KIF18A INHIBITORS.

Abstract

Compounds of formula (I): (see Formula) (I), as defined herein, and synthetic intermediates thereof, capable of modulating the KIF18A protein, thereby altering the cell cycle process and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions comprising the compounds, and methods for treating pathological conditions related to KIF18A activity.

Description

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). 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 spindle tension. Depletion of human KIF18A leads to longer mitotic spindles, an increase QR7 Lnn / Zznz / E / YIAI -2of metaphase chromosome wobble, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr etal., 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 MT-based KIF18A modulatory activity and, in particular, KIF18A inhibitory activity. To this end, the invention also provides the use of these compounds, as well as the pharmaceutically acceptable salts thereof, in the preparation and manufacture of a pharmaceutical composition or medicine for the therapeutic, prophylactic, acute or chronic treatment of diseases and the KIF18A-mediated disorders, 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 (I), A compound of formula I: L is -(C=O)-NR8- or -NR8-(C=O)-; -3R1 is a group -Z-R9; where Z is absent, or is -NR11-, -NR11SO2-C1.4 alkyl-, NR11SO2NR11, -NR11SO2NR11-C(=O)-O-, -N=S(=O)<, -SO2NR11-alkyl CM-, alkyl C0^-S(=O)(=NH)-, alkyl C0.4-S (=O)(=N+(CH3)2)-, C1.4-alkyl-, C0-4-S-alkyl, Co-4-S-alkyl(=0)-, C0-4SO2-alkyl-, -O-, -P-, -P(=O), -P(=O)2, -(C=O)-, -(C=O)NR11-, -C=N(OH)- or -NR11(C=O); R2 is a -Y-R10 group, where Y is absent, or is alkyl C0-4-S-, alkyl Co-4-S=0, alkyl Co-4-S(=0)2, -SO2NR10c-C0-4alkyl-, -NR10c-, -NR10c-SO2-C0-4alkyl-, -C0-4alkyl-S(=O)(=NH)-, -OC0-4alkyl-, -( C=O)-, -alkyl C0-4-(C=O)-O- 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 Ci^ haloalkyl; R7 is H, halo, C-m alkyl or C1.4 haloalkyl; R8 is H or C1-4 alkyl; R9es H, R9a or R9b; R10is halo, R10aor R10b; QR7 Lnn / Zznz / E / YIAI QR7 Lnn / Zznz / E / YIAI OR RxIS A C2.8 ALKYL SUBSTITUTED WITH 0, 1, 2, 3, 4 OR 5 GROUP(S) SELECTED BETWEEN F, CL, BR, -CH2F, -CHF2, -CF3, -C(=O) ORA, -ORA, -OHALOALKYL Ci^, CN, NH2, NH(CH3), N(CH3)2O RXM; O RxES PHENYL OR UNSATURATED 5-MEMBER MONOCYCLIC RING SUBSTITUTED WITH 0, 1, 2, 3, 4 OR 5 GROUP(S) SELECTED FROM F, CL, BR, Ci-6 ALKYL, -HALO Ci-6 ALKYL, - C(=O)ORA, -ORA, -O-HALOALKYL Cw, CN, NH2, NH(CH3), N(CH3)2O Rxm; WHERE SAID 5-MEMBER MONOCYCLIC RING CONTAINS 0.1,203 ATOMS OF N AND 0 OR 1 ATOM SELECTED BETWEEN O AND S; each of RXa, RXb, RXc, RXd, RXe, RXf, RXg, RXh, RXi, RXL RXk and RXIes H, halo, RXno RXO; or, alternatively, each of the pair RXay RXb, pair RXcy RXd, pair RXey Rxf, pair RXgy RXh, pair RXiy RXj, and pair RXky RXI, independently, can be combined with the atom -5carbon bonded to each of them to form a saturated or partially saturated 3, 4, 5, 6-membered monocyclic spiro ring with the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepanyl ring; wherein said 3, 4, 5, 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 3, 4, 5, monocyclic ring contains 6 members is substituted with 0, 1,2 or 3 group(s) selected from F, Cl, Br, C1-6 alkyl, C1-4 haloalkyl, -ORa, -O-C-m haloalkyl, CN, -NRaRau oxo; each RXmy RXn is independently selected, in each case, from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 8-, 9-, 10-, 11- or 12-membered bicyclic 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, 3 or 4 group(s) selected from F, Cl, Br, alkyl C1-6, C1-4 haloalkyl, -ORa, -O-haloalkyl C-m, 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, -Ci-6-alkyl-N(Ra)C(=O )Rb, - alkyl Ci-6-OC(=O)Rb, -alkyl Ci-6-C(=O)NRaRa, -alkyl Ci-6-C(=O)ORay oxo; RXose is independently selected, in each case, from the group consisting of C1.8 alkyl substituted with 0, 1.2, 3, 4 or 5 group(s) selected from F, Cl, Br, -CH2F, -CHF2 , -CF3, -C(=O)ORa, -ORa, -O-C1-4haloalkyl, CN, NH2, NH(CH3) or N(CH3)2; R9ay Rioase is independently selected, in each case, from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 8-, 9-, 10-, 11- or 12-membered bicyclic 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, Cl, Br, C1-6 alkyl, haloalkyl C«, -ORa, -O-haloalkyl C-m, 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, -Ci-6-alkyl-N(Ra)C(=O )Rb, QR7 Lnn / Zznz / E / YIAI -Ci-6-alkyl(=O)Rb, -Ci-6-alkyl(=O)NRaRa, -Ci-6-alkyl(=O)ORa, R11y oxo; R9b and R10b are independently selected, in each case, from the group consisting of Ci-θ alkyl substituted with 0,1,2, 3,4 or 5 group(s) selected from F, Cl, Br, -CH2F, - CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl Cu, CN, NH2, NH(CH3) or N(CH3)2; R10ces H or C1-4 alkyl; R11is H or C-i-s alkyl; 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 substituted with 0,1,2 or 3 substituents selected from halo, -OH, -O-C1-4 alkyl, - NH2, -NH-C1-4 alkyl, - OC(=O)C1-4alkyl, or -N(Ci-4alkyl)C1-4alkyl; and the phenyl or benzyl is substituted with 0, 1,2 or 3 substituents selected from halo, C1-4 alkyl, haloC1-3 alkyl, -OH, -O-C1-4 alkyl, -NH2, -NH-C1 alkyl- 4, -OC(=O)C-m alkyl, or -N(Ci-4 alkyl)C1.4 alkyl. In embodiment 2, the present invention provides compounds wherein L is -NR8(C=O); which have the formula (la): wherein said RXa and RXb pair can combine 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 piperidinyl 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, Ci6 alkyl, C1-4 haloalkyl, -ORa, -O-C-m haloalkyl, CN, -NRaRau oxo. In embodiment 3, the present invention provides compounds wherein L is (C=O)-NR8-; which have the formula (Ib): Lnn / Zznz / E / YIAI wherein said RXa and RXb pair can combine 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 piperidinyl 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, Ci6 alkyl, C1-4 haloalkyl, -ORa, -O-C-m haloalkyl, CN, -NRaRau oxo. In embodiment 4, the present invention provides compounds wherein R8 is H or methyl. In embodiment 5, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein each of RXc, RXd, RXe, RXf, RXg, RXh, RXi, RXj, RXk and RXIes H, halo, C1.6 alkyl or Ci^ haloalkyl; and each of the RXa and RXb pair combines with the carbon atom bonded to each of them to form a 3-, 4-, or 5-membered spiro-saturated monocyclic ring with the piperidinyl ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S. In embodiment 6, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein each of RXc, RXd, RXe, RXf, RXg, RXh, RXi, RXj, RXk and RXIes H, methyl or ethyl; and each of the RXa and RXb pair combines with the carbon atom attached to each of them to form a cyclopropyl, cyclobutyl or cyclopentyl spiro ring with the piperidinyl ring. In embodiment 7, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein Rx is selected from (a) ethynyl substituted with isobutyl or cyclopentyl; (b) phenyl substituted with 0, 1, 2 or 3 group(s) F, Cl, CF3, CH2OCH3, methyl, ethyl, propyl, isopropyl, tere-butyl or cyclopropyl; (c) or pyrazolyl substituted with 0, 1, 2 or 3 group(s) F, Cl, CF3, CH2OCH3, methyl, ethyl, propyl, isopropyl, tert-butyl or cyclopropyl; -8Lnn / Zznz / E / YIAI In embodiment 8, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein Rx is selected from: -9In embodiment 9, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts of the themselves, where Rxes . In embodiment 10, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein