2-(6azaspiro[2.5]octan-6yl)benzamide 577.2 100- 14 „ δ H f|l 9 ΐ X Λ N Τι ί °° H LA / oz N-(3-(N -(tert-butyl)sulfamoyl)phenyl)-4-(3methyloxetan-3-yl)-2-(6azaspiro[2.5]octan-6yljbenzamide 512.3 100- 15 Λ ¿ Ó"o H LA / OH or N-(3- (N-(tert-butyl)sulfamoyl)phenyl)-4-(3hydroxyoxetan-3-yl)-2-(6azaspiro[2.5]octan-6yl)benzamide 514.1 caz Lnn / zznz / Ε / γΐΛΐ 100 Example 101: A / -(3-((1-hydroxy-2-methylpropan-2-yl)amino)pheníl)-4-( / \ / -(3-methyloxetan-3Lnn / zznz / E / YiAi ¡ l)sulfamoyl)-2-(6-azaspiro[2.5]octane-6-l)benzamide To a solution of 4-(A / -(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6yl)benzoic acid (0.25 g, 0.66 mmol, Intermediate 12) and 2 -((3-aminophenyl)amino)-2methylpropan-1-ol (0.130 g, 0.72 mmol, Intermediate 2-2) in DMF (3 ml), 4-(4,6-dimethoxy-1, 3,5-triazin-2-1)-4-methylmorpholinium (0.291 g, 0.986 mmol) and stirred at rt for 18 h. The reaction was partitioned between water and EtOAc. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification using SFC prep. gave A / -(3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(A / -(3methyloxetan-3-yl)sulfamo¡l)-2-(6-azaesp ¡ro[2.5]octan-6-yl)benzamide (0.26 g, 0.48 mmol, 73% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.61 (s, 1 H) 8.16 (s, 1 H) 7.87 (d, J = 8.48 Hz, 1 H) 7.26 (d, J = 2.06 Hz, 1 H) 7.17(t, J= 1.95 Hz, 1 H) 7.05-7.10 (m, 2 H)6.99 - 7.04 (m, 1 H) 6.42 - 6.46 (m, 1 H) 3.39 (s, 2 H) 3.18 (s, 3 H) 2.96 (t a, J = 5.16 Hz, 4 H) 1.58 (s a, 4 H) 1.42 (s, 3 H) 1.26 (s, 6 H) 1.18 - 1.22 (m, 2 H) 0.84 (d, J = 2.06 Hz, 2 H) 0.37 (s, 4 H). m / z (ESI, positive ion): 527.3 (M+H)+. Table 8: Examples 101-1 to 101-3 were prepared analogously to the preparation of Example 101: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 101-1 t δ \ / r π o N H Í H 0 0 Vo / V-(2-fluoro-3-((1-hydrox ¡-2methylpropan-2yl)amino)phenyl)-4-( / \ / -(3methyloxetan-3-yl)sulfamoyl)2-(6-azaspiro[2.5]octan-6yl)benzamide 561.2 101-2 I O IZ <> IZ Vo QO / \ / -(2-fluoro-3-(( 1 -hydroxy-2methylpropan-2¡l)amino)phenyl)-4-((1 methylcyclopropane)-1sulfonamido)-2-(6azaspiro[2.5]octan- 6iljbenzamide 545.4 101 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 101-3 x n Λ / -(3-((1-hydroxy-2methylpropan-2¡l)amino)phenyl)-4-(( 1-methylcyclopropane)-1-sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 527.2 Example 102:A / -(3-(A / -(tert-but¡l)sulfamoyl)phenyl)-4-((1-methylcyclopropane)-1caz ίηη / ζζηζ / Ε / γίΛΐ sulfonamido)-2-(6- azaesp¡rol2.51octane-6-l)benzamide. A 250 ml glass tube was charged with a solution of N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]octan-6- il)benzamide (15.0 g, 26.4 mmol, Intermediate compound 19) and DMF (100 ml). To this solution, tribasic potassium phosphate (16.83 g, 79.0 mmol), copper (I) iodide (1.26 g, 6.61 mmol), trans-N,N'dimethylcyclohexane-1,2-diamine (1.0 ml, 6.61 mmol), and 1-methylcyclopropane-1-sulfonamide (4.3 g, 31.7 mmol). The reaction mixture was degassed and purged with nitrogen for 10 min. The tube was sealed and shaken at 100 °C for 16 h. The reaction mixture was cooled to RT and quenched with a satd aqueous solution. of NH4CI (100 mi). The reaction mixture was extracted with DCM (3 x 50 ml) and washed with water (50 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography eluting with a gradient of 40% EtOAc in hexanes, giving a brown solid. This solid was further purified by trituration with heptane (75 mL) and EtOAc (25 mL), giving the title compound (10.0 g, 66% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe): δ 11.63 (s, 1H), 10.16 (s, 1H), 8.34 (d, J= 2.1 Hz, 1H), 7.91 (dt, J = 8.0, 1.7 Hz, 1H ), 7.78 (d, J = 8.4 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.22 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 2.96 (t, J = 5.4 Hz, 4H), 1.48 (d, J = 5.6 Hz, 4H), 1.42 (s, 3H), 1.21 (c, J = 4.5 Hz, 2H), 1.12 (s, 9H), 0.89 - 0.80 (m, 2H), 0.33 (s, 4H). m / z (ESI): 575.2 [M+1]. 102 Table 9: Examples 102-1 to 102-6 were prepared analogously to the caz ίηη / ζζηζ / Ε / γίΛΐ preparation of Example 102: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 102-1 —v- ZI Ο=ω=ο p ciP IZ ω=θ / o N-(3-(N-(tert-butyl) sulfamoyl)phenyl)-4(methylsulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 535.2 102-2 \ ZT O-P-O O IZ IZ ω=ο e N-(3-(N-(tertbutyl)sulfamoyl)phenyl)- 4(ethylsulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 549.2 102-3 \ ZI O-P-O P IZ ω=ο -p N-(3-(N-(tertbutyl)sulfamoyl)phen¡l)-4(( 1methylethyl)sulfonamido)-2(6-azaspiro[2.5]octan6-yl)benzamide 563.2 102-4 9^ Ο=ω o=\ ZI q O=t / )=O IZ \ N-(3-(N -(tert-butyl)sulfamoyl)phenyl)-4(cyclopropanesulfonamide)-2-(6azaspiro[2.5]octan-6yljbenzamide 561.2 102-5 V λ°ΧΧ aJL ° H tPpp Η P N-(3-(N-(tert-butyl) sulfamoyl)pheníl)-4((1,1dimethylethyl)sulfonamido)2-(6azaspiro[2.5]octan-6yljbenzamide 577.2 102-6 C\ oP J ΖΣ q O=(Z>=O / ΤΔ_ N-( 3-(N-(tert-butyl)sulfamoyl)phenyl)-4(1,1-d ioxidoisothiazol i n2-¡l)-2-(6azaspiro[2.5]octan-6yljbenzamide 561.2 103 Example 103: A / -(3-(A / -(tert-but¡l)sulfame¡ITen¡l)-4-((2-hydroxyethyl¡l)sulfonamido)-2-(6azaspiro [2.5]octan-6-¡l)benzamide. caz ίηη / ζζηζ / Ε / γίΛΐ Step 1: In a sealed tube (10 ml), A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-iodo2-(6-azaspiro[2.5]octan-6 was taken. -yl)benzamide (0.25 g, 0.44 mmol, Intermediate 19) in dioxane (2.5 ml). To this solution at RT, ethyl 2-sulfamoylacetate (0.15 g, 0.88 mmol) and potassium carbonate (0.15 g, 1.10 mmol) were added. The reaction mixture was degassed and purged with nitrogen for 10 min. To this, Xantphos (0.013 g, 0.022 mmol) and Pd2dbas (0.020 g, 0.022 mmol) were added. The reaction tube was sealed and shaken at 110 °C for 16 h. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc (2 x 50 ml). The organic layer was washed with brine (10 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (60-120 mesh) using 50% EtOAc in hexanes, giving 2-( / V-(4-((3-(A / -(tert-butyl) ethyl sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-l)phenyl)sulfamoyl)acetate (100 mg, 37% yield) in the form of a brown spongy solid. 1H NMR (400 MHz, DMSO-ds): or 11.50 (s, 1H), 10.45 (s, 1H), 8.32 (d, J= 8.0 Hz, 1H), 7.90 - 7.70 (m, 1H), 7.547.44 (m, 3H), 7.12 - 6.97 (m, 2H), 4.33 (s, 2H), 4.09 (c, J = 7.08 Hz, 2H), 3.07 (s, 1H), 3.00 (s a, 4H), 1.47 ( s a, 4H), 1.20- 1.02 (m, 12H), 0.33 (s, 4H). m / z (ESI): 607.2 [M+1], Step 2: to a solution of 2-(A / -(4-((3-( / V-(tert-butyl)sulfamo¡l)phenyl)carbamo¡l)-3-(6azaspiro[2.5]octan-6 -yl)phenyl)sulfamoyl)acetate (0.18 g, 0.297 mmol) in THF (4 ml), lithium borohydride (2.0 M in THF, 0.22 ml, 0.445 mmol) was added at 0 °C and stirred for 1 hour. The reaction mixture was quenched with a satd aqueous solution. of NH4Cl (10 ml) and extracted with EtOAc (2x15 ml). The combined organic extracts were washed with satd solution. of brine (10 ml), dried with Na2SÜ4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel. 104 using 50% EtOAc in hexanes, giving A / -(3-(A / -(tert-butyl)sulfamoyl)pheníl)-4-((2hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]octan-6-¡l)benzamide (80 mg, 48% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-cfe): δ 11.56 (s, 1H), 10.10 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 7.52 Hz, 1H), 7.77 (d, J = 8.48 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.14 (s, 1H), 7.01 (d, J = 8.48 Hz, 1H), 4.98 (t, J=5.44 Hz, 1H), 3.76 (dt , J = 6.24, 5.44 Hz, 2H), 3.34 (t, J= 6.24 Hz, 2H), 2.98 (s a, 4H), 1.48 (s a, 4H), 1.12 (s, 9H), 0.32 (s, 4H) . m / z (ESI): 565.2.1 [M+1], Lnn / zznz / E / YiAi Table 10: Examples 103-1 to 103-4 were prepared analogously to the preparation of Example 103: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 103-1 o O XZ χο ωί o -(2methylmorpholino)phenyl)2-(6azaspiro[2.5]octan6-yl)benzamide 529.2 103-2 n δ oO í kk v / ''Ν'^'Ά'ΌΗ H (R)-M-(2-fluoro- 3-(2methylmorpholino)phenyl)4-((2hydroxyethyl)sulfonami do)-2-(6azaspiro[2.5]octan6-l)benzamide 547.2 103-3 A · N H (R)-A / -(3 -fluoro-5-(2methylmorpholino)pheníl)4-((2hydroxyethyl)sulfonamí do)-2-(6azaspiro[2.5]octan6-íl)benzamide 547.2 103-4 •X H (R)- / V -(4-fluoro-3-(2methylmorpholino)phenyl)4-((2hydroxyethyl)sulfonamí do)-2-(6azaspiro[2.5]octan6-íl)benzamide 547.2 105 Example 104: / 7-(3-(4,4-difluoropiper¡din-1-¡l)-5-methylphenyl)-4-((2-hydroxy¡ethyl)sulfonamido )2-(6-azaspiro[2.51octan-6-yl)benzamide. caz ίηη / ζζηζ / Ε / γίΛΐ A mixture of 4-bromo- / 7-(3-(4,4-difluoropiper¡din-1-¡l)-5-methylphen¡l)-2-(6azaspiro[2.5]octane) was stirred. 6-yl)benzamide (0.5 g, 0.96 mmol, Intermediate 20), potassium phosphate (0.614 g, 2.89 mmol), 2-hydroxyethane-1-sulfonamide (0.181 g, 1.45 mmol), (1R,2R) / 71, / 72-dimethylcyclohexane-1,2-diamine (0.069 g, 0.48 mmol) and copper (I) iodide (0.092 g, 0.48 mmol) in DMF (5 ml) at 90 °C for 16 h. The reaction mixture was quenched with icewater, filtered through a pad of CELITE® and extracted with EtOAc. The organic extract was washed with brine, dried Na2SO4, filtered, concentrated and purified by silica gel column chromatography using 40% EtOAc in petroleum ether, yielding / 7-(3-(4.4 -difluorop¡perídin-1-¡l)-5-methylphen¡l)-4-((2-hydroxy¡ethyl)sulfonamido)-2-(6azaspiro[2.5]octan- 6-yl)benzamide (0.31 g, 0.54 mmol, 56% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.55 (s, 1 H), 10.09 (s, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.12 - 7.16 (m, 3 H ), 7.03 (dd, J = 8.5, 2.1 Hz, 1 H), 6.60 (s, 1 H), 4.97 (s a, 1 H), 3.76 (t, J = 6.6 Hz, 2 H), 3.30 - 3.34 ( m, 6 H), 2.97 (t, J = 5.3 Hz, 4 H), 2.27 (s, 3 H), 2.00 - 2.10 (m, 4 H), 1.55 (s a, 4 H), 0.36 (s, 4 H). m / z (ESI): 563.2 (M+H)+. Table 11: Examples 104-1 to 104-2 were prepared analogously to the preparation of Example 104: Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 104-1 η. θ F Oj Y F H N-(3-AAdifluoropiperidin-1yl)phenyl)-4-((2hydroxyethyl)sulfonamide)-2-(6azaspiro[2.5]octan6-¡l)benzamide 549.2 104-2 n · í F H / 7 -(3-(4,4difluoropiperidin-1 -yl)2-fluorophenyl)-4-((2hydroxyethyl)sulfonamide 0)-2-(6azaspiro[2.5]octan6-l)benzamide 567.2 106 Examples 105-1 and 105-2: (S)- / V-(3-( / V-(tert-butyl)sulfamoyl)phen¡l)-4-((2-hydrOx¡-1methylethyl) sulfonamido)-2-(6-azaspiro[2.5]octan-6-¡l)benzamide and (R)-N-(3-(N-(tertbut¡l)sulfamo¡l)phen¡l) -4-((2-hydroxy¡-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.51octan-6¡Dbenzamide. caz ίηη / ζζηζ / Ε / γίΛΐ Step 1: a glass tube was loaded with A / -(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-iodo-2-(6azaspiro[2.5]octan-6-yl)benzamide (1.0 g, 1.76 mmol, Intermediate Compound 19) and dioxane (10 mi). To this solution, ethyl 2-sulfamoylpropanoate (0.64 g, 3.52 mmol, Intermediate 28) and potassium carbonate (0.61 g, 4.41 mmol) were added. The reaction mixture was degassed and purged with nitrogen for 10 min. Xantphos (0.051 g, 0.088 mmol) and Pd2dba3 (0.081 g, 0.088 mmol) were added to the reaction mixture. The reaction vessel was sealed and stirred at 110 °C for 16 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 50% EtOAc in hexanes, giving 2-(N-(4-((3-(A / -(tert-butyl)sulfamoyl)phenyl Ethyl )carbamoyl)-3-(6azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propanoate (400 mg, 38% yield) as a brown solid. 1H NMR (400 MHz, Chloroform-ó): ó 8.28 (d, J - 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 9.0 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.39 (s, 1H), 7.21 (s, 1H), 7.14 107 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 93.0 Hz, 1H), 4.59 (d, J = 9.7 Hz, 1H), 4.28 (dd, J = 8.0, 5.6 Hz, 2H), 3.83 - 3.66 (m, 8H), 3.10 (d, J = 5.3 Hz, 3H), 1.29 (s a, 12H), 0.45 (s, 4H). m / z (ESI): 621.2 [M+1], Step 2: to a solution of 2-(A / -(4-((3-( / V-(tert-butyl)sulfamoyl)phenyl)carbamol)-3-(6azaspiro[2.5]octan-6-yl )phenyl)sulfamoyl)propanoate (0.4 g, 0.64 mmol) in THF (4 ml), 2 M lithium borohydride in THF (0.387 ml, 0.773 mmol) was added at 0 ° C and stirred for 2 h. The reaction mixture was quenched with a sat. of NH4Cl (25 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with satd solution. of brine (20 ml), dried with Na2SÜ4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 50-100% EtOAc in hexanes, giving A / -(3-(A / -(tert-but¡l)sulfamo¡l)phenyl)- 4-((2-hydroxy-1methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (300 mg, 80% yield) as a whitish solid. 1H NMR (400 MHz, DMSO-cfe): or 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J= 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H ), 7.76 (d, J = 8.5 Hz, 1H), 7.66-7.47 (m, 3H), 7.16 (d, J= 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J= 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 - 2.92 ( m, 4H), 1.48 (s a, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1], The racemic material was subjected to preparative SFC using a Chiralpak AD-H (250 χ 30 mm, 5 pm) with a mobile phase of 75% liquid CO2 and 25% of MeOH and a flow rate of 100 ml / min, generating the following compounds of Examples 105-1 and 105-2: Example 105-1: (S)-A / -(3-(A / -(tert-but¡l)sulfamoyl)phenyl)-4-((2-hydroxy¡-1methylethyl)sulfonamido) -2-(6-azaspiro[2.5]octan-6-¡l)benzamide. First elution maximum, 100% ee; 1H NMR (400 MHz, DMSO-cfe): or 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H ), 7.76 (d, J = 8.5 Hz, 1H), 7.66 - 7.47 (m, 3H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J = 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 2.92 (m , 4H), 1.48 (s a, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1], Example 105-2: (F?)-A / -(3-(A / -(fert-butyl)sulfamoyl)phenyl)-4-((2-hydroxyl-1methylethyl)sulfonamido )-2-(6-azaspiro[2.51octan-6-yl)benzamide. Second elution maximum, ee of 97.5%; 1H NMR (400 MHz, DMSO-cfe): or 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J= 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H ), 7.76 (d, J = 8.5Hz, 1H), 7.66 - 7.47 (m, 3H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J = 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 2.92 (m , 4H), 1.48 (s a, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1], CAZ Lnn / Zznz / E / YIAI 108 Stereochemistry assignments were arbitrary. Example 106: A / -(3-(2-hydroxy¡-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6- ¡l)benzam¡da. ^OMe xS ri H2N π (1R,2R)-N,N-Dimethyl1,2-cyclohexanediamine Cul, K3PO4, DMF, 90 °C 16 h, Br Stage 1 caz ίηη / ζζηζ / Ε / γίΛΐ Step 1: A mixture of 4-bromo-A / -(3-(2-hydroxy-2-methylpropoxy)phenyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide (0.260) was stirred. g, 0.549 mmol, Intermediate 27), methyl 2sulfamoylacetate (0.126 g, 0.82 mmol), tribasic potassium phosphate (0.233 g, 1.10 mmol), copper (I) iodide (0.105g, 0.55 mmol) and (1R, 2R)-A / , A / '-dimethyl-1,2cyclohexanediamin (0.039 g, 0.27 mmol) in DMF (5 ml) at 90 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 40-50% EtOAc in petroleum ether, providing 2-(N-(4-((3-(2-hydroxy-2-methylpropoxy¡)phenyl Methyl carbamoyl)-3-(6azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.260 g, 0.476 mmol, 87% yield) as a light yellow oil. 1H NMR (300 MHz, DMSO-de): δ ppm 11.53 (s, 1 H), 10.53 (s, 1 H), 7.95 (s, 1 H), 7.82 (d, J = 8.5 Hz, 1 H), 7.59 (s, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.14 - 7.20 (m, 1 H), 6.96 - 7.07 (m, 1 H), 6.67 (d, J = 8.3 Hz, 1 H), 4.65 (s, 1 H), 4.36 (s, 2 H), 3.70 (s, 2 H), 3.65 (s, 3 H), 2.95 - 3.02 (m, 4 H), 1.53 (s a, 4 H), 1.21 (s, 6 H), 0.35 (s, 4 H). m / z (ESI): 546.2 (M+H)+. Step 2: to a solution of 2-(A / -(4-((3-(2-hydroxy-2-methylpropoxy¡)phenyl)carbamo¡l)-3-(6azaspiro[2.5]octan-6- methylyl)phenyl)sulfamoyl)acetate (0.260 g, 0.476 mmol) in THF (10 ml), lithium borohydride (0.95 ml, 1.91 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was quenched with a satd aqueous solution. of NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried with Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography eluting with 45-50% EtOAc in petroleum ether, providing A / -(3-(2-hydroxy¡-2 109 methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan -6-yl)benzamide (0.032 g, 0.062 mmol, 13% yield) as a solid white. 1H NMR (400 MHz, DMSO-cfe): δ 11.54 (s, 1 H), 10.08 (s, 1 H), 7.81 (d, J = 8.5 Hz, 1 H), 7.47 (t, J = 2.1 Hz, 1 H), 7.27 (t, J =8.2 Hz, 1 H), 7.19 - 7.10 (m, 2 H), 7.01 (dd, J =8.5,2.1 Hz, 1 H), 6.75 - 6.64 (m, 1 H ), 4.95 (s, 1 H), 4.65 (s, 1 H), 3.82 - 3.62 (m, 4 H), 2.94 - 3.01 (m, 4 H), 1.52 (s a, 4 H), 1.40- 1.46 ( m, 2 H), 1.21 (s, 6 H), 0.34 (s, 4 H). m / z (ESI): 518.2 (M+H)+. Example 107: 4-(Azetidin-1-ylsulfonyl)-A / -(3-(A / -(tert-but¡l)sulfamoyl)phenyl)-2-(6azaspiro|2.51octan-6-¡l)benzamide. Lnn / zznz / E / YiAi Step 1: A 250 ml round bottom flask was charged with 4-bromo-A / -(3-(A / -(tertbutyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl )benzamide (3.98 g, 7.65 mmol, Intermediate Compound 19-1), xantphos (0.227 g, 0.39 mmol), Pd2dba3 (0.18 g, 0.2 mmol) and dioxane (25 mi) under Ar atmosphere. While the mixture was degassed by bubbling Ar through, DIPEA (2.96 ml, 22.94 mmol) was added followed by benzyl mercaptan (0.95 ml, 8.03 mmol). The reaction mixture was heated at 100 °C for 1 h. The mixture was cooled to rt and partitioned between water (40 ml) and EtOAc (30 ml). The aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with water (30 ml). The organic phase was dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2 x 10 ml) and the solvent was removed in vacuo. The raw product was taken to the next stage. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.78 (s, 1H), 8.28 (s, 1H), 8.18 (d, J = 8.22 Hz, 1H), 7.98 (dd, J = 1.08, 8.12 Hz, 1H) , 7.63 (d, J= 7.82 Hz, 1H), 7.45-7.52 (m, 1H), 7.28-7.40 (m, 5H), 7.22 (dd, J= 1.66, 8.31 Hz, 1H), 7.17 (d, J = 1.56 Hz, 1H), 4.56 (s, 1H), 4.22 (s, 2H), 2.99 (t, J = 5.28 Hz, 4H), 1.601.67 (m, 4H), 1.28 (s, 9H), 0.43 (s, 4H). in DMSO-d6: Ή NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.32 (s, 1H), 7.88 (d a, J = 7.24 Hz, 1H), 7.70 (d, J = 8.61 Hz, 1H), 7.50-7.59 (m, 3H), 7.44 (d, J= 7.24 Hz, 2H), 7.33 (t, J= 7.34 Hz, 2H), 7.22-7.29 (m, 1H), 7.14 (dd , J= 2.54, 4.11 Hz, 2H), 4.36 (s, 2H), 2.96 (t a, J = 4.99 Hz, 4H), 1.45 (s a, 4H), 1.11 (s, 9H), 0.31 (s, 4H) . 110 Step 2: A 100 ml round bottom flask was charged with 4-(benzylthio)-A / -(3-(A / -(ercbutyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6 -l)benzamide (1.01 g, 1.781 mmol), ACN (8 mi), water (0.2 mi) and acetic acid (0.3 mi). The mixture was cooled in an ice water bath and 1,3-dichloro-5,5-dimethylhydantoin (0.57 g, 2.91 mmol) was added portionwise. The mixture was stirred at 0 °C for 20 min before adding satd solution. NaHCOs (20 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with brine and dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2x10 ml). The organic extracts were concentrated and purified by silica gel chromatography with 2-50% EtOAc in hexanes, yielding 4-((3-(A / -(tert-butyl)sulfamoyl)phenyl)carbamoyl chloride. )-3-(6-azaspiro[2.5]octan-6-íl)benzenesulfonyl. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.14 (s, 1H), 8.48 (d, J = 8.22 Hz, 1H), 8.30 (s, 1H), 7.91-8.00 (m, 3H), 7.69 (d, J = 7.82 Hz, 1H), 7.51-7.57 (m, 1H), 4.62 (s, 1H), 3.18 (t, J = 5.18 Hz, 4H), 1.67 (s a, 4H), 1.29 (s, 9H), 0.47 (s, 4H). Step 3: a glass vial was loaded with 4-((3-(A / -(tertbutyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]octan-6 chloride -l)benzene-1-sulfonyl (0.085 g, 0.157 mmol), DIPEA (0.082 ml, 0.47 mmol), azetidine (0.013 ml, 0.19 mmol) and DCM (1 ml). The mixture was stirred at rt for 20 min before concentrating. The crude material was purified by Biotage (SNAP25, Ultra, eluent 20-80% EtOAc in heptane) and then lyophilized to obtain 0.071 g of the title compound as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 11.05 (s, 1H), 8.33 (s, 1H), 7.98 - 7.91 (m, 1H), 7.87 (d,J = 7.9 Hz, 1H), 7.58 (da, J = 6.2 Hz, 3H), 7.50 (d, J= 8.1 Hz, 1H), 7.43 (s, 1H), 3.73 (t, J = 7.6 Hz, 4H), 3.10 (t a, J = 4.7 Hz, 4H) , 2.03 (quin, J = 7.7 Hz, 2H), 1.41 (s a, 4H), 1.12 (s, 9H), 0.28 (s, 4H). caz ίηη / ζζηζ / Ε / γίΛΐ Table 12: Examples 107-1 to 107-8 were prepared analogously to the preparation of Example 107: Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 107-1 . δ s S 593.2 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 107-2 / / \x 0 0 N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4(N-(2hydroxyethyl) )sulfamoyl)-2(6-azaspiro[2.5]octan6-¡l)benzamide 565.2 107-3 V A' 0 0 N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4( / V,A / - dimethylsulfamo¡l)2-(6azaspiro[2.5]octan-6yljbenzamide 549.2 107-4 n ° '5 / / \\ o o N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4(A / -methylsulfamoyl) -2-(6azaspiro[2.5]octan-6yl)benzamide 535.2 107-5 V βΛϊ\ H oz o Vo N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4(M-(oxetan-3yl)sulfamoyl )-2-(6azaspiro[2.5]octan-6yljbenzamide 577.2 107-6 P TZ oO wC __ / O o=( ZI c wC IZ ° ?v N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4 ( / V-cyclopropylsulfamoyl)2-(6azaspiro[2.5]octan-6yljbenzamide 561.2 107-7 V m r^Pi 0 / / p V 0 o v N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4(M -(1methylcyclopropyl)sulfameyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 575.2 caz Lnn / zznz / Ε / γΐΛΐ 112 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 107-8 n h ¿'o H ULnh2 ó-'ó N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-2( 6-azaspiro[2.5]octan6-¡l)-4sulfamoylbenzamide 521.2 Examples 108-1 and 108-2: (R)-A / -(3-(A / -(tert-butyl)sulfamoyl)phen¡l)-4-(1,2-dih¡droxy¡propan-2yl) -2-(6-azaspiro[2.51octan-6-yl)benzamide and (S)- / V-(3-( / Werc-butyl)sulfamo¡l)phen¡l)-4-(1,2d ¡hydroxy¡propan-2-¡l)-2-(6-azaspiro[2.5]octane-6-¡l)benzamide. 