Z is absent, or is -NH-, -NHSO2-, -SO2NH- or -CH2SO2-. In embodiment 11, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, R9 is selected from: a) H; (b) Ci-e alkyl substituted with 0, 1,2 or 3 group(s) selected from F, Cl, Br, -CF3 or -OH; or (c) 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, Cl, Br, methyl, ethyl, -CF3, CH2OH, -OH, -OCH3, -NH2u oxo. In embodiment 12, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R9 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, diazirinyl, oxazolidinyl, isothiazolidinyl, pyrazolyl or pyrrolidinyl. In embodiment 13, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R1 is a group -Z-R12, where R1 is a group -Z-R9, where Z is absent, or is -NH-, -NHSO2-, -SO2NH- or -CH2SO2-; and R9 is cyclopropyl or oxazolinyl substituted with 0, 1.2 or 3 OH, -CH2OH, methyl or oxo group(s), or R9 is Ci-substituted alkyl with 0, 1.2 or 3 OH or CF3 group(s). In embodiment 14, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R1 is a group -Z-R9, wherein Z is -NHSO2- and R9es -CH2-CH2-OH. - 10In embodiment 15, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R2 is a group -Y-R10, where Y is absent, or is -NH-, -NHSO2-, SO2NH- or SO2-; and R10 is 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, Cl, Br, methyl, ethyl, CF3, CH2OH, -OH, -OCH3, -NH2, -NH(CH3) and oxo; either; R10 is Ci-6 alkyl substituted with 0, 1.2, 3, 4 or 5 group(s) selected from F, Cl, Br, -OH or -CF3. In embodiment 16, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R2 is a morpholinyl, thiomorpholinyl, cyclobutyl, cyclopentyl or piperidinyl ring, wherein each of said rings is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2 or oxo. In embodiment 17, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, R2 is morpholinyl or piperidinyl substituted with 0, 1,2 or 3 selected from F or methyl. In embodiment 18, the present invention provides compounds according to embodiments 1-17, or pharmaceutically acceptable salts thereof, wherein R3 is H or F. In embodiment 19, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R4 is H. In embodiment 20, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R5 is H. In embodiment 21, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R6 is H, F or methyl. In embodiment 22, the present invention provides compounds according to any of the above embodiments, or pharmaceutically acceptable salts thereof, wherein R7 is H. IN EMBODIMENT 23, THE PRESENT INVENTION PROVIDES COMPOUNDS IN ACCORDANCE WITH ANY OF THE PREVIOUS EMBODIMENTS, QR7 Lnn / Zznz / E / YIAI - 11 OR ANY PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, SELECTED FROM THE GROUP CONSISTING OF: / V-(3-(W-(ert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5 ]octan-6-yl)pyrazine-2-carboxamide; A / -(3-(A / -(íert-butíl)sulfamo¡l)pheníl)-5-((1-hydroxy¡-2-methylpropan-2-yl)amino)- 3-(4methylpiperidin-1-l)pyrazin-2-carboxamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-3-(4,4-difluoropiperidin-1 -11)-5-((1 -hydroxy-2methylpropan-2-yl) amino)pyrazin-2-carboxamide; A / -(3-(A / -(fert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4(trifluoromethyl)piper¡d¡ n-1-yl)pyrazine-2-carboxamide; / \ / -(3-(N-(ferc-butyl)sulfamo¡l)phen¡l)-3-(4-eth¡lp¡perid¡n-1-¡l)-5-((1-h droxy-2-methylpropan-2yl)amino)pyrazín-2-carboxamide; / V-(3-(N-(fert-butíl)sulfamoyl)phenyl)-3-(4,4-dimethylpiperidin-1-yl)-5-((1-hydroxy-2methylpropan-2-yl )amino)pyrazín-2-carboxamide; / V-(3-(W-(ferc-butyl)sulfamoyl)phen¡l)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4¡sopropylpiper ¡din-1-¡l)pyrazin-2-carboxamide; 3-(4-(tert-butyl)p¡perídin-1-¡l)-A / -(3-(N-(tert-butyl)sulfamo¡l)phen¡l)-5-( (1-hydiOx¡-2methylpropan-2-yl)amino)pyrazine-2-carboxamide; 3-(4-(sec-butyl)piperid¡n-1-yl)-A / -(3-(N-(ferc-butyl)sulfamo¡l)phenyl)-5-((1-hydiOX¡ -2methylpropan-2-yl)amino)pyrazine-2-carboxamide; N-(3-(W-(fert-but¡l)sulfamoyl)phenyl)-5-((1-hydroxy¡-2-methylpropan-2-yl)amino)-3-(4prop¡lp¡peridin -1-l)pyrazin-2-carboxamide; A / -(3-(A / -(ert-butyl)sulfamo¡l)phen¡l)-3-(4-cyclopropylpipendin-1-¡l)-5-((1-hydroxy¡-2methylpropan- 2-yl)amino)pyrazín-2-carboxamide; A / -(3-(A / -(fert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4(methoxymethyl)piperidin- 1-yl)pyrazine-2-carboxamide; / V-(3-(W-(fert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(2azaspiro[3.3]heptan-2 -yl)pyrazin-2-carboxamide; / V-(3-(W-(ert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(2azaspiro[3.5 ]nonan-2-yl)pyrazin-2-carboxamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(3-oxa-9azaspiro[5.5] undecan-9-yl)pyrazín-2-carboxamide; A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(7azaspiro[3.5]nonan-7- il)pyrazín-2-carboxamide; A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-3-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-5-((1hydroxy-2- methylpropan-2-yl)amino)pyrazine-2-carboxamide; QR7 Lnn / Zznz / E / YIAI - 12 / V-(3-(W-(fert-butyl)sulfamoyl)phenyl)-5-((1 -hydroxy-2-methylpropan-2-yl)amino)-3-(8azaspiro[4.5]decan -8-yl)pyrazín-2-carboxamide; / V-(3-(W-(ert-but¡l)sulfamoyl)-5-methylphen¡l)-5-((1-hydroxy¡-2-methylpiOpan-2-yl)amino)- 3-(6azaspiro[2.5]octan-6-¡l)pyrazine-2-carboxamide; 5-((1-hydroxy¡-2-methylpropan-2-¡l)amino)-3-(6-azaspiro[2.5]octan-6-yl)-N-(3-((1, 1,1trifluoro-2-met¡lpropan-2-¡l)sulfon¡l)phen¡l)pyrazín-2-carboxamide; A / -(3-(ert-butylsulfonyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-íl)pyrazin -2-carboxamide; 5-((1 -hydroxy¡-2-methylpropan-2-¡l)amino)- / V-(3-((1-methylc¡clobut¡l)sulfonyl)phen¡l)- 3-(6azaspiro[2.5]octan-6-yl)pyrazín-2-carboxamide; / V-(3-(W-(fert-butyl)sulfamo¡l)-5-fluorophen¡l)-5-((1-hydroxy¡-2-methylprapan-2-¡l)amino) -3-(6azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide; A / -(3-(A / -(fert-butyl)sulfamoyl)-2-fluorophenyl)-5-((1-hydroxyl-2-methylpropan-2-yl)amino)-3 -(6azaspiro[2.5]octan-6-yl)pyrazín-2-carboxamide; A / -(3-(1,1-d¡oxy¡dothiomorpholino)phen¡l)-5-((1-hydroxy-2-methylpropan-2-¡l)amino)-3-(6azaspiro [2.5]octan-6-yl)pyrazín-2-carboxamide; 5-((1 -hydroxy¡-2-methylpropan-2-¡l)amino)-A / -(3-morphol¡nophen¡l)-3-(6-azaesp¡iO[2.5]octan-6yl )pyrazine-2-carboxamide; 5-((1-hydroxy-2-methylpropan-2-¡l)amino)-N-(3-((1-hydroxy¡-2-methylpiOpan-2-¡l)amino)phenyl)3 -(6-azaspiro[2.5]octan-6-¡l)pyrazine-2-carboxamide; (S)-A / -(3-((3,3-difluorocyclopentyl)sulfon¡l)phen¡l)-5-((1-hydroxy¡-2-methylpropan-2-yl)am¡ no)-3(6-azaspiro[2.5]octan-6-yl)pyrazin-2-carboxamide; (R)-A / -(3-((3,3-difluoroc¡clopentyl)sulfon¡l)phen¡l)-5-((1-hydroxy¡-2-methylpropan-2- l)amino)-3(6-azaspiro[2.5]octan-6-yl)pyrazin-2-carboxamide; A / -(3-(cyclopentylsulfonyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-íl)pyrazin-2 -carboxamide; 5-((1 -hydroxy-2-methylpropan-2-yl)amino)- / \ / -(3-(piperidin-1 -ylsulfonyl)phenyl)-3-(6azaspiro[2.5]octan-6-yl)pyraz n-2-carboxamide; / V-(3-(cyclopentylsulfonyl)phenyl)-5-((1-(hydroxymethyl)cyclopropyl)amino)-3-(6azaspiro[2.5]octan-6-yl )pyrazin-2-carboxamide; / V-(3-(W-(ferc-butyl)sulfamoyl)phenyl)-5-((1-(hydroxymethyl)cyclopropyl)amino)-3-(6azaspiro[2.5]octan-6- il)pyrazín-2-carboxamide; 5-((2-hydroxy-2-methylpropyl)amino)-A / -(3-(piperidin-1-ylsulfonyl)phenyl)-3-(6azaspiro[2.5]octan-6-yl)pyrazín- 2-carboxamide; A / -(3-(A / -(ferc-but¡l)sulfamo¡l)phenyl)-3-(4-chlorophen¡l)-5-((1-hydroxy¡-2-methylpropan-2 ¡l)amino)pyrazín-2-carboxamide; QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI - 13 / V-(3-(W-(tert-but¡l)sulfamo¡l)phenyl)-3-(4-fluorophen¡l)-5-((1-hydroxy¡-2-met¡ lpropan-2yl)amino)pyrazine-2-carboxamide; / V-(3-(W-(ert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpiOpan-2-yl)amino)-3-(4(trifluoromethyl )phenyl)pyrazine-2-carboxamide; A / -(3-(A / -(tert-but¡l)sulfamo¡l)phen¡l)-3-(4-ethylphenyl)-5-((1-hydroxy¡-2-methylpropan -2yl)amino)pyrazín-2-carboxamide; A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4isopropylphenyl)pyrazine-2-carboxamide; (R)-A / -(3-(A / -(fert-butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-¡l)-5-(1,1,1 - trifluoro-2hydroxypropan-2-l)pyrazin-2-carboxamide; (S)- / V-(3-(A / -(fert-butyl)sulfamo¡l)phen¡l)-3-(6-azaspiro[2.5]octan-6-¡l)-5-( 1,1,1-trifluoro-2hydroxypropan-2-l)pyrazin-2-carboxamide; either A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5] octan-6-yl)pyrazín-2-carboxamide. In embodiment 24, the present invention provides a compound, or pharmaceutically acceptable salts thereof, selected from: Example No. Chemical Structure Name 100 V Η Π Η | S N η Ν x , / / / \\ |_| I \ / 1 o o H H A / -(3-(A / -(te / 'c-Butyl)sulfamoyl)pheníl)-5-((1 hydroxy-2-methylpropan-2-íl)amí no)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide 100-1 -Ύ O.. ,ZI v IZ ^=o IZ o I / V-(3-(AA(tert-Butyl) sulfamo¡l)phen¡l)-5-((1 hydroxy-2-methylpropan-2-¡l)amino)-3-(4met¡lp¡peridín-1-¡l)pyraz¡ n-2-carboxamide 100-15 o. ,ZI IZ IZ or I / V-(3-(A / -(tert-butyl)sulfamoyl)pheníl)-5-((1 hydroxy-2-methylpropan-2-yl)amino)- 3-(7azaspiro[3.5]nonan-7-yl)pyrazín-2carboxamide Example No. Chemical structure Name 101 X o. ,ZI O' IZ o I A / -(3-(A / -(tert-Butyl)sulfamoyl)-5methylphenyl)-5-((1-hydroxy-2-methylpropan-2yl)amino)-3-(6 -azaspiro[2.5]octan-6yl)pyrazin-2-carboxamide 101-3 / ,Α A'X'n Ti N \ / 0 0 H N A® X / OH N H 5-((1 -Hydrox¡-2-met¡ lpropan-2-yl)amino)Λ / -(3-((1 -methylcyclobutyl)sulfonyl)phenyl)-3(6-azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide 101-4 F X h FS II 1 An / aaA^n 1 o 0 H AX. / OH v N H A / -(3-(A / -(tert-Butyl)sulfamoyl)-5fluorophenyl)-5-((1-hydroxy-2-methylpropan2-¡l)amino)-3-(6-azaspiro[2.5 ]octan-6yl)pyrazin-2-carboxamide 101-8 I Chili pepper ZI O ZI o T 5-((1 -Hydroxy-2-methylpropan-2-¡l)amino)- A / -(3- ((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-3-(6-azaspiro[2.5]octan- 6-yl)pyrazine-2-carboxamide 102-1 O. X ΞΕΖ S= o yíx IZ O I (S)-A / -(3-((3,3-Difluorocyclopentyl)sulfonyl)phenyl)-5-((1 hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[ 2.5]octan-6-¡l)p¡raz¡n-2carboxamide 102-2 V fax / Πί ϊ Ϊ f^asaa ia v o o H N^A X / OH H (R)- / V-(3-((3, 3- Difluorocyclopentyl)sulfonyl)phenyl)-5-((1 hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide 103 o. n ’ '5 '^AX^iAA . , l-l 1 \ / O 0 H -yl)pyrazine-2carboxamide QR7 ίηη / 77η7 / Ε / ΥΙΛΙ Example No. Chemical structure Name 103-1 O A u v 00 / OH H 5-((1 -Hydrox¡-2-methylpropan-2-¡l)amino)A / -(3-(piperid¡n-1 -ylsulfonyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazín-2carboxamide 103-3 • u ¿ X A N Ti N vv V Ό Η Η I \ / lOO M ΜXk,X / OH H / V-(3-(N-(tert-Butyl)sulfamo¡l)phenyl)-5-((1 (hydroxymethyl)c¡clopropyl)amino)-3-(6azaspiro[2.5]octan-6- il)pyrazine-2carboxamide 104 Cl ÍJ Η n Y X^X XX X A N 'η Ν . , X ZX l-l I \ / 1 o O H N X -2yl)amino)pyraz¡n-2-carboxamide 105-1 V μ iX^X 0 ΑΛΛγΝ 1 o O H CF3 (R)-A / -(3-(A / -(tert-Butyl)sulfamoyl)phenyl)- 3(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1trifluoro-2-hydroxypropan-2-yl)pyrazin-2carboxamide 105-2 O X \ XX X -6-yl)-5-(1,1,1trifluoro-2-hydroxypropan-2-yl)pyrazin-2carboxamide 106 V H A Η 1 \ / Ν' ΑΧ XX / OH X A N Ti n < z<x 1-4 1 / 1 0 O H N 2-methylpropan-2yl)amino)-3-(6-azaspiro[2.5]octan-6yl)pyrazín-2-carboxamide 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. QR7 Lnn / Zznz / E / YIAI - 16In embodiment 25, the present invention provides pharmaceutical compositions comprising a compound, or pharmaceutically acceptable salts thereof, according to any one of embodiments 1-24, 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 26, 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 1-24 or composition according to embodiment 25. In embodiment 27, the present invention provides the method of claim 26, 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 27a, the present invention provides the method of embodiment 26, 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 Q«7 ίηη / 77Π7 / Ε / ΥΙΛΙ Lnn / Zznz / E / YIAI - 17Biomarkers and Molecular Targets for Cancer Therapy, Cancer 2010; 116:5150-60. VC 2010 American Cancer Society. In embodiment 28, 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 1-24 or the composition of according to embodiment 25. In embodiment 29, the present invention provides a method of 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 1-24, or the composition according to claim 25. In embodiment 30, 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 1-24, or the composition of according to embodiment 25. 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 31, the invention provides a method for preparing a compound of Formula (I) as described herein. In embodiment 32, 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 - 18carbon-14, that is, 14C, are particularly useful for this purpose in view of their ease of incorporation and the available detection means. 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 pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other 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. - 19The terms oxo and thioxo represent the groups =0 (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(Ca-p alkyl)-Ca-p alkyl group, where a and β are as defined above, include substituents where the two Cap alkyl groups together form a ring, optionally including an N, O or S atom , 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 carbons), or heterocyclic (ring atoms consist, for example, of 1, 2, or 3 heteroatoms, such as N, O, or S, in addition to carbon atoms. ). 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., tetraline). 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: (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 Ca-p alkyl. 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: QR7 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, malic 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 -22The 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, triphyl 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 of 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 QR7 Lnn / Zznz / E / YIAI -23can 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) ¡l)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 in combination with imidazole or DMF. Methods for the silylation of amines and the removal of 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 free amine. The carboxy protecting group, such as methyl, ethyl, benzyl, tere-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, QR7 Lnn / Zznz / E / YIAI -24heteroaryl groups substituted with heteroatoms (Y1= O, S, NR), and the like, which are illustrated in the following examples: QR7 Lnn / Zznz / E / YIAI 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 AZ-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 Lnn / Zznz / E / YIAI -25 groups of Markush). 