113 Step 1: A solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10.0 g, 25 mmol, Intermediate 8-4) in dioxane (100 ml) was collected in a tube. of glass (250 mi). To this reaction mixture, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5 g, 27.5 mmol) and an aqueous solution were added. of Na2CO3 (2 M solution, 31.2 ml, 62.5 mmol) at RT. The reaction mixture was degassed and nitrogen gas was purged for 15 min. Tetrakis(triphenylphosphine)palladium (1.44 g, 1.25 mmol) was added to the reaction mixture and the reaction vessel was sealed and heated at 110 °C for 16 h. The reaction mixture was concentrated under low pressure. The crude residue was purified by silica gel column chromatography using EtOAc in hexanes (0-10%), giving 4-(prop-1-en-2-yl)-2-(6-azaspiro[2.5]octan Benzyl-6yl)benzoate (8.0 g, 89% yield) as a yellow oil. 1H NMR (400 MHz, Chloroform-d): δ 7.72 (d, J = 8.12 Hz, 1H), 7.47 (d, J = 7.24 Hz, 2H), 7.31 - 7.42 (m, 3H), 7.13 (s, 1H ), 7.04 (d, J =8.12 Hz, 1H), 5.40 (s, 1H), 5.36 (s, 2H), 5.14 (s, 1H), 3.03-3.13 (m, 4H), 2.14 (s, 3H) , 1.44- 1.51 (m, 4H), 0.31 (s, 4H). m / z (ESI): 362.2 [M+1], Step 2: to a solution of 4-(prop-1-en-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (8.0 g, 22.13 mmol) in acetone (80 ml) and water (40 ml), 4-methylmorpholine- / \ / -oxide (5.19 ml, 44.3 mmol) and osmium tetroxide (4% by weight in H2O, 3.47 ml, 11.07 mmol) were added to RT, and stirred for 3 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine solution (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, giving 4-(1,2dihydroxypropan-2-¡l)-2-(6-azaesp¡ Benzyl ro[2,5]octan-6-yl)benzoate (9.0 g, crude) as a viscous oil. The crude product was further used without any purification, m / z (ESI): 396.2 [M+1], Step 3: to a stirred solution of 4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2,5]octan6-yl)benzoate (9.0 g, 22.70 mmol) in THF (90 ml), 2,2-dimethoxypropane (8.34 ml, 68.1 mmol) and p-toluenesulfonic acid monohydrate (0.864 g, 4.54 mmol) were added under a nitrogen atmosphere and the reaction mixture was heated at 60 °C for 5 h . The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine solution (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure, giving 2-(6-azaspiro[2.5]octan-6-yl)-4- (2,2,4trimethyl-1,3-dioxolan-4-íl)benzoate (7.0 g, crude) as a viscous yellow oil. The crude product was further used without any purification, m / z (ESI): 436.2 [M+1]. Step 4: to a stirred solution of benzyl 2-(6-azaspiro[2,5]octan-6-yl)-4-(2,2,4-trimethyl-1,3dioxolan-4-yl)benzoate (7.0 g, 16.03 mmol) in EtOH, ammonium formate (2.02 g, 32.1 mmol) and Pd-C (10%, 5.12 g, 4.81 mmol) were added under N2 atmosphere and heated at 60 °C for 30 min. The reaction mixture was cooled to RT, filtered through a pad of CELITE® and washed with EtOAc (100 ml). The filtrate was concentrated under reduced pressure. Caz ίηη / ζζηζ / Ε / γίΛΐ was extracted 114 the crude residue with EtOAc (200 ml), and washed with water (100 ml) and brine solution (100 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3- dioxolan-4-yl)nicotine (5.0 g, crude) as an off-white solid. The crude product was further used without any purification. Ή NMR (400 MHz, DMSO-c / 6): <5 8.00 (d, J = 8.22 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J = 1.27, 8.12 Hz, 1H), 4.11 -4.17 (m, 1H), 4.04-4.09 (m, 1H), 3.10 (t, J = 5.38 Hz, 4H), 1.59 (s a, 4H), 1.52 (s, 3H), 1.45 (s, 3H), 1.31 (s, 3H), 0.44 (s, 4H). Step 5: to a solution of 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3dioxolan-4-yl)nicotinic acid (2.0 g, 5.77 mmol) in DMF (20 ml), 3-amino-A / -(tert-butyl)benzenesulfonamide (1.32 g, 5.77 mmol), HATU (2.195 g, 5.77 mmol) and DIPEA (1.01 ml, 5.77 mmol) were added. at rt and stirred for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether (50 ml), filtered and dried in vacuo, giving N(3-(A / -(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan- 6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4¡l)nicotinamide (2.0 g, 62% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d): <512.94 (s, 1H), 8.31 (s, 1H), 8.27 (s a, 1H), 8.01 (d, J =8.22 Hz, 1H), 7.64 (d, J = 7.82 Hz, 1H), 7.46 - 7.55 (m, 2H), 7.23 (d, J = 8.22 Hz, 1H), 4.54 (d, J = 8.61 Hz, 1H), 4.08-4.17 (m, 1H), 3.04 - 3.18 (m, 4H), 1.66 (s, 3H), 1.67 - 1.59 (m, 4H), 1.57 (s, 3H), 1.43 (s, 3H), 1.29 (s, 9H), 0.45 (s, 4H) ). m / z (ESI): 556.2 [M+1]. Step 6: to a stirred solution of A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-2-(6azaspiro[2.5]octan-6-¡l)-6-(2,2, 4-trimethyl-1,3-dioxolan-4-yl)nicotinamide (2.1 g, 3.78 mmol) in dioxane (21 ml), hydrochloric acid (2 N, 8.89 ml, 37.8 mmol) was added ), and stirred at RT for 5 h. The reaction mixture was quenched with a satd aqueous solution. of NaHCOa (50 ml) and extracted with EtOAc (2 x 100 ml). The organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was triturated with diethyl ether, yielding a solid. The solid was filtered and dried, giving N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-¡l)-2-(6-azaspiro[2.5]octan -6-yl)benzamide (1.4 g, 72% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-de): δ 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.51 - 7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J =8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J =5.77 Hz, 1H), 3.44 (d , J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H). m / z (ESI): 516.2 [M+1], The racemic mixture was separated by preparative SFC using a Chiralpak IC (250 x 30 mm, 5 pm) with a mobile phase of 60% liquid CO2 and 40% MeOH , and a flow rate of 100 ml / min to generate: caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi 115 Example 108-1: (R)-A / -(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-iI)-2-(6azaspiro[2.5] octan-6-l)benzamide. First elution maximum, 100% ee; 1H NMR (400 MHz, DMSO-c / 6): or 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H ), 7.51 -7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J = 8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J = 5.77 Hz, 1H), 3.44 (d, J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H) . m / z (ESI): 516.2 [M+1]. Example 108-2: (S)-A / -(3-(A / -(te / 'c-butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxy¡propan-2-yl)- 2-(6azaspiro[2.5]octan-6-yl)benzamide. Second elution maximum, ee of 100%; 1H NMR (400 MHz, DMSO-de): <5 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H) , 7.51 -7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J = 8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J = 5.77 Hz, 1H), 3.44 ( d, J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H). m / z (ESI): m / z: 516.2 [M+1], Stereochemistry assignments were arbitrary. Example 109: A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-imidazol-2-yl)-2-(6azaspiro[2.51octane-6-¡ l)benzamide. To a round flask, 4-bromo-A / -(3-(A / -(tert-butyl)sulfamo¡l)phen¡l)-2-(6azaspiro[2.5]octan-6-yl)benzamide was added. 94 mg, 0.181 mmol, Intermediate 19-1), tetrakis(triphenylphosphine)palladium, linked polymer (0.06 mmol / g) (300 mg, 0.260 mmol, SigmaAldrich), 1-methyl-2 -(tr¡butylstanil)¡m¡dazole (0.087 ml, 0.271 mmol, Alfa Aesar) and dioxane (2 ml). The solution was stirred at 90 °C for 48 h. The reaction was allowed to cool to RT and filtered through a short pad of CELITE®. The residue was washed with EtOAc (2x10 ml). The filtrate was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® preloaded silica gel column eluting with 0-100% EtOAc in heptane, yielding the title compound (6 mg, 0.012 mmol, 7% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.82 (s, 1 H), 8.31 - 8.38 (m, 2 H), 8.01 (d, J = 7.7 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.39 (s, 1 H), 7.34 (dd, J = 8.1, 1.3 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 4.57 (s, 1 H), 3.75 (s, 3 H), 3.14 (t, J = 5.3 Hz, 4 H), 1.58 - 1.64 (m, 4 H), 1.30 (s, 9 H), 0.46 (s, 4 H). m / z (ESI): 522.2 (M+H)+. 116 Table 13: Examples 109-1 to 109-3 were prepared analogously to the preparation Lnn / zznz / E / YiAi from Example 109: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 109-1 V 4 ¿o H UU V N-(3-(N-(tertbutyl)sulfamoyl)phenyl)4-(1 -methyl -1 H-pyrazol5-yl)-2-(6azaspiro[2.5]octan6-yl)benzamide 522.2 109-2 n ° 1 N \ N-(3-(N-(tertbutyl)sulfamoyl)phenyl)4-(1 - methyl-1 H-pyrazol4-¡l)-2-(6azaspiro[2.5]octan6-yl)benzamide 522.2 109-3 \=z ZI M.. ω; ° N-(3-(N-(tertbutyl)sulfamoyl)phenyl)4-(oxazol-2-¡ I )-2-(6azaspiro[2.5]octan6-¡l)benzamide 509.1 Example 110: / V-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)2-(6-azaspiro[ 2.5]octan-6-íl)benzamide. Step 1: To an MFR, 2,2'-bis(diphenylphosphino)-1,1-binaphthyl (10 mg, 0.015 mmol, Sigma-Aldrich), tris(dibenzylideneacetone)dipalladium (8.7 mg, 9.50 pmol, Strem 117 Chemicals, Inc.) and toluene (1 mi). The solution was stirred for 5 min. The reaction was then treated with 4-bromo-A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide. (103 mg, 0.198 mmol, Compound 19-1), 1-((tert-buildimethylsilyl)oxy)-2-methylpropan2-amine (59 mg, 0.290 mmol), and sodium fert-butoxide (63 mg, 0.656 mmol, Sigma -Aldrich). The solution was stirred at 90 °C for 16 h. The reaction was allowed to cool to RT and diluted with water (20 ml) and EtOAc (10 ml). The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® prepacked silica gel column, eluting with 0-75% EtOAc in heptane, providing (38 mg, 0.059 mmol, 30% yield), in the form of a gold film, m / z (ESI): 643.2 (M+H)+. Stage 2: to a solution of A / -(3-(A / -(tert-butyl)sulfamoyl)pheníl)-4-((1 -((tert-butyldimethyl)lsil)ox¡) -2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (38 mg, 0.041 mmol) in THF (1 mi) At 0 °C, tetrabutylammonium fluoride was added (1 M in THF, 0.124 ml, 0.124 mmol, Sigma-Aldrich). The solution was stirred in the cooling bath as it expired. After 20 h, the reaction was concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a REDI-SEP® prepacked silica gel column eluting with 0-70% EtOAc in heptane, providing the title compound (18 mg, 0.034 mmol, 82% yield), as an off-white solid. 1H NMR (400 MHz, chloroform-Oí) or ppm 12.92 (s, 1 h), 8.31 (s, 1 h), 7.98 (d, j = 8.6 Hz, 1 h), 7.68 (d a, j = 8.0 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 6.67 (dd, J = 8.6, 2.2 Hz, 1 H), 6.57 (d, J = 2.2 Hz, 1 H), 5.29 (s, 1 H), 3.77 (s, 2 H), 2.89 (t a, J = 4.9 Hz, 4 H), 1.39 - 1.45 (m, 6 H), 1.16 - 1.35 (m, 13 H), 0.38 (s, 4 H). [Note: protons are not observed for OH and 1 NH], m / z (ESI): 529.1 (M+H)+. caz ίηη / ζζηζ / Ε / γίΛΐ Table 14: Example 110-1 was prepared analogously to the preparation of Example 110: Ex. No. Chemical structure LRMS name: (ESI, positive ¡on) m / z 110-1 V u h%l 0 z ° ° H H N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-4- ((2hydroxyethyl)amino)-2-(6azaspiro[2.5]octan-6yljbenzamide 501.1 118 Example 111: / VM3-( / V-(tert-butyl)sulfamo¡l)phenyl)- / \ / 4-(2-hydroxyethyl)-2-(6azaspiro[2.51octan-6-¡l)terephthalamide. LiOH H2N-^oh DMTMM DMF Stage 2 MeOH, THF.ta, 16 h Stage 1 of Hn^oh Stage 1: to a solution Methyl 4-((3-(A / -(tert-butyl)sulfamoyl)phen¡l)carbamoyl)-3-(6caz ίηη / ζζηζ / Ε / γίΛΐ azaspiro[2.5]octan-6-yl)benzoate (197 mg, 0.394 mmol, Intermediate 19-2) and THF: MeOH (3:2, 8 ml), LiOH (2 ml, 2 mmol, 1 M) was added. The solution was stirred at RT for 16 h. The reaction was concentrated in vacuo to remove organic solvents. The aqueous solution was acidified with 2 N HCl and extracted with EtOAc (3x10 ml). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo, providing the crude title compound (200 mg, 0.412 mmol), as a white solid which was further used, m / z (ESI): 486.0 ( M+H)+. Step 2: to a solution of 4-((3-(A / -(tert-butyl)sulfamo¡l)phenyl)carbamo¡l)-3-(6azaspiro[2.5]octan-6-yl)benzoic acid (60 mg, 0.124 mmol) and DMF (2 ml), 4(4,6-dimethoxy¡-1,3,5-tr¡azin-2-¡l)-4-methylmorpholine-4 chloride was added -io (51.3 mg, 0.185 mmol, Sigma-Aldrich). The solution was stirred at RT for 30 min, then ethanolamine (17 pl, 0.283 mmol, SigmaAldrich) was added and stirred at RT for 2 h. The reaction was diluted with water (25 ml) and stirred for 30 min. The aqueous solution was extracted with EtOAc (3x10 ml). The combined EtOAc extracts were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® prepacked silica gel column eluting with 0-75% EtOAc:EtOH (3: 1) in heptane, providing the title compound (52 mg, 0.1 mmol, 80% yield), as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 11.58 (s, 1 H), 8.62 (t, J = 5.6 Hz, 1 H), 8.35 (s, 1 H), 7.92 (d a, J = 7.2 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.75 (s, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.54 - 7.62 (m, 3 H), 4.75 ( s a, 1 H), 3.53 (c, J = 5.6 Hz, 2 H), 3.34 - 3.39 (m, 2 H), 3.05 (t a, J = 4.9 Hz, 4 H), 1.47 (s a, 4 H), 1.12 (s, 9 H), 0.32 (s, 4 H). m / z (ESI): 529.1 (M+H)+. 119 Table 15: Examples 111-1 to 111-4 were prepared analogously to the preparation Lnn / zznz / E / YiAi from Example 111: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 111-1 0 N1-(3-(N-(tertbutyl)sulfamoyl)phenyl)A / 4-methyl-2-(6azaspiro[2.5 ]octan6-yl)terephthalamide 499.1 111-2 V 0 Nñ(3-(N-(tertbutyl)sulfamoyl)phenyl)A / 4-(2-hydroxyethyl)-A / 4methyl-2-(6azaspiro[2.5]octan6 -yl)terephthalamide 543.2 111-3 + ·δ or 4 ' N1-(3-(N-(tertbutyl)sulfamoyl)phenyl)Λ / 4-(1 -hydroxy-2methylpropan-2-yl)-2-(6azaspiro[ 2.5]octan6-¡l)terephthalamide 557.2 111-4,,. δ / । |Ί 0 N -ν - „ O Nd(3(cyclopentylsulfonyl)phen ¡l)-N4-(2-hydroxy¡ethyl)-2(6azaspiro[2.5]octan6-¡l)terephthalamide 526.1 Examples 112-1 and 112-2: (R)-A / -(3-(azetidin-1-sulfonimidoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane -6-yl)benzamide and (S)-A / -(3-(azetidin-1sulfonimidoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.51octan-6- l)benzamide. 120 TBAF, THF. 0 °C to rt, 3 h Stage 2 caz ίηη / ζζηζ / Ε / γίΛΐ Step 1: a solution of 4-bromo-A / -(3-(A / -(tert-but¡ldimet¡ls¡l¡l)azetidin-1sulfonimido¡l)phen¡l)-2- was treated. (6-azaspiro[2.5]octan-6-l)benzamide (0.2 g, 0.32 mmol, Intermediate 26) in DMF (3 ml) with methyl 2-sulfamoylacetate (0.074 g, 0.486 mmol), phosphate tribasic potassium (0.137 g, 0.65 mmol), copper (I) iodide (0.062 g, 0.324 mmol) followed by (1R,2R)-A / ,A / '-dimethyl-1,2-cyclohexanediamine (0.023 g, 0.162 mmol) and the resulting mixture was heated at 90 °C for 16 h. The reaction was quenched with cold water and filtered through a short pad of CELITE®, washed with EtOAc. The filtrate was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure, obtaining the crude product. The crude product was purified by silica gel column chromatography using a gradient of 0-35% EtOAc in petroleum ether, yielding 2-(N-(4-((3-(N-(tertbut¡ld¡methylsilyl methyl)azetidin-1-sulfonimidol)phenyl)carbamol)-3-(6-azaspiro[2.5]octan-6¡l)phenyl)sulfamoyl)acetate (0.18 g, 0.26 mmol, 81% yield) in the form of a pale yellow gum. 1H NMR (400 MHz, DMSO-cfe): δ ppm 11.66 (s, 1 H), 10.53 (s, 1 H), 8.10- 8.17 (m, 2 H), 7.78 (d,J = 8.4 Hz, 1 H ), 7.63 (t,J = 7.9 Hz, 1 H), 7.46 (d, J = 7.7 Hz, 1 H), 7.13 (d, J = 2.2 Hz, 1 H), 7.01 (dd, J = 8.5, 2.0 Hz, 1 H), 4.32 (s, 2 H), 3.64 (s, 3 H), 3.53 (dt, J = 22.3, 7.6 Hz, 4 H), 2.98 (t, J = 5.3 Hz, 4 H), 1.85 - 1.87 (m, 2 H), 1.48 (s, 4 H), 0.88 (s, 9 H), 0.30 (s, 4 H), 0.08 (s, 3 H), 0.06 (s, 3 H). m / z (ESI): 690.2 (M+H)+. Step 2: to a solution of 2-(A / -(4-((3-(A / -(ferc-butyldimethylsilyl)azetidin-1 sulfonimido¡l)phen¡l)carbamo¡l)-3-(6- Methyl azaspiro[2.5]octan-6-l)phenyl)sulfamoyl)acetate (0.18 g, 0.261 mmol) in THF (4 ml), tetrabutylammonium fluoride (1.0 M in THF, 0.391 ml) was added. 0.391 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with ammonium chloride solution and extracted with EtOAc (2 times). The combined EtOAc layers were washed with water and brine, dried over anhydrous Na2SÜ4, and concentrated to provide 2-(A / -(4((3-(azetidin-1-sulfonamidoyl)phen). Methyl l)carbamol)-3-(6-azaspiro[2.5]octan-6¡l)phenyl)sulfamoyl)acetate (0.13 g, 0.23 mmol, 87% yield) as a 121 whitish solid. 1H NMR (400 MHz, DMSO-cfe): δ ppm 11.68 (s, 1 H), 10.52 (s, 1 H), 8.29 (s, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.79 (dd, J = 8.5, 2.7 Hz, 1 H), 7.64 (td, J = 7.9, 2.6 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 6.99 - 7.05 (m, 1 H), 4.34 (d, J = 2.6 Hz, 2 H), 4.26 (d, J = 2.6 Hz, 1 H), 3.64 (d, J = 2.6 Hz , 3 H) 3.57 (t, J = 7.5 Hz, 4 H), 2.98 (d, J = 6.2 Hz, 4 H), 1.81-1.92 (m, 2 H), 1.49 (s, 4 H), 0.31 ( d, J = 2.6 Hz, 4 H). m / z (ESI): 576.2 (M+H)+. Step 3: to a solution of 2-(A / -(4-((3-(azetidine-1-sulfonimidoyl)phenyl)carbamoyl)-3-(6azaspiro[2.5]octan-6 Methyl -yl)phenyl)sulfamoyl)acetate (0.13 g, 0.226 mmol) in THF (2 ml), lithium borohydride (2.0 M in THF, 0.226 ml, 0.452 mmol) was added dropwise at 0 °C and stirred at rt for 3 h. The reaction mixture was quenched with a satd solution. of NH4Cl and extracted with EtOAc. The EtOAc layer was washed with water and brine, dried over anhydrous Na2SÜ4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC, yielding A / -(3-(azetidine-1-sulfonamidoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido) -2-(6azaspiro[2.5]octan-6-yl)benzamide (0.1 g, 0.18 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) δ ppm 11.69 (s, 1 H), 10.11 (s, 1 H), 8.30 (t, J = 1.9 Hz, 1 H), 8.13-8.05 (m, 1 H) , 7.79 (d, J = 8.4 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 7.15 (d, J= 2.1 Hz, 1 H), 7.02 (dd, J = 8.4, 2.1 Hz, 1 H), 4.98 (s, 1 H), 4.27 (s, 1 H), 3.77 (t, J = 6.5 Hz, 2 H), 3.62 - 3.54 (m, 4 H), 3.35 (s, 1 H), 3.32 (s, 1 H), 2.99 (t, J = 5.0 Hz, 4 H), 1.86 - 1.88 (m, 2 H), 1.49 (d, J = 5.7 Hz, 4 H), 0.31 (s, 4 H). m / z (ESI): 548.1 (M+H)+. The racemic compound was subjected to chiral separation by SFC [Column: Chiralpak IC (250 x 30 mm, 5 pm); mobile phase: 70:30 (A:B), A = liquid CO2, B = methanol, flow rate: 120 ml / min, providing the following compounds of Examples 112-1 and 112-2: Example 112-1: (R)- / V-(3-(azetidine-1-sulfonimidoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2(6- azaspiro[2.5]octan-6-yl)benzamide. First elution maximum; 1H NMR (400 MHz, DMSO-cfe) δ ppm 11.83 (s, 1 H), 8.29 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.82 - 7.75 (m, 1 H) , 7.64 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.11 (s, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 4.31 4.23 (m, 1 H), 3.80 - 3.70 (m, 2 H), 3.58 (t, J = 1J Hz, 4 H), 3.31 - 3.27 (m, 2 H), 2.99 (d, J = 5.3 Hz, 4 H), 1.86 - 1.88 (m, 2 H), 1.51 (d, J = 5.4 Hz, 4 H), 0.32 (s, 4 H). m / z (ESI): 548.1 (M+H)+. Example 112-2: (S)- / V-(3-(azet¡din-1-sulfon¡m¡do¡l)phen¡l)-4-((2-hydroxy¡ethyl) )sulfonamido)-2(6-azaspiro[2.5]octan-6-íl)benzamide. Second elution maximum; 1H NMR (400 MHz, DMSO-cfe) δ ppm 11.86 (s, 1 H), 8.30 (s, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H), 7.64 (t, J = 7.9 Hz, 1 H), 7.55 (d, J = 7.7 Hz, 1 H), 7.10 (s, 1 H), 6.98 (d, J = 8.7 Hz, 1 H) , 4.26 (s, 1 H), 3.76 (t, J = 6.6 Hz, 2 H), 3.58 (t, J = 7.9 Hz, 4 H), 3.28 (t, J = 6.5 Hz, 2 H), 2.98 ( t, J = 5.1 Hz, 4 H), 1.86 - 1.88 (m, 2 H), 1.51 (s, 4 H), 0.32 (s, 4 H). m / z (ESI): 548.1 (M+H)+. CAZ Lnn / Zznz / E / YIAI 122 Table 16: Examples 113-1 to 113-2 and 114-1 to 114-2 were prepared analogously to the preparation of Examples 112-1 and 112-2: caz ίηη / ζζηζ / Ε / γίΛΐ Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 113-1 o. % H ° (R)-4-((2hydroxy¡ethyl)sulfonamido)N-(3-(Smethylsulfonim¡dol)phen¡l)2-(6azaspiro[2.5]octan-6yljbenzamide 507.1 113-2 > l0T (S)-4-((2hydroxyethyl)sulfonamido)N-(3-(Smethylsulfonimido¡l)phenyl)2-(6azaspiro[2.5]octan-6yljbenzamide 507.1 114-1 vo3 hn'% ° s^OH H ° (R)-4-((2hydroxyethyl)sulfonamido)A / -(3-(2-methylpropan-2ylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 549.2 114-2 V HN% h ¡or %^oh (S)-4-((2hydroxyethyl)sulfonamido)A / -(3-(2-methylpropan-2ylsulfonimidoyl)phenyl)-2-(6azaspiro[2.5]octan-6yljbenzamide 549.2 123 Example 115: A / -(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.51octan-6-yl)phenyl)-3 Lnn / zznz / E / YiAi (piperidin-1 -Dbenzamide. T3P, Et3N Stage 1 Cul, K3PO4 Stage 2 Step 1: to a solution of 3-plperidinbenzoic acid (0.40 g, 1.95 mmol, Matrix Innovation Inc.), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)anilíne (0.50 g, 1.78 mmol, Intermediate 18) and Et3N (0.49 ml, 3.56 mmol) in DCM (10 ml) at 0 °C, T3P (50 wt% in EtOAc) (1.58 ml, 2.67 mmol) was added. The mixture was stirred at RT for 3 h, then diluted with 50 ml of DCM, and washed with 5 ml of water and then with 5 ml of 1 N NaOH. The organic layer was concentrated in vacuo and adsorbed onto a silica gel plug and chromatographed through a Redi-Sep® prepacked silica gel column, eluting with 10-35% EtOAc in heptane, yielding A / -(4-bromo-2-(6- azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1yl)benzamide (0.77 g, 1.64 mmol, 92% yield) as a brown amorphous solid, m / z (ESI): 468.1 / 470.1(M+H)+. Ή NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.15 (d, J = 8.71 Hz, 1H), 7.27-7.46 (m, 5H), 7.17 (dd, J = 1.97, 8.19 Hz , 1H), 3.22-3.28 (m, 4H), 2.88 (t, J = 5.29 Hz, 4H), 1.47-1.67 (m, 10H), 0.35 (s, 4H). Step 2: A mixture of 2-hydroxyethane-1-sulfonamide (90 mg, 0.72 mmol, Enamine), potassium phosphate (381 mg, 1.79 mmol), dimethylglycine (37 mg, 0.36 mmol, Oakwood), copper iodide was degassed. (I) (34 mg, 0.17 mmol, Strem) in 3 ml of DMF in a glass tube for 3 min. The mixture was heated at 50 °C for 5 min under argon and then treated with N-(4bromo-2-(6-azaspiro[2.5]octan-6-¡l)phenyl)-3-(p¡ perídin-1-íl)benzamide (168 mg, 0.36 mmol). The glass tube was sealed and then heated at 100 °C for 24 h. The mixture was cooled to RT and then partitioned between 5 ml of water and 50 ml of EtOAc. The layers were separated. The organic layer was washed with 3 ml of brine and concentrated. The residue was purified on a gel column. 124 silica (15-90% EtOAc in heptane), giving A / -(4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-¡l)phen¡l)-3- (piperidn-1-l)benzamide (151 mg, 0.29 mmol, 82% yield) as an off-white solid, m / z (ESI): 513.