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 can 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, Lnn / Zznz / E / YIAI -26L-lysine acetate, 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, chloride hydrochloride of thiamine, vitamin A palmitate, 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 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 , malic 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; -27 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 it possible to formulate the compounds herein as tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions and the like for oral ingestion by the patient to be treated. 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% of QR7 Lnn / Zznz / E / YIAI -28compound 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, with due regard to pH, isotonicity, stability and the like, is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection usually contains, in addition to a compound disclosed herein, an isotonic vehicle. 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 sufficiently fluid so that it can be easily administered with a syringe. 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's possible QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI -29maintaining adequate fluidity, for example, by using a coating, such as lecithin, maintaining the required particle size of the compound in making the dispersion and by using 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 that produce a powder of the active ingredient plus any desired additional ingredients from 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 gastrointestinal 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. They can be formulated Lnn / Zznz / E / YIAI -30 capsules and cartridges, 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 composition may be in powder form to be reconstituted with a suitable vehicle (eg, 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 dosable 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%. 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 QR7 Lnn / Zznz / E / YIAI -32may 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. 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 modulatory 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) QR7 Lnn / Zznz / E / YIAI -33include human papillomavirus (HPV) infection, including HPV-associated neoplasms. The compounds are also useful for cilia-related diseases, as well as for ablation of the haploid germ cell population that 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 (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 pleural lesions induced by tumors and malignant asditis. 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; postinfectious arthritis, (when lifeless pathogenic organisms can be found on or inside the affected part of the body), seronegative spondylarthritis, such QR7 Lnn / Zznz / E / YIAI -34as 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 oval 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 regimen 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), antibodies QR7 ίηη / 77Π7 / Ε / ΥΙΛΙ Lnn / Zznz / E / YIAI -35therapeutics (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 inadequate. 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. Said agents are included in several main categories, such as antibiotic-type agents, alkylating agents and alkylating analogues, antimitotic agents, targeting agents that are low molecular weight molecules, antimetabolite agents, hormonal agents, immunological agents, antiangiogenic agents, agents interferon type, 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 -36chemotherapeutic 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); 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); cyclophosphamide; thiotepa; taxanes, e.g. 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 cellular 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; QR7 Lnn / Zznz / E / YIAI -37mercaptopurine; 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-A / -allylamino-17-desmethoxy¡geldanam¡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, exatecan, exisulind, ferruginol, forodesin, phosphestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplat ino , 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 a QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI -38tissue diseased with 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, radiation and 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, MMPLnn / Zznz / E / YIAI 8, ΜΜΡ-10, ΜΜΡ-11, ΜΜΡ-12 and ΜΜΡ-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 (Novels), 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, exisulind, fadrozole , filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetoprotein, ibadronic acid, idarubicin, (imiquimod , interferon a, interferon a, natural, interferon a-2, interferon a-2a, interferon a-2b, interferon a-N1, interferon a-n3, interferon alfacón-1, interferon a, natural, interferon β, interferon β- la, interferon β-1 b, interferon y, natural interferon y-1a, interferon y-1b, interleukin-1 β, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole , leukocyte interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pen tazocine , nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon 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, thymalfasin, 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 or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 -40(Genta), APC 8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, immunogen gastrin 17, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetane, ilomastat, IM 862 (Cytran), interleukin-2, iproxyfen, LDI 200 (Milkhaus), leridistim , Lintuzumab, CA 125 monoclonal antibody (Biomira), Cancer monoclonal antibody (Japan Pharmaceutical Development), HER-2 and Fe monoclonal antibody (Medarex), Idiotypic 105AD7 monoclonal antibody (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, ethyltin purpurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York College of Medicine) York), 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 in combination 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 to QR7 Lnn / Zznz / E / YIAI -41 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 bind specifically to it), EGFR inhibition agents (e.g., antibodies or antigen-binding regions that specifically bind to the antigen) 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 anti-Tie2 kinase inhibition agents (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. of hepatocytes (HGF, Hepatocyte Growth Factor, also known as dispersal factor), and antibodies or antigen-binding regions that specifically bind to its c-met receptor. 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); CGP QR7 Lnn / Zznz / E / YIAI -4279787 (Novartis, Switzerland, document EP 970070); ARGENT technology (Arlad, USA); YIGSR Stealth (Johnson & Johnson, USA); fibrinogen fragment E (BioActa, GB); Anglogenesis 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, Italy); angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneran, 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 -43Institute 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, infraocular, 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, 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); irsogladine (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, it is possible to use siRNA or antisense that inhibits the expression of proteins including, but not limited to, ATG5 (those involved in autophagy). QR7 Lnn / Zznz / E / YIAI -44Additional 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 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 ( p. 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 coordination complexes platinum (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., GS-1101 and TGR-1202), PI3K δ inhibitor and y (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. Hormone Releasing Hormone) (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 (HLJMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI -45y 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 (e.g. BT062), Torcí / 2-specific kinase inhibitor (e.g. INK128), kinase inhibitor (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. 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 spheroid. Suitable spheroids may include, but are not limited to, 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoxymetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fluchloronide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcino nida, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexol ona, 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 in combination 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. -46EGFR 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 October 3, 1996; 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; PCT international publication WO 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; international publication QR7 Lnn / Zznz / E / YIAI -47PCT 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; PCT international publication WO 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 PCT International Publication WO 92 / 20642 published November 26, 1992. Some additional non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described 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 the 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-(1 H-indazol-4-yl)-6-[[4(methylsulfonyl)piperaz, n-1 -¡l]methyl¡l]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publications No. WO 09 / 036 082 and WO 09 / 055 730), 2-methyl2-[4-[3-methyl-2-oxo-8-(quinolin-3-¡l)-2,3-dihydro¡midazo [4,5-c]quinolin-1-yl]phenyl]propionitrilo (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806) )piperazin-1 -yl)-2-hydroxypropan-1-one (described in PCT Publication No. WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-pheníl-4H-1- benzopyran-4-one available from Axon Medchem), Pl 103 hydrochloride (3-[4-(4-morpholinylpyride-[3',2':4,5]furo[3,2] hydrochloride QR7 ίηη / 77Π7 / Ε / ΥΙΛΙ -48d]pririm¡din-2-yl]phenol available from Axon Medchem), PIK 75 (N'-[(1E)-(6bromo¡midazo[1,2-a]p¡r¡ hydrochloride d¡n-3-¡l)methylene]-N,2-dimethyl¡l-5-nitrobenzenesulfon-hydrazide available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dih dro-¡m¡dazo[1,2-c]quinazolin-5yl)-nicotinamide available from Axon Medchem), GDC-0941 bismesylate (2-(1H¡ndazol-4-¡l)-6-(4) bismesylate -methanesulfonyl-p¡peraz¡n-1-ylmethyl)-4-morphol¡n-4-¡l-thieno[3,2-d]p¡nm¡na available from Axon Medchem), AS-252424 ( 5-[1-[5-(4-fluoro-2-hydroxy¡-phen¡l)-furan-2-yl]-met-(Z)ylidene]-thiazolidin-2,4-dione available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)-9[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one available from Axon Medchem), XL-765 and XL147. 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 AEZS-136. 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 et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole3-carbinol and derivatives thereof (e.g., US Patent No. 6,656,963; Sarkar and Li (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 (TON 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; QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI -49phosphorus-containing rapamycin derivatives (eg, 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 CTLA4). 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 Pat. 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 by Lnn / Zznz / E / YIAI -50separate. 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. Because 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 of separate pharmaceutical compositions in kit form. 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: ac or ac. aqueous BOC or Boc tert-butyloxycarbonyl DAST diethylaminosulfur trifluoride DCE 1,2-dichloroethane DCM dichloromethane DMAP 4-dimethylaminopyridine DMF Λ / , W-d i m eti Ifo rmam i d a DMSO dimethyl sulfoxide DMTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-¡l)-4-methylmorpholinium chloride ESI or ES {ElectroSpray lonization) electrospray ionization Et ethyl Et2O diethyl ether EtOH ethyl alcohol EtOAc EtOAc g grams H hour HMPA hexamethylphosphoramide HPLC high performance liquid chromatography ¡Pr isopropyl / Pr2NEt or DIPEA A / -ethyl-diisopropilamine (Hünig base) LDA lithium diisopropylamide LC MS, LCMS, LC-MS or LC / MS ( Liquid Chromatography Mass Spectroscopy LG {Leaving Group) leaving group (e.g., halogen, mesylate, triflate) m / z mass divided by charge Me Methyl MeCN or ACN Acetonitrile MeOH Methanol Met metal species for the cross-coupling (e.g., MgX, ZnX, SnR3, SiR3, B(OR)2) mg milligrams min minutes mi milliliters MS Mass Spectrum MsCI methanesulfonyl chloride MTBE tert-butyl methyl ether NMP 1 -methyl-2- pyrrole ¡dine n-BuL¡ n-buty l-lithium NMR Nuclear Magnetic Resonance Pd / C palladium on carbon QR7 ίηη / 77η7 / Ε / ΥΙΛΙ Pd2(dba)3 tris(dibenzylideneacetone)dipalladium (0) Pd(dppf)CI2-DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane Pd(PPh3)4 tetrakis (triphenylphosphine)palladium (0) Ph Phenyl PR or PG or Prot. group. protective group MFR or mfr round bottom flask RP-HPLC (Reverse Phase High Pressure Liquid Chromatography) reverse phase high pressure liquid chromatography TA or ta room temperature sat. or satd. Saturated SFC (Supercritical Fluid Chromatography) TBAF tetra-n-butylammonium fluoride tmscf3 trimethyl(trifluoromethyl)silane t-BuOH tert-butanol TEA or Et3N Trimethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC (Thin Layer Chromatography) T3P 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane TsCl 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. QR7 Lnn / Zznz / E / YIAI -53In 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, Nhidroxlbenzotriazole and the like. Examples of nucleophiles include, but are not limited to, amines, phyols, 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 were normally used without further 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 Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer 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. 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. Low-resolution mass spectral (MS) data 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. . 