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.06 (d, J = 8.71 Hz, 1H), 7.35-7.46 (m, 2H), 7.27-7.31 (m, 1H), 7.15 ( d, J = 7.65 Hz, 1H), 7.10-7.13 (m, 1H), 6.96 (d, J = 8.91 Hz, 1H), 6.73 (s, 1H), 4.88 (t, J = 5.70 Hz, 1H), 3.12-3.28 (m, 8H), 2.85 (m, 4H), 1.43-1.71 (m, 10H), 0.35 (s, 4H). BIOLOGICAL EXAMPLES In the study of the illustrative compounds of the invention, the following tests were used. Data for these examples tested according to the procedures described below are presented in Table A below. KIF18A enzyme assay: Microtubule-stimulated ATPase activity was used to measure KIF18A enzyme activity after treatment with the compound. The compounds were diluted with a dilution factor of 2 serially in DMSO (Sigma Inc) in a concentration range of 22 points. Recombinant human KIF18A protein (His-tagged at 1-467) was expressed using a baculovirus system and purified by affinity chromatography by Amgen Inc. The concentrations of KIF18A protein, microtubules (MT), and ATP in the reaction were optimized for standardized homogeneous enzyme assay using the ADP-Glo™ Kinase / ATPase Assay Kit (Promega Inc.). The assay measures the ADP formed from the ATPase reaction. Prepare the reaction buffer [(15 mM Tris, pH 7.5 (Teknova Inc), 10 mM MgCl (JT Baker Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 μΜ Taxol (Cytoskeleton Inc) and 30 pg / ml pig microtubules (Cytoskeleton Inc).] The compound and KIF18A protein (30 nM) are added to the prepared reaction buffer and incubated for 15 minutes at RT, then ATO is added (at a Km , 75 pM) to the reaction mixture and incubate for a further 15 minutes at RT. 5 pl of ADP-Glo™ reagent and 2.5 pl of the reaction mixture are mixed and incubated for 40 minutes at RT. 10 pl are added of ADP-Glo™ Detection Reagent and incubated for 40 minutes at RT. Luminescence is read using an EnVision microplate reader with an ultraluminescence module (Perkin Elmer Inc). IC50 determination and adjustment of the concentration response curve using Genedata Screener software (Standard 15.0.1, Genedata Inc) with a four-parameter logistic regression fitting model. Table A provides data for the illustrative compounds of the present application and the priority document thereof, as representative compounds of the present invention, as follows: chemical name (named according to ACD software or ChemDraw (Professional 15.0)) and biological data (IC50 in pm). Example # refers to Example # caz ίηη / ζζηζ / Ε / γίΛΐ 125 caz ίηη / ζζηζ / Ε / γίΛΐ TABLE A: BIOLOGICAL DATA Ex. No. Compound name KIF18A ATPase IC50 (pM) 100 A / -(3-(M-(tert-butyl)sulfamo¡l)phen¡l)-4-((3-methyloxetan-3yl) sulfonyl)-2-(6-azaspiro[2.5]octan-6-¡l)benzamide 0.173 100-1 A / -(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(methylsulfon¡ l)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.061 100-2 A / -(3-isopropylphenyl)-4-(methylsulfonyl)-2-(6azaspirof2.5]octan-6-yl) benzamide 0.094 100-3 A / -(3-cyclopropylphenyl)-4-(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.187 100-4 N-(3-(tert-butyl) phenyl)-4-(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.362 100-5 4-(methylsulfonyl)-A / -(quinolin-8-yl)- 2-(6azaspiro[2.5]octan-6-yl)benzamide 0.246 100-6 A / -(4-methylquinol¡n-8-¡l)-4-(methylsulfon¡l)-2-(6azaspiror2.5 ]octan-6-yl)benzamide 0.061 100-7 A / -(chroman-8-yl)-4-(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.045 100-8 / V- (benzofuran-7-yl)-4-(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.200 100-9 A / -(benzo[b]thiophen-7-yl)-4 -(methylsulfonyl)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.630 10DIO 100- 11 4-(methylsulfonyl)-A / -(3-morpholinophenyl)-2-(6azaspiro[2.5]octan- 6-yl)benzamide A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-((methylsulfonyl)methyl)2-(6-azaspiro[2.5]octan-6-yl)benzamide 0.862 0.051 100- 12 A / -(3-(A / -(tert-butyl)sulfamo¡l)phenyl)-4-(((2hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6yl )benzamide 0.075 100- 13 4-(A / -(tert-butyl)sulfamoyl)-N-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5] octan-6yl)benzamide 0.076 100- 14 M-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-(3-methyloxetan-3-yl)- 2-(6-azaspiro[2.5]octan -6-yl)benzamide 0.130 100- 15 W-(3-(N-(tert-butyl)sulfamo¡l)phenyl)-4-(3-hydroxy¡oxetan-3yl)-2-(6-azaspiro[2.5 ]octan-6-yl)benzamide 0.088 101 A / -(3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(A / -(3methyloxetan-3-yl) sulfamoyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.198 101-1 A / -(2-fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl )4-( / V-(3-methyloxetan-3-yl)sulfamoyl )-2-(6azaspirof2.5]octan-6-yl)benzamide 0.066 101-2 A / -(2-fluoro-3-((1 -hydroxy-2-methylpropan-2-yl)amino)phenyl)4-((1-methylcyclopropane)-1-sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.298 126 Ex. No. Compound name KIF18A ATPase IC50(pM) 101-3 W-(3-((1-hydroxy-2-methylpropan-2-¡l)amino)phen¡l)-4-(( 1methylcyclopropane)-1-sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.115 102 A / -(3-(A / -(tert-Butyl)sulfamoyl)phenyl)-4-((1 methylcyclopropane )-1-sulfonamido)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.061 102-1 N-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-(methylsulfonamido)- 2(6-azaspiro[2.5]octan-6-yl)benzamide 0.027 102-2 W-(3-(N-(tert-butyl)sulfamo¡l)phen¡l)-4-(ethylsulfonamido)-2 (6-azaspiro[2.5]octan-6-yl)benzamide 0.034 102-3 W-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-((1methylethyl)sulfonamido)-2-(6 -azaspiro[2.5]octan-6yl)benzamide 0.026 102-4 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4(cyclopropanesulfonamido)-2-(6-azaspiro[2.5]octan- 6yl)benzamide 0.030 102-5 W-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-((1,1dimethylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl) benzamide 0.063 102-6 W-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(1,1diox¡doisot¡azolidín-2-¡l)-2-(6-azaspiro[ 2.5]octan-6yl)benzamide 0.045 103 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl )benzamide 0.051 103-1 (R)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(2methylmorpholino)phenyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.071 103-2 (R)-A / -(2-fluoro-3-(2-methylmorpholino)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.101 103-2 (R)- / V-(3-fluoro-5-(2-methylmorpholino)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan- 6yl)benzamide 0.131 103-4 (R)- / V-(4-fluoro-3-(2-methylmoriolino)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane -6yl)benzamide 0.177 104 / V-(3-(4,4-difluoropiperidin-1 -yl)-5-methylphenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl )benzamide 0.034 104-1 104-2 A / -(3-(4,4-difluorop¡peridin-1 -yl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5 ]octan-6yl)benzamide A / -(3-(4,4-difluoropiperidin-1 -yl)-2-fluorophenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl )benzamide 0.012 0.029 105-1 (S)-M-(3-( / V-(fert-butyl)sulfamo¡l)phen¡l)-4-((2-hydroxy¡-1 methylethyl)sulfonamido) -2-(6-azaspiro[2.5]octan-6yl)benzamide 0.042 caz Lnn / zznz / Ε / γΐΛΐ 127 Ex. η 0 Compound name KIF18A ATPase IC50 (μΜ) 105-2 (R)-A / -(3-(A / -(erc-butyl)sulfamoyl)pheníl)-4-((2-hydroxy- 1 methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.057 106 A / -(3-(2-Hydroxy-2-methylpropoxy)phenyl)-4-((2hldroxyethyl)sulfonamido) -2-(6-azaspiro[2.5]octan-6yl)benzamide 0.078 107 4-(Azetidin-1 -ylsulfonyl)- / \ / -(3-(A / -(iert-butyl)sulfamoyl)phenyl)- 2- (6-azaspiro[2.5]octan-6-yl)benzamide 0.044 107-1 A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-4-( / V-(1 -hydroxy-2methylpropan -2-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.060 107-2 A / -(3-(A / -(ferc-butll)sulfamoyl)phenyl)-4-( / \ / -(2hydroxy¡ethyl)sulfamo¡l)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.043 107-3 N-(3-( / V-(tert-butyl)sulfamoyl )phenyl)-4-(A / ,A / dimethylsulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 0.070 107-4 N-(3-(M-(tert-butyl) sulfamoyl)phenyl)-4-( / \ / -methylsulfamo¡l)-2(6-azaspiro[2.5loctan-6-yl)benzamide 0.029 107-5 N-(3-( / V-(ferc-but ¡l)sulfamo¡l)phen¡l)-4-( / V-(oxetan-3yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 0.060 107-6 / V -(3-( / V-(tert-but¡l)sulfamo¡l)phenyl)-4-( / \ / cycloprop¡lsulfamoyl)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.036 107-7 A / -(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(A / -(1 methylcyclopropyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6yl )benzamide 0.052 107-8 A / -(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6azaspiro[2.5]octan-6-l)-4-sulfamoylbenzamide 0.040 108- 1 (R)-A / -(3-(N-(fert-but¡l)sulfamo¡l)phenyl)-4-(1,2dihydroxypropan-2-¡l)-2-(6-azaspiro[ 2.5]octan-6yl)benzamide 0.092 108-2 (S)- / V-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(1,2dihydroxypropan-2-yl)-2 -(6-azaspiro[2.5]octan-6yl)benzamide 0.141 109 N-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-imidazol2-yl)-2- (6-azaspiro[2.5]octan-6-yl)benzamide 0.124 109-1 N-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazole-5yl) -2-(6-azaspiro[2.5]octan-6-¡l)benzamide 0.601 109-2 N-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-(1-methyl- 1H-pyrazol-4yl)-2-(6-azaspiro[2.5]octan-6-¡l)benzamide 1.09 109-3 A / -(3-(M-(tert-butyl)sulfamoyl)phen¡ l)-4-(oxazol-2-¡l)-2-(6azaspiro[2.5]octan-6-yl)benzamide 0.534 110 N-(3-(A / -(tert-Butyl)sulfamoyl)phenyl)-4 -((1-hydroxy-2methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.058 110-1 A / -(3-( / V-(tert-butyl)sulfamoyl )phenyl)-4-((2hydroxyethyl)amino)-2-(6-azaspiro[2.5]octan-6yl)benzamide 0.134 111 A / 1-(3-(A / -(erc-Butyl)sulfamoyl )phenyl)- / \ / 4-(2-hydroxyethyl)-2-(6azaspiro[2.5]octan-6-yl)terephthalamide 0.124 caz Lnn / zznz / Ε / γΐΛΐ 128 Ex. No. Compound name KIF18A ATPase IC50 (μΜ) 111-1 A / 7-(3-(A / -(fert-butyl)sulfamo¡l)phen¡l)-A / 4-methyl- 2-(6azaspiro[2.5]octan-6-yl)terephthalamide 0.132 111-2 / \ / 1-(3-( / V-(erc-but¡l)sulfamoyl)phenyl)- / \ / 4-(2- hydroxyethyl)- / \ / 4methyl-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide 0.201 111-3 A / 7-(3-(A / -(te / c-butyl)sulfamoyl)phenyl)-A / 4-(1-hydroxyl-2methylpropan-2-yl)-2-(6-azaspiro[2.5]octan-6ylterephthalamide 0.272 111-4 A / 7-(3-(cyclopentylsulfonyl)phenyl)-A / 4-(2-hydroxyethyl)-2-(6azaspiro[2.5]octan-6-yl)terephthalamide 0.139 112-1 (R)-A / -(3- (Azetidin-1-sulfonimidoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.142 112-2 (S)-A / -(3-( Azetidin-1-sulfonamidoyl)phenyl)-4-((2hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.160 113-1 (R)-4-((2- hydroxyethyl)sulfonamido)- / V-(3-(Smethylsulfonamido¡l)phenyl)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.429 113-2 (S)-4-( (2-hydroxyethyl)sulfonamido)-A / -(3-(Smethylsulfonamidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.488 114-1 (R)-4-(( 2-hydroxyethyl)sulfonamido)-A / -(3-(2-methylpropan-2ylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.194 114-2 ( S)-4-((2-hydroxyethyl)sulfonamido)-A / -(3-(2-methylpropan-2ylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]octan-6yljbenzamide 0.323 115 A / -(4-((2-hydroxyethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6-íl)pheníl)-3-(piperidin-1-yl)benzamide 0.026 caz ίηη / ζζηζ / Ε / γίΛΐ The above invention has been described in some detail by way of illustration and as an example, for the purposes of better understanding and clarity. One skilled in the art understands that certain changes and modifications may be implemented within the scope of the appended claims. Therefore, it will be understood that the foregoing description is intended to be illustrative and not restrictive. Therefore, the scope of the invention shall be determined not with reference to the foregoing description but, on the contrary, shall be determined with reference to the claims appended below, together with the full scope of the equivalents to which they are entitled. such claims. All patents, patent applications and publications cited herein are incorporated herein by reference in their entirety for all purposes and in the same manner as if each individual patent, patent application or publication were cited individually.