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 QR7 Lnn / Zznz / E / YIAI -54are 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 purposes of clarity in this general synthesis section, the Compounds of Formula (I), as defined in the compendium of inventions may be drawn schematically to contain Ring Ar1 and Ring Ar2 as follows: QR7 Lnn / Zznz / E / YIAI where the group L is -NR8-(C=O)- or -(C=O)-NR8-; Ring Ar1 is located to the left of the connector, and ring Ar2 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 Ar1 Ring compound with the Ar2 Ring compound. -55The following Generic Schemes A-D are intended to serve as a guide to experienced synthetic chemists, who will readily observe 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, the following Schemes A-C provide a generic preparation of a compound of Formula (I), wherein L is -NR8-(C=O); which has the following formula (l-A): QR7 Lnn / Zznz / E / YIAI R1(l-A); where preferably R5 is H. An example of a compound of formula (la) includes, but is not limited to, (l-A-1); where preferably R5 is H. (I-A-1). SCHEME A: PREPARATION OF THE COMPOUND (l-A): According to Scheme A, in one embodiment, a compound of Formula (I) as disclosed herein can be synthesized as follows: Step A-1: ​​Preparation of Ar1 Ring Compound: R6p4 I p5 1. Formation of sulfonyl chloride Wr~^NO22. Amine R10 R3 R10 Rs RT H o''Ó r3 A-1 A-2 r5 Reduction NO2 R10 Rs R4^R5 Η IN'S^ τ W I O O r3 A-3 NH2 Compound A-1, where W1 is H, can be converted to the corresponding sulfonyl chloride intermediate by treatment with chlorosulfonic acid. -56Alternatively, compound A-1, where W1 is F, can be converted to the corresponding sulfonyl chloride intermediate by a two-step procedure, which is treatment with benzylmercaptan followed by oxidative chlorination with 1,3- dichloro-5,5-dimethylhydantoin. Compound A-1 is commercially available or can be synthesized by methods known to those skilled in the art. Examples of compound A-1 include, but are not limited to, 1-methyl-3-nitrobenzene, 1-chloro-4-nitrobenzene, 1-methoxy-4-nitrobenzene, 1-methoxy-3-nitrobenzene or 3,5-difluoronitrobenzene. Further reaction of the sulfonyl chloride intermediate obtained above with an amine-containing group R10 in the presence of a suitable base, in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like give sulfonamides A -2, where R2= SO2R10. Examples of bases include, but are not limited to, diisopropylethylamine amine, potassium carbonate or sodium hydride. Examples of R10 amines include, but are not limited to, tert-butylamine, cyclopropylamine, cyclohexylamine, piperidine or 4,4-difluoropiperidine. Compound A-2 can then be reacted with a suitable reducing agent, such as a palladium catalyst and a hydrogen source, such as Pd / C in the presence of hydrogen gas, forming compound A-3. Step A-1-a: preparation of the Ar1 Ring compound: 1. Amine R10, base 2. CuO2, NH3 A-3 QR7 Lnn / Zznz / E / YIAI Alternatively, compound A-4 can be reacted with an amine reagent R10, followed by a metal-catalyzed amination reaction, where a suitable palladium or copper catalyst and a base can be used, forming the compound. A-3, where R2= SO2R10, as defined in step A-1. Step Α-1-b: preparation of the Ar1 Ring compound: QR7 Lnn / Zznz / E / YIAI Even alternatively, the thiol compound A-5 can be reacted with a reagent R10 through a thiol alkylation reaction followed by an oxidation reaction forming compound A-3, where R2= SO2R10. Examples of R10 reagents that can be used in this manner include, but are not limited to, methylenecyclobutane, trifluoroethanol or cyclopent-2-enone. Step Α-1-c: preparation of the Ar1 Ring compound: Even, alternatively, the compound A-1, where W1 is halo, for example, fluorine, chlorine or bromine, can be reacted with a suitable 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, followed by reaction with a suitable reducing agent such as a palladium catalyst and a hydrogen source, such as Pd / C in the presence of hydrogen gas, forming compound A- 3. Compound A-1 is commercially available or can be synthesized by methods known to those skilled in the art. 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 . Some examples of R2 reagents include, but are not limited to, (1) (R)-2methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3- trifluoropropan-1-ol, (5) 2-aminoethane-1-ol or (6) 2-amino-3-methylpropan-1-ol. Examples of bases include, but are not limited to, diisopropylethylamine amine, potassium carbonate or sodium hydride. Step Α-1-d: preparation of the Ar1 Ring compound: A-1 1. Reagent R2, metal catalyst and base A-3 2. Reduction Even alternatively, compound A-1, where W1 is halo, as defined in step Α-1-c, can be reacted with a reagent R2 in the presence of a metal catalyst, such as palladium or copper catalyst, and in the presence of a base, such as 1Q cesium carbonate, potassium carbonate or potassium phosphate in an amination reaction, followed by reaction with a suitable reducing agent, such as palladium catalyst and a hydrogen source, such as Pd / C in the presence of hydrogen gas, forming the compound A-3. Step A-2: Preparation of Ar2 Ring Compound: 25A-9 In Step A-2, Compound A-6, where each of W2 and W3 is independently halo, for example, fluorine, chlorine, bromine or iodine, can react with MeOH in the presence of H2SO4 forming the methyl ester A-7 which then reacted with an R1, such as 2-amino-2-methyl-1-propanol, (l-aminocyclopropyl)methanol or 2-aminoethane-1-ol, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran , DMF, DMSO and the like, forming Compound A-8. Compound A-8 is then hydrolyzed with lithium chloride and neutralized with HCl forming A-9 Step A-3a: coupling of the ring compound Ar1 with the ring compound Ar2 followed by the introduction of R1: In Step A-3a, can compound A-9, which was obtained from Step A-2, be reacted with an activating agent such as an acid chloride (COCl)? or SOCI2, in a suitable organic solvent such as tetrahydrofuran, methylene chloride and the like, forming an acid chloride derivative, which can then be reacted with compound A-3 to form compound A-10. Alternatively, compound A-3 can be directly coupled with compound A-9, which was obtained in Step A-2, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride and the like, in the presence of a coupling reagent, such as Ν,Ν'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzothazol-1-íl)-hexafluorophosphate N,N,N',N'-tetramethyluronio, thionyl chloride, carbonyldiimidazole and polyphosphonic anhydride. Those skilled in chemical synthesis will readily understand that other coupling reagents can be used. Additional manipulation of the halogen group W2 can be used by reacting with a reagent Rx such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4 hydrochloride -trimethylpiperidine, (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, sodium chloride methylene, DMSO, forming the Compound (la). Those skilled in the art will readily understand that the coupling reaction, as shown in Step A-3, can be carried out under different known conditions. Alternatively, the halogen group W2 can be reacted in a palladium-catalyzed coupling reaction with a boronic acid and a palladium catalyst, forming the compound (la) SCHEME B: ALTERNATIVE PREPARATION OF THE COMPOUND (l-A): -60Step B-1: preparation of ring compound Ar1: see Steps A-1 to A-1d of SCHEME A above Step B-2: Preparation of Ar2 Ring Compound: QR7 Lnn / Zznz / E / YIAI Protective group OPG1W4 B-2 Protective group OPG1W4 B-3 Rx Reagent B-4 OPG1Rx Deprotection agent NPG2 R7 B-5 Scheme B provides an alternative method for the formation of compounds of Formula (la), as disclosed herein. Following any of Steps A-1 to A-1d as described in Scheme A, group R1 may alternatively be introduced into Ring Ar2 in Step B-2 instead of in Step B-3 as in Scheme A. According to Step 2b, compound B-1, wherein each of W4 and W5 is independently a halo, 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, forming compound B-2, where each of W4 and W5 are as defined in compound B-1. Compound B-2 can be reacted with the appropriate protected amine (PG2 reagent), for example, 4,4-dimethyloxazolidin-2-one, in the presence of a base such as potassium tert-butoxide to form compound B-2. 