Claims

1. A compound of formula I: Lnn / zznz / E / YiAi or any pharmaceutically acceptable salt thereof, wherein: each of RXa, RXb, RXc, RXd, RXe, RXf, RXg, RXh, RXi, RXj, RXk and RXI is H, halo, RXm or RXn; or, alternatively, each of the pair RXa and RXb, pair RXc and RXd, pair RXe and RXf, pair RXg and RXb, pair RXi and RXj, and pair RXk and RXI, independently, can be combined with the carbon atom attached to each of them to form a saturated or partially saturated 3, 4, 5, 6-membered spiro monocyclic ring with the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepanyl ring; wherein said 3, 4, 5, 6-membered monocyclic ring contains 0 atoms of N, O and S, and further wherein said 3, 4, 5, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, Ci-e alkyl, C1-4 haloalkyl, ORa, -O-haloalkyl Cm, CN, -NRaRa or oxo; or even, alternatively, each of the pair RXa and RXb, pair RXc and RXd, pair RXo and RXf,Pairs RXg and RXh; pairs RXi and Rxi; and pairs RXk and RXI, independently, can combine to form a double bond; R1 is a group -Z-R12; where Z is absent, or is -alkyl Co-4-S-alkyl C0-4-, alkyl Cq. 4-S(=O)-alkyl Co-4-, - alkyl Co-4-S02-alkyl Co-4-, -alkyl Co-4-NR1'-alkyl C0-4-, -alkyl Co-4-NR11S02-alkyl Co-4, -alkyl Co-4-S02NR11-alkyl Co-4-, - alkyl Co4-NR11S02NR11-alkyl Co-4-, -alkyl Co4-0-alkyl Co-4-, -alkyl Co4-C(=0)-alkyl C0-4-, -alkyl Co-4-C(=0)-0-alkyl Co-4-, - alkyl Co-4-(C=0)NR11-alkyl C0-4-, -alkyl Co-4-NR11(C=0)-alkyl C0-4-, -alkyl C0-4S(=O)(=NH)-, -N=S(=O)<, -(C=O)-, o -C(=N-OH)-; R2 is a group -Y-R13, where Y is -alkyl Co-4-S-alkyl Co-4-, alkyl Co-4-S(=0)-alkyl C0-4-, -alkyl Co-4-S02-alkyl C0-4-, -alkyl Co-4-NR13c-alkyl C0-4-, -alkyl Co-4-S02NR13c-alkyl Co4-, -alkyl Co-4-NR13cSC2-alkyl Co-4-, -alkyl Co-4-S(=0)(=NH)-, -alkyl Co-4-O-alkyl C0-4-, -alkyl Co-4-C(=0)-alkyl C0-4-, -alkyl Co-4-C(=0)-0-alkyl Co-4-,- alkyl C0-4-(C=O)NR13c-alkyl Co-4-, -alkyl C0-4-NR13c(C=O)-alkyl Co-4- or -N=S(=O)<; R3 is H, halo, C1.4 alkyl or C1-4 haloalkyl; R4 is H, halo, C1-4 alkyl or C1-4 haloalkyl; R5 is H, halo, C1-8 alkyl or C1.4 haloalkyl; R6 is H, halo, C1-8 alkyl or C1.4 haloalkyl; R7 is H, halo, C1.4 alkyl or C14 haloalkyl; R8 is H, halo, C1-8 alkyl or C1.4 haloalkyl; or, alternatively, R2 and R8 can combine with the carbon atoms attached to each of them to form a saturated or partially saturated 5- or 6-membered monocyclic ring fused with the phenyl ring; wherein said 5- or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein said 5- or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 group(s) selected from F, Cl, Br, Ci-6 alkyl, Ci^ haloalkyl, -ORa, -O-C1-4 haloalkyl, CN, NRaRa, or oxo; R9 is H, halo,alquilo C1-4 o haloalquilo C1.4; L es -(C=O)-NR10- o -NR10-(C=O)-; R10 es HO alquilo C1-4; R11esHo alkyl C1-4; R12 es H, halo, OH, CN, R12a o R12b; R13es halo, R13a o R13b; R13c es HO alquilo C14; R12a and R13a are selected independently, in each case, from the group that consists of a monocyclic ring saturated, partially saturated or unsaturated of 3, 4, 5, 6 or 7 members, or a bicyclic ring of 8, 9, 10, 11 or 12 members that contains 0, 1,2 or 3 atoms of N and 0 or 1 atom selected between O and S, which is substituted with 0, 1,2 or 3 group(s) selected from the group that consists of F, Cl, Br, C1.6 alkyl, C1.4 haloalkilo, -ORa, -O-haloalkilo C1.4, CN, -C(=O)Rb, -C(=O)ORa, -C(=O)NRaRa, -C(=NRa)NRaRa, -OC(=O)Rb, -OC(=O)NRaRa, -O-alquil C2-6-NRaRa, -O-alquil C2-6-ORa, -SRa, -S(=O)Rb, -S(=O)2Rb, C2-6-NRaRa, NRa-alquil C2-6-ORa,-alkyl Ci-e-NRaRa, -alkyl Ci-6-ORa, -alkyl Ci-6-N(Ra)C(=O)Rb, -alkyl C1-6OC(=O)Rb, -alkyl Ci-6-C(=O)NRaRa, -alkyl Ci-6-C(=O)ORa, a saturated, partially saturated or unsaturated 3, 4, 5 or 6-membered monocyclic ring, and oxo; Ri2b and Ri3b are independently selected, in each case, from the group consisting of C1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 group(s) selected from the group consisting of F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl Ci^, CN, NH2, NH(CH3), N(CH3)2, and a saturated, partially saturated or unsaturated 3, 4, 5 or 6-membered monocyclic ring; Ra is independently, in each case, H or Rb; and Rb is independently, in each case, C1-6 alkyl, phenyl, or benzyl, wherein the C1-6 alkyl is being substituted with 0, 1, 2, or 3 substituents selected from halo, -OH, -O-C1-4 alkyl, -NH2, -NH-C1-4 alkyl, -OC(=O)Cu alkyl, or -N(C1-4 alkyl)C1-4 alkyl; and the phenyl or benzyl is being substituted with 0, 1,2 or 3 substituents selected from halo, Cm alkyl, Ci-3 haloalkyl, -OH, C1-4 -O alkyl, -NH2, C1.4 -NH alkyl, -OC(=O)C1.4 alkyl or -N(C1-4 alkyl)C1.4 alkyl. 132, 2. The compound of any one of the preceding claims, wherein Rx is selected from H, wherein each of RXa, RXb, RXc and RXd is H, halo, RXm or RXn; or, alternatively, each of the pair RXa and RXb, and the pair RXc and RXd, independently, can be combined with the carbon atom attached to each of them to form a saturated or partially saturated 3, 4, 5, or 6-membered spiro monocyclic ring with the pyrrolidinyl, piperidinyl or morpholinyl ring; wherein said 3, 4, 5, 6-membered monocyclic ring contains 0 atoms of N, O and S, and further wherein said 3, 4, 5, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C1-6 alkyl, C1-4 haloalkyl, -ORa, -O-C1.4 haloalkyl, CN, -NRaRa or oxo; or even, alternatively, each of the pair RXa and RXb or pair RXc and RXd independently, can combine to form a double bond.

3. The compound of any one of the preceding claims, wherein each of RXa, RXb, RXc and RXd is selected from a) H, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3 or cyclopropyl; b) alternatively, each of the pair RXa and RXb, and pair RXc and RXd, independently, may combine with the carbon atom attached to each of them to form a cyclopropyl ring, a cyclobutyl ring or a cyclopentyl ring, wherein each ring is spiro with the pyrrolidinyl, piperidinyl or morpholinyl ring; and wherein each of said rings is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, Ci-6 alkyl, Cm haloalkyl or methoxy; oc) Alternatively, each of the pair RXa and RXb or pair RXc and RXd, independently, can combine to form a >C=CH or >C=CH-CH3; and wherein each of RXe, RXf, RXg, RXh, RXi, RX), RXk and RXI is H, F or methyl.

4. The compound of any one of the preceding claims, wherein L is -NR10-(C=O)-.

5. The compound of any one of the preceding claims, wherein L is -(C=O)-NR10-. 133 6. The compound of any one of the preceding claims, wherein L caz ίηη / ζζηζ / E / γίΛΐ is -NR10-(C=O); having the formula (la): (la); wherein Rx is 7. The compound of any one of the preceding claims, wherein L is -(C=O)-NR10-; having the formula (Ib): R4 (Ib); wherein Rx 8. The compound of any one of the preceding claims, wherein Rx 9. The compound of any one of the preceding claims, wherein R10 is H or methyl.

10. The compound of any one of the preceding claims, wherein Z is absent, or is -SO2-, -CH2-SO2, -NH-, -NHSO2-, -SO2NH-, -SO2N(CH3)-, -O-, -(C=O)O-, (C=O)NH-, -(C=O)N(CH3)-, -S(=O)(=NH)-, -CH2-N(CH3)- or -C(=N-OH)-. 134 11. The compound of any one of the preceding claims, wherein R12 is selected from: a) H, F, Br, OH or CN; b) R12a selected from a saturated, partially saturated or unsaturated 3, 4, 5, 6 or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, and 0 or 1 atom selected from O and S, substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, ethyl, -CF3, -CH2OH, -OH, -OCH3, -NH2 or oxo; c) R12b selected from C1.6 alkyl substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, -CF3 or -OH.

12. The compound of any one of the preceding claims, wherein R12 is R12a selected from cyclopropyl, oxethanyl, imidazoyl, isothiazolidinyl, azetidinyl, oxazolyl, pyrazolyl or diazirinyl; each of which is independently substituted with 0, 1, 2 or 3 group(s) selected from methyl, ethyl, -CF3 or oxo; or R12b selected from methyl, ethyl, isopropyl, tert-butyl, -ethenyl, substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, -CF3 or -OH.

13. The compound of any one of the preceding claims, wherein R1 is a -Z-R12 group, wherein Z is absent, or is -SO2-, -CH2SO2-, -(C=O)NH-, -NH-, -NHSO2 or -SO2NH-; and R12 is a cyclopropyl, oxethanyl, azetidinyl or imidazoyl ring, each of which is independently substituted with 0, 1 or 2 group(s) selected from methyl, CF3 or oxo; or R12 is methyl, ethyl, isopropyl or tere-butyl, each of which is independently substituted with 0, 1, 2 or 3 group(s) F, -CF3 or OH.

14. The compound of any one of the preceding claims, wherein R1 is a -Z-R12 group, wherein Z is -NHSO2- and R12 is -CH2-CH2-OH or -CH(CH3)CH2OH.

15. The compound of any one of the preceding claims, wherein Y is absent, or is -SO2NH-, NH-, -SO2-, -S(=O)(=NH)- or -O-.

16. The compound of any one of the preceding claims, wherein R13 is H or F; R13a is selected from morpholinyl, piperidinyl, cyclopentyl, cyclopropyl, azetidinyl or oxethanyl; wherein each of said rings is substituted with 0, 1, 2 or 3 OH group(s) selected from methyl or -OH; or R13b is selected from methyl, ethyl, propyl, isopropyl, tere-butyl or isopentyl; each of which is independently substituted with 0, 1, 2 or 3 OH group(s).

17. The compound of any one of the preceding claims, wherein R2 and R8 can be combined with the carbon atoms attached to each of them to form a saturated or partially saturated 6-membered monocyclic ring fused with the phenyl ring; wherein said 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein said 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, C1-6 alkyl, C1,4 haloalkyl or oxo.

18. The compound of any one of the preceding claims, wherein R4 Lnn / zznz / E / YiAi is H.

19. The compound of any one of the preceding claims, wherein R5 is H.

20. The compound of any one of the preceding claims, wherein R6 is H or F.

21. The compound of any one of the preceding claims, wherein R7 is H or F.

22. The compound of any one of the preceding claims, wherein R8 is H, F, or methyl; or, alternatively, R2 and R8 may combine with the carbon atoms bonded to each of them to form a saturated 6-membered monocyclic ring fused to the phenyl ring; selected from the group:

23. The compound of any one of the preceding claims, wherein R2 a) a group -Y-R13a, wherein Y is absent or is -S(=O)(=NH)-; and R13 is piperidinyl or azetidinyl; wherein each of said rings is independently substituted with 0, 1, 2 or 3 F group(s); b) a group -Y-R13b, wherein Y is -SO2NH-, -O-.NH-; and wherein R13b is tert-butyl substituted with 0, 1, 2 or 3 OH group(s); c) alternatively, the carbon atoms attached to R2 and R8 combine to form a saturated 6-membered monocyclic ring fused to the phenyl ring; wherein said 6-membered monocyclic ring is unsubstituted.

24. The compound of any one of the preceding claims, wherein R2 is the -SO2NH-tert-butyl group or the -NH-tert-butyl-OH group. 136 25. The compound of any one of the preceding claims, wherein R8 is H.

26. The compound of any one of the preceding claims, wherein R9 is H.

27. The compound of any one of the preceding claims, wherein R10 is H.

28. The compound of any one of the above claims, or the pharmaceutically acceptable salt thereof, selected from the group consisting of: A / -(3-(A / -(ferc-butyl)sulfamo¡l)phen¡l)-4-((3-met¡loxetane-3-¡l)sulfonyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(N-(tert-butyl)sulfamoyl)phen¡l)-4-(met¡lsulfonyl)-2-(6-azaespiro[2.5]octane-6yl)benzamide; A / -(3-isopropylphenyl)-4-(methylsulfonyl)-2-(6-azaespiro[2.5]octane-6-¡l)benzamide; A / -(3-cyclopropylphenyl)-4-(methylsulfonyl)-2-(6-azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(tert-butyl)phenyl)-4-(methylsulfonyl)-2-(6-azaespiro[2.5]octane-6-yl)benzamide; 4-(methylsulfon¡l)-A / -(qu¡nolin-8-¡l)-2-(6-azaespiro[2.5]octane-6-¡l)benzamide; A / -(4-met¡lqu¡nolin-8-¡IH-(meth¡lsulfon¡l)-2-(6-azaesp¡ro[2.5]octane-6-¡l)benzamide; A / -(chroman-8-yl)-4-(methylsulfon¡l)-2-(6-azaespiro[2.5]octan-6-yl)benzamide A / -(benzofuran-7-yl)-4-(methylsulfonyl)-2-(6-azaespiro[2.5]octan-6-yl)benzamide; A / -(benzo[b]thiophen-7-yl)-4-(met¡lsulfonyl)-2-(6-azaesp¡ro[2.5]octane-6-¡l)benzamide; 4-(methylsulfon¡l)-A / -(3-morpholinophen¡l)-2-(6-azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(A / -(terc-but¡l)sulfamoyl)phen¡l)-4-((methylsulfonyl)met¡l)-2-(6-azaespiro[2.5]octane-6yl)benzamide; / V-(3-(W-(tert-butyl)sulfamoyl)phenyl)-4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; 4-(A / -(te / 'c-but¡l)sulfamoyl)-N-(3-(A / -(te / 'c-butyl)sulfamo¡l)phen¡l)-2-(6-azaesp¡ro[2.5]octane-6yl)benzamide; A / -(3-(A / -(terc-but¡l)sulfamoyl)phen¡l)-4-(3-met¡loxetan-3-yl)-2-(6-azaesp¡ro[2.5]octane-6yl)benzamide; A / -(3-(A / -(terc-but¡l)sulfamo¡l)phenyl)-4-(3-h¡droxyoxetan-3-¡l)-2-(6-azaesp¡ro[2.5]octane-6yl)benzamide; A / -(3-((1-hydroxy¡-2-methylpropan-2-yl)amino)phenyl)-4-(A / -(3-methyloxetane-3-yl)sulfamoyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(2-fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(A / -(3-methyloxetane-3yl)sulfamoyl)-2-(6-azaespiro[2.5]octane-6-yl)benzam¡da; caz ίηη / ζζηζ / Ε / γίΛΐ Lnn / zznz / E / YiAi 137 A / -(2-fluoro-3-((1 -hydroxy-2-methylpropane-2-yl)am¡no)phenyl)-4-(1cyclopro -panomethyl sulfonamide)-2-(6-azaespiro[2.5]octane-6-yl)benzam¡da; A / -(3-(((1-h¡drox¡-2-methylpropane-2-¡l)am¡no)phenyl)-4-((1-met¡lc¡clopropane)-1-sulfoname¡do)2-(6-azaespiro[2.5]octan-6-yl)benzamide; A / -(3-(A / -(irc-but¡l)sulfamo¡l)phen¡l)-4-((1-methylc¡clopropane)-1-sulfoname¡do)-2-(6azaespiro[2.5]octan-6-yl)benzam¡da; / V-(3-(W-(ferc-butyl)sulfamoyl)phenyl)-4-(methylsulfonamido)-2-(6-azaespiro[2.5]octan-6yl)benzamide; A / -(3-(A / -(ferc-butyl)sulfamo¡l)phen¡l)-4-(et¡lsulfonam¡do)-2-(6-azaespiro[2.5]octan-6yl)benzamide; / V-(3-(W-(terc-but¡l)sulfamo¡l)phen¡l)-4-((1-met¡let¡l)sulfoname¡do)-2-(6-azaesp¡ro[2.5]octane6-l)benzamide; / V-(3-(W-(ferc-but¡l)sulfamoyl)phen¡l)-4-(c¡clopropanosulfoname¡do)-2-(6azaespiro[2.5]octan-6-yl)benzam¡da; A / -(3-(A / -(terc-butyl)sulfamoyl)phen¡l)-4-((1,1-dimethyleth¡l)sulfoname¡do)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(A / -(tert-butyl)sulfamoyl)phen¡l)-4-(1,1-dioxidoisothiazol¡d¡n-2-¡l)-2-(6azaespiro[2.5]octane-6-yl)benzamide; / V-(3-(W-(terc-butyl)sulfamoyl)phen¡l)-4-((2-hydroxyethyl)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamide)- / \ / -(3-(2-methylmorpholino)phen¡l)-2-(6-azaespiro[2.5]octane6-¡l)benzamide; (R)-A / -(2-fluoro-3-(2-methylmorpholine)phen¡l)-4-((2-hydrox¡et¡l)sulfonam¡do)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (R)-A / -(3-fluoro-5-(2-methylmorpholine)phenyl)-4-((2-hydrox¡et¡l)sulfonam¡do)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (R)-A / -(4-fluoro-3-(2-methylmorpholine)phen¡l)-4-((2-hydroxyethyl)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(4,4-d¡fluoropiperidin-1-¡l)-5-meth¡lphenyl)-4-((2-h¡drox¡et¡l)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; / V-(3-(4,4-d¡fluoropiperidin-1-¡l)phen¡l)-4-((2-h¡diOxiet¡l)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(4,4-difluoropipendin-1-yl)-2-fluorophenyl)-4-((2-hydroxyethyl)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (S)-A / -(3-( / V-(terc-but¡l)sulfamo¡l)phen¡l)-4-((2-h¡droxy-1-methylethyl)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; 138 (R)-N-(3-( / V-(terc-but¡l)sulfamoyl)phenyl)-4-((2-h¡drox¡-1 -methylethyl)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; A / -(3-(2-h¡droxi-2-meth¡lpropox¡)phen¡l)-4-((2-h¡droxyethyl)sulfonam¡do)-2-(6azaespiro[2.5]octane-6-yl)benzamide; 4-(azetidin-1-¡lsulfon¡l)- / \ / -(3-(A / -(íerc-but¡l)sulfamo¡l)phen¡l)-2-(6-azaesp¡ro[2.5]octane-6yl)benzamide; / V-(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-4-( / V-(1-h¡droxy-2-methylpropan-2-¡l)sulfamoyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; / V-(3-(N-(ferc-but¡l)sulfamo¡l)phen¡l)-4-( / V-(2-h¡drox¡et¡l)sulfamo¡l)-2-(6azaespiro[2.5]octane-6-yl)benzamide; / V-(3-(W-(ferc-but¡l)sulfamo¡l)phen¡l)-4-(A / ,Nd¡met¡lsulfamo¡l)-2-(6-azaesp¡iO[2.5]octan-6il)benzamida; A / -(3-(A / -(ferric-butyl)sulfamoil)fen¡l)-4-( / \ / -met¡lsulfamoil)-2-(6-azaesp¡ro[2.5]octan-6il)benzamida; A / -(3-(A / -(ferric-butyl)sulfamo¡l)fen¡l)-4-(A / -(oxetan-3-¡l)sulfamoil)-2-(6-azaesp¡ro[2.5]octan6-¡l)benzamida; / V-(3-(W-(ferric-butyl)sulfamoyl)fenyl)-4-( / Vcclopropylsulfamoyl)-2-(6-azaespiro[2.5]octan-6-il)benzamida; / V-(3-(N-(terc43util)sulfamoil)fenyl)-4-(A / -(1-methylciclopropyl)sulfamoyl)-2-(6azaespiro[2.5]octan-6-il)benzamida; / V-(3-(A / -(terc-butyl)sulfamoil)fenyl)-2-(6-azaespiro[2.5]octan-64l)-4-sulfamoilbenzamida; (R)-A / -(3-(W-(ferc43util)sulfamo¡l)fen¡l)-4-(1,2-dihidroxipropan-2-il)-2-(6azaespiro[2.5]octan-6-il)benzamida; (S)- / V-(3-(A / -(terc43util)sulfamo¡l)fen¡l)-4-(1,2-dihidroxipropan-2-il)-2-(6azaespiro[2.5]octan-6-il)benzamida; A / -(3-(A / -(terc-butil)sulfamoil)fenil)-4-(1-met¡l-1H-imidazol-2-il)-2-(6-azaespiro[2.5]octan6-¡l)benzamida; / V-(3-(W-(terc-but¡l)sulfamoil)fen¡l)-4-(1-met¡l-1H-pirazol-54l)-2-(6-azaespiro[2.5]octane-6yl)benzamide; / V-(3-(W-(ferc-but¡l)sulfamo¡l)phen¡l)-4-(1-met¡l-1H-p¡razol-4-¡l)-2-(6-azaesp¡ro[2.5]octane-6yl)benzamide; A / -(3-(A / -(terc-butyl)sulfamoyl)phenyl)-4-(oxazole-24l)-2-(6-azaespiro[2.5]octane-6yl)benzamide; / V-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6azaespiro[2.5]octane-6-yl)benzamide; case ίηη / ζζηζ / Ε / γίΛΐ 139 / V-(3-(W-(terc-butyl)sulfamo¡l)phenyl)-4-((2-hydrox¡et¡l)amino)-2-(6-azaesp¡ro[2.5]benzamide); / V1-(3-(N-(ferc-butyl)sulfamoyl)phen¡l)-N4-(2-h¡droxyethyl)-2-(6-azaespiiO[2.5]octane-6yl)terephthalamide; A / p3-(N-(tert-butyl)sulfamoyl)phenyl)-A / 4-methyl-2-(6-azaespirc>[2.5]octane-6-yl)terephthalamide; / V1-(3-(N-(ferc-but¡l)sulfamo¡l)phen¡l)- / V4-(2-h¡drox¡ethyl)-A / 4-met¡l-2-(6-azaesp¡ro[2.5]octan6-yl)terephthalamide; A / 7-(3-( / \ / -(ferc-but¡l)sulfamoyl)phenyl)-A / 4-(1-h¡droxy-2-methylpropane-2-¡l)-2-(6azaespiro[2.5]octane-6-yl)terephthalamide; A / í-(3-(c¡clopentylsulfonyl)phen¡l)- / \ / 4-(2-h¡drox¡ethyl)-2-(6-azaesp¡ro[2.5]octane-6yl)terephthalamide; (R)-A / -(3-(azet¡d¡n-1-sulfonim¡doyl)phen¡l)-4-((2-hydrox¡et¡l)sulfonamide)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (S)-A / -(3-(azetidin-1-sulfonimidoyl)phenyl)-4-((2-h¡droxyethyl)sulfonam¡do)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (R)-4-((2-h¡drox¡et¡l)sulfonam¡do)-N-(3-(S-methylsulfon¡m¡do¡l)phenyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonam¡do)-A / -(3-(S-methylsulfon¡m¡do¡l)phenyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamide)-A / -(3-(2-methylpropan-2-ylsulfonim¡do¡l)phen¡l)-2-(6azaespiro[2.5]octane-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonamide)- / \ / -(3-(2-methylpropan-2-ylsulfonim¡doyl)phenyl)-2-(6azaespiro[2.5]octane-6-yl)benzamide; or A / -(4-((2-hydroxy¡ethyl)sulfonamide)-2-(6-azaespiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1yl)benzamide.

29. The composition of a list of previous indications, such as ίηη / ζζηζ / Ε / γίΛΐ selected from the group that consists of: Example n.° Chemical structure No. 100 Λ N-(3-(N-(tercButyl)sulfamoyl)phenyl)-4-((3methyloxetan-3-yl)sulfonyl)-2(6-azaespiro[2.5]octan-6yljbenzamida 140 Example n.° Estructura química Nombre 100-7 η δ 0 0 A / -(Croman-8-yl)-4(methylsulfonyl)-2-(6azaespiro[2.5]octan-6yl)benzamida 100-11 V+oJ s N Τι μ OO o H Uüí N-(3-(N-(tercButyl)sulfamoyl)phenyl)-4((methylsulfonyl)methyl)-2-(6azaespiro[2.5]octan-6yl)benzamida 100-13 c ,ZI δω :p O. / '(f) ZI A 4-(A / -(terc-Butyl)sulfamoyl)-N(3-(N-(terc-butyl)sulfamoyl)phenyl)-2-(6azaespiro[2.5]octan-6yljbenzamida 101 . . Ó AZ\ 0 o\ / o / V-(3-((1-Hidroxi-2methylpropan-2¡l)amino)phen¡l)-4-(A / -(3methyloxetan-3-yl)sulfamoyl)-2(6-azaespiro[2.5]octan-6yljbenzamida 101-1 y n. 5 ho^A^nAA HJH Vsa Λ u A / -(2-Fluoro-3-((1-hidrox¡-2methylpropan-2¡l)amino)phenyl)-4-( / \ / -(3methyloxetan-3-yl)sulfamoyl)-2(6-azaespiro[2.5]octan-6yl)benzamide 102 V -xíijXI jUL T s η uva Η / V N-(3-(N-(tert-Butyl)sulfamoyl)phen¡l)-4-((1methylcyclopropane)-1 sulfonamido)-2-(6azaespiro[2.5]octan-6yl)benzamide 141 Example no. Structure chemistry Nombre 102-3 —V ZI O=W=OP IZ o=\ ZT q Ο=ω=ο / IZ \ N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4(cyclopropanesulfonamido)2-(6-azaespiro[2.5]octan-6yljbenzamide 103 τ :p IZ\ ,O ωχ I ° cr zr N-(3-(N-(tertButyl)sulfamoyl)phenyl)-4-((2hydroxyethyl)sulfonamide)-2(6-azaspiro[2.5]octan-6yljbenzamide 104 “Π OIA / -(3-(4,4-Difluoropiperid¡n1-¡l)-5-methylphenyl)-4-((2hydroxyethyl)sulfonam¡do)-2(6-azaspiro[2.5]octan-6yl)benzamide 104-1 n ° $ FXj hXS VFHA / -(3-(4,4-Difluoropiperidin1-¡l)phenyl)-4-((2hydroxyeth¡l)sulfonam¡do)-2(6-azaspiro[2.5]octan-6yl)benzamide 104-2 η ·δ F cXX v FT^ f ^Vs--^oh FHA / -(3-(4,4-D¡fluoropiper¡din1-¡l)-2-fluorophenyl)-4-((2hydroxyet¡l)sulfonamido)-2(6-azaespiro[2.5]octan-6yljbenzamide c«z ίηη / ζζηζ / Ε / γίΛΐ 142 Ex n.° Chemical structure Name 105-1 ΞΕ O o yo ''Ί ° ZI o=\ ZI Q. 'o (S)- / V-(3-( / V-(tertButyl)sulfamoyl)phenyl)-4-((2hydroxy-1 methylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 105-2 ΞΕ O o ° ZI ZI Q. t / do (R)-A / -(3-(A / -(tertButyl)sulfamoyl)phenyl)-4-((2hydroxy-1 methylethyl)sulfonamido)-2-(6azaspiro[2.5]octan-6yljbenzamide 106 r, · 0 H0 IHHIH 0 A / -(3-(2-Hydrox¡-2methylpropoxy)phenyl)-4-((2hydroxyethyl)sulfonam¡do)-2(6-azaspiro[2.5]octan-6yljbenzamide 107 V 0 . <n h ul,no z o 0' xo 4-(azetidin-1 -ilsulfonil)- \ -(3(a -(ferc-butil)sulfamoil)fenil)2-(6-azaespiro[2.5]octan-6iljbenzamida 108-1 .n · á1njvl i °''b h ul· poh όη ( ?)- v-(3-(a -(tercbutil )su lfamoil)fenil)-4-( 1,2dihidrox¡propan-2-¡l)-2-(6azaespiro[2.5]octan-6iljbenzamida caz lnn zznz ε γΐλΐ 143 ejemplo n.° estructura química nombre 108-2 τ'όη (s)-n-(3-{n-(terc- butil )sulfamoil)fenil)-4-( 109 . δ 4 η υψ ν- n-(3-(n-(tercbutil)sulfamoil)fenil)-4-(1 metil-1 h-imidazol-2-il)-2-(6azaespiro[2.5]octan-6iljbenzamida 110 η ’δ n-(3-(n-(tercbutil)sulfamoil)fenil)-4-(( 1 hidroxi-2-metilpropan-2il)amino)-2-(6azaespiro[2.5]octan-6iljbenzamida 111 । ί| 0 ν ο w-(3-(n-(tercbutil)sulfamoil)fenil)-a 4-(2hidroxietil)-2-(6azaespiro[2.5]octan-6iljtereftalamida 112-1 o r,="δ" íi ηα ' (r)-a -(3-(azetidin-1sulfonimidoil)fenil)-4-((2hidroxietil)sulfonam¡do)-2(6-azaespiro[2.5]octan-6iljbenzamida 144 e yiai 115 (s)- v-(3-(azetidin-1sulfonimidoil)fen¡l)-4-((2hidroxietil)sulfonamido)-2(6-azaespiro[2.5]octan-6iljbenzamida m-(4-((2hidroxietil)sulfonamido)-2(6-azaespiro[2.5]octan-6il)fenil)-3-(piperidin-1 iljbenzamida ; cualquier sal farmacéuticamente aceptable del mismo.

30. A pharmaceutical composition comprising the compound according to any one of the preceding claims or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

31. A method for treating a condition treatable with KIF18a inhibitors, the method comprising administering to a patient in need a therapeutically effective amount of the compound according to any one of claims 1 to 29, or the composition according to claim 30.

32. The method of claim 31, wherein said condition is a proliferative disorder selected from cancer, psoriasis, atopic dermatitis, an autoimmune disorder, or inflammatory bowel disease; wherein said cancer may be melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia; wherein said autoimmune disorder may be rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome, or an autoimmune disease of the central nervous system, such as multiple sclerosis, myasthenia gravis, and encephalomyelitis; and wherein the inflammatory bowel disease may be ulcerative colitis or Crohn's disease. 145 33. A method for reducing the size of a solid tumor in a subject, the method comprising administering to the subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 29, or the composition according to claim 30.

34. A method for treating a cell proliferation disorder in a subject, the method comprising administering to the subject in need a therapeutically effective amount of the compound according to any one of claims 1 to 29, or the composition according to claim 30.

35. A method for inhibiting KIF18A in a cell, comprising bringing the cell into contact with a compound, or pharmaceutically acceptable salts thereof, according to any one of claims 1 to 29, or the composition according to claim 30.

36. The method of claim 31, wherein said condition is cancer selected from the group consisting of (a) a solid tumor or hematologically derived tumor selected from bladder, endometrial, squamous cell lung, breast, colon, kidney, liver, lung, small cell lung cancer, esophageal, gallbladder, brain, head and neck, ovary, pancreatic, stomach, cervix, thyroid, prostate, and skin cancer, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome, and leukemia promyelocytic, (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma,(e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma,< / n>