3. This can be reacted with an Rx reagent, such as (1) 6-azaspiro[2.5]octane hydrochloride, (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 the Compound B-4, which can then be reacted with an appropriate carboxylic acid deprotecting agent to form compound B-5. Carboxylic acid protecting groups and protective agents are known to those skilled in the art. -61 appropriate deprotection, p. 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 and removal of the protecting group: Lnn / Zznz / E / YIAI A-3 Deprotection agent Vulnerability (the) Step B-3 can be performed under conditions similar to those of the coupling reaction described above in Step A-3. SCHEME C: ALTERNATIVE PREPARATION OF THE COMPOUND (l-A): Step C-1: preparation of ring compound Ar1: see Steps A-1 to A-1d of SCHEME A above Step C-2: Preparation of Ar2 Ring Compound: C-3 Scheme C provides an alternative method for the formation of compounds of Formula (l-A), as disclosed herein. According to Step C-2, the compound B-2, where each of W4 and W5 is independently halo, for example, chlorine, -62bromine or iodine, can react with tributyl(1-ethoxy¡vinyl)tin, in the presence of a palladium catalyst such as bis-(di-fert-butyl(4-dimethyllam¡nophenyl)phosphine )dichloropalladium, giving the enol ether C-1. Compound C-1 can be reacted with an Rx reagent, such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4 hydrochloride -trimethylpiperidine, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride or (5) 7azaspiro[3.5]nonane hydrochloride, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO and the like, forming Compound C-2, which is then treated with HCl followed by trimethylsilyl trifluoromethane, giving compound C-3. Compound C-3 can then be further reacted with an appropriate carboxylic acid deprotecting agent forming compound C-4. 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 C-3 can be performed under conditions similar to those of the coupling reaction described above in Step A-3 of Scheme A. SCHEME D: PREPARATION OF THE COMPOUND (l-B): In another embodiment, a compound of formula (I) where L is -(C=O)-NR8- having the formula (l-B) Lnn / Zznz / E / YIAI (l-B), where preferably R5 is H, can be prepared according to the following Scheme D. An example of a compound of formula (l-B) includes, but is not limited to: RXaRXb (l-B-1); where preferably R5 is H. Step D-1: Preparation of Ar1 Ring Compound: Preparation of Ring compound Ar1: an embodiment of Ring compounds Ar1includes the compound D-1, which has the formula: D-1 Reagent R2base D-2 QR7 Lnn / Zznz / E / YIAI In Step D-1, the compound D-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, forming compound D-2. Examples of compound D-1 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 D-2: preparation of the Ar2 ring compound: Rx Reagent In step d-2, the compound d-3, where each of w7 and w8 is independently a halo, 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-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, methylene chloride, dmso and the like, forming compound d-4. Examples of compound d-3 include, but are not limited to: (1) 5-bromo-3-chloropyrazin2-amine, (2) 5-bromo-6-chloro-6-methylpyrazín-2-amine or (3) 3,5-dichloroprazin-2-amine. Step D-3: coupling of ring compound ar1 with ring compound ar2: In step d-3, compound d-2, which was obtained in step d-1, can be reacted with compound d-4, which was obtained in step d-2, in a suitable organic solvent such as such as acetonitrile, tetrahydrofuran, dmf, methylene chloride and the like, in the presence of a coupling agent, such as n, n'-diisopropylcarbodiimide, n-(3dimethylaminopropyl)-n'-ethylcarbod m¡da, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, o-(benzotriazol-1-¡l)-n,n,n',n'-tetramethyluronium hexafluorophosphate, carbonyl-diimidazole or polyphosphonic anhydride, forming a compound d-5. Those skilled in the art will readily understand that other coupling agents can be used, then further manipulation of the halo group w8 can 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-1-sulfonamide, (7) 2-mercaptopropan-1- ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethane-1-ol or (10) cyclopropanethiol, forming compound (i-b). Those skilled in the art will readily understand that the coupling reaction, as shown in step d-3, can be carried out under various known conditions, those skilled in the art will recognize that the above transformations could also be carried out in steps previous steps of the synthesis process based on the feasibility of the transformations. PREPARATION OF SYNTHETIC INTERMEDIATE COMPOUNDS PREPARATION OF AR1 RING INTERMEDIATE COMPOUNDS Intermediate compound 1: 3-amino-n-(tert-butyl)-5-methylbenzenesulfonamide CISO3H, 80 °C, 3 h Stage 1 DIPEA, t-BuNH2DCM, RT, 2 h Stage 2 Intermediate compound 1 QR7 Lnn / Zznz / E / YIAI Step 1: To ice-cooled 1-methyl-3-nitrobenzene (2g, 14.58 mmol), chlorosulfonic acid (14.57 ml, 219 mmol) is slowly added over 15 minutes. The resulting mixture was heated to 80 °C for 3 h. The reaction mixture was quenched with crushed ice and extracted with EtOAc (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-methyl-5-nitrobenzenesulfonyl chloride as a brown liquid. The raw product was taken to the next stage immediately. 1H NMR (400 MHz, Chloroform-d) δ 8.70 (t, J = 1.9 Hz, 1H), 8.52 - 8.39 (m, 1H), 8.18 (t, 1.7 Hz, 1H) and 2.66 (s, 3H). Step 2: To an ice-cold solution of 2-methylpropan-2-amine (1.09 g, 14.94 mmol) in DCM (50 ml), DIPEA (3.56 ml, 20.37 mmol) and a solution of 3-chloride were slowly added. methyl-5-nitrobenzene-1-sulfonyl (3.2 g, 13.58 mmol) in DCM (50 ml). After addition, the reaction mixture was slowly warmed to room temperature and stirred for 2 h. Water (100 ml) was then added, stirred for 10 min and the aqueous phase was extracted with DCM (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with 10% EtOAc in petroleum ether to provide A / -(tert-butyl)-3-methyl-5-nitrobenzene-sulfonamide ( 1.9g, 6.98 mmol, 51% yield) as a light yellow solid. 1H NMR (300 MHz, Chloroformod)ó8.56 (d, J=5.8 Hz, 1H), 8.27 - 8.16 (m, 1H), 8.10 - 7.99 (m, 1H), 4.86 (s, 1H), 2.57 (s , 3H) and 1.27 (s, 9H). MS (ESI, negative ion) m / z: 271.2 (M-1). Step 3: A mixture of A / -(tert-butyl)-3-methyl-5-nitrobenzene-sulfonamide (1.9 g, 6.98 mmol) and 10% Pd / C (0.6 g, 0.56 mmol) was stirred in MeOH (50 ml) under a hydrogen atmosphere (balloon pressure) for 3 h and then filtered through a short pad of CELITE®. The short bed was washed with MeOH (150 ml) and the filtrate was concentrated under reduced pressure, giving a white residue. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with a gradient of 15-20% EtOAc in -66petroleum ether, providing 3-amino- / V-(tert-butyl)-5-methylbenzene-sulfonamide (1.2 g, 4.95 mmol, 71% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-c / e) δ 7.33 - 7.13 (m, 1H), 6.83 (de, J = 4.7, 2.2 Hz, 1H), 6.76 (dd, J = 3.8, 2.2 Hz, 1H), 6.52 (c, J = 3.5, 2.6 Hz, 1H), 5.55-5.29 (m, 2H), 2.16 (s, 3H) and 1.09 (s, 9 H). m / z (ESI): 243.1 (M+1). Intermediate compound 2: 3-amino-n-(tert-butyl)-5-fluorobenzenesulfonamide Lnn / Zznz / E / YIAI Intermediate compound 2 Step 1: To a 25 ml round bottom flask, 3,5-difluoronitrobenzene (1 ml, 8.80 mmol), potassium carbonate (0.59 ml, 9.68 mmol), benzylmercaptan (1.1 ml, 9.24 mmol) and DMF ( 10 ml) at 0 °C, then stirred at RT for 2 h and water (10 ml) was added. The resulting mixture was extracted with EtOAc (3 x 100 ml), the combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacuo, yielding the crude product which was used without further purification. Step 2: To a 100 ml round bottom flask, benzyl(3-fluoro-5nitrophenyljsulfane (1.63g, 6.19 mmol), acetonitrile (12 ml), water (0.3 ml) and acetic acid (0.45 ml) were added. The reaction mixture was cooled to 0 ° C and 1,3-dichloro-5,5dimethylhydantoin (1.14 ml, 8.67 mmol) was added in portions. Once the addition was complete, the reaction mixture was stirred at 0 ° C for 20 min. The reaction mixture was then diluted with sat. NaHCOs and extracted with EtOAc. The organic extract was washed with water and dried over Na2SO4. The solution was filtered and concentrated in vacuo, giving 3-fluorochloride. 5-nitrobenzene-1-sulfonyl (1.48 g, 6.19 mmol, 100% yield) as a white solid which was used without further purification, m / z (ESI): 240.2 (M+1). Step 3: To a 100 ml round bottom flask, 3-fluoro-5nitrobenzene-1-sulfonyl chloride (1.66 g, 6.92 mmol), DCM (10 ml), tert-butylamine (0.51 ml, 6.92 mmol) was added. and DIPEA (1.81 ml, 10.38 mmol). The reaction mixture was stirred at RT for 3 h, diluted with satd NaHCOa. and was extracted with DCM (6 ml). The organic extract was washed with water and dried. -67about Na2SO4. The solution was filtered and concentrated in vacuo, giving the crude material as a white oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with a gradient of 0-25% EtOAc in heptane, yielding A / -(tert-butyl )-3-fluoro-5nitrobenzenesulfonamide (1.02 g, 3.70 mmol, 54% yield) as a white solid, m / z (ESI): 290.2 (M+Na). Step 4: To a 25 ml glass vial (red cap), iron (0.30 g, 5.43 mmol), ammonium chloride (48 mg, 0.91 mmol) were added, followed by A / -(fert-butyl)-3 -fluoro-5nitrobenzenesulfonamide (0.50 g, 1.81 mmol) in EtOH (6 ml) and water (0.5 ml). The reaction mixture was stirred at 80 °C for 1 h, cooled to rt, filtered through CELITE®, and the solvent was removed in vacuo. The reaction mixture was diluted with satd NH4CI. (10 ml) and extracted with EtOAc (10 ml). The organic extract was washed with water (10 ml) and dried over Na2SO4. The solution was filtered and concentrated in vacuo, giving the crude material as a white oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with a gradient of 0-40% EtOAc in heptane, yielding 3-amino-A. / -(tert-butyl)-5-fluorobenzenesulfonamide (0.33 g, 1.36 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 6.99 (t, J = 1.76 Hz, 1H), 6.93 (td, J = 1.91,8.12 Hz, 1H), 6.51 (td, J = 2.35, 10.17 Hz, 1H) , 4.52 (s, 1H), 1.26 (s, 9H). m / z (ESI): 247.1 (M+1). Intermediate compound 3: 3-amino-n-(tert-butyl)-2-fluorobenzenesulfonamide QR7 ίηη / 77Π7 / Ε / ΥΙΛΙ Stage 2 Intermediate compound 3 Step 1: To a solution of 3-bromo-2-fluorobenzenesulfonyl chloride (4.0 g, 14.62 mmol) in DCM (40 ml), triethylamine (6.12 ml, 43.9 mmol) and tert-butylamine (2.33 ml, 21.94 mmol) were added. ) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (30 ml) and the biphasic mixture was extracted with DCM (3 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under pressure -68reduced. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography, eluting with 5-8% EtOAc in hexanes, giving 3-bromo-A / - (tert-butyl)-2-fluorobenzenesulfonamide (3.5 g, 77% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-όβ): δ 8.01-7.95 (m, 2H), 7.857.80 (m, 1H), 7.36-7.31 (m, 1H), 1.13 (s, 9H). m / z (ESI): 308.1 [M-1], Step 2: To a solution of 3-bromo- / V-(tert-butyl)-2-fluorobenzenesulfonamide (3.2 g, 10.32 mmol) in ethylene glycol (5 ml), A / ^A^-dimethylethane-l,2 was added -diamine (0.091 g, 1.032 mmol), potassium carbonate (0.285 g, 2.06 mmol), copper (I) oxide (0.074 g, 0.516 mmol) and aqueous ammonia (7.5 mi) under a nitrogen atmosphere. The reaction vessel was sealed and stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water (30 ml) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine solution (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by silica gel chromatography, eluting with 25-35% EtOAc in hexanes, giving 3-amino-A / -(fert-butyl)-2 -fluorobenzenesulfonamide (0.9 g, 3.65 mmol, 35% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-όβ): δ 7.56 (s, 1H), 6.98-6.88 (m, 3H), 5.50 (s, 2H), 1.12 (s, 9H). m / z (ESI): 247.2 [M+1] Intermediate compound 4: 3-((1-methylcyclobutyl)sulfonyl)aniline Intermediate compound 4 Step 1: To a mixture of 3-aminobenzenethiol (3.0 g, 23.96 mmol) and methylenecyclobutane (2.94 g, 43.1 mmol) in diethyl ether (30.0 ml), concentrated H2SO4 (3.83 ml, 71.9 mmol) was carefully added and stirred. at room temperature for 45 min. The reaction mixture was quenched by pouring it into a satd aqueous solution. cold NaHCOs (200 ml) and extracted with EtOAc (3 x 200 ml). The combined organic extracts were washed with cold water (5 x 50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a silica gel column, eluting with a gradient of 1-15% EtOAc in hexanes, giving 3-((1-methylcyclobutyl)thio)anline (3.2 g, 69% of -69yield) in the form of a colorless oil. 1H NMR (400 MHz, DMSO-cfc): δ 7.02 - 6.95 (m, 1H), 6.63 (s, 1H), 6.55 - 6.45 (m, 2H), 2.27 - 2.14 (m, 2H), 2.08 - 1.84 ( m, 4H), 1.45 (m, 3H), NH2 protons were not visible, m / z (ESI): 194.2 [M+1], Step 2: To a solution of 3-((1-methylcyclobutyl)thio)aniline (3.0 g, 15.5 mmol) in THE (30 ml), Boc anhydride (7.21 ml, 31.0 mmol) and Et3N (3.24 ml) were added. e, 23.28 mmol) at room temperature and stirred for 18 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (200 ml). The organic layer was washed with water (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a silica gel column, eluting with a gradient of 5-8% EtOAc in hexanes, giving (3((1- methylcyclobut¡l)thio)phenyl)tert-butyl carbamate (3.2 g, 70% yield) as a white solid. 1H NMR (300 MHz, Chloroform-d): δ 7.44 - 7.33 (m, 2H), 7.30 - 7.20 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 2.42 -2.26 (m, 2H), 2.16-1.93 (m,4H), 1.57 (s, 9H), 1.54 (s, 3H). m / z (ESI): 294.2 [M+1], Step 3: To a solution of (3-((1-methylcyclobutyl)thio)phenyl)fert-butyl carbamate (2.0 g, 6.82 mmol) in MeOH (40 ml) and water (20 ml), oxone ( 9.22 g, 15.00 mmol), and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7 using 10% aqueous NaHCO3 solution (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic extracts were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a silica gel column, eluting with a gradient of 1-40% EtOAc in hexanes, giving (3-((1-methylcyclobutyl)sulfonyl)phenyl)tert-butyl carbamate (1.8 g, 81% yield) as a white solid. 1H NMR (400 MHz, DMSO-c / 6) δ 9.78 (s, 1H), 8.05 (s, 1H), 7.78 - 7.68 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 ( d, J = 7.8 Hz, 1H), 2.72-2.64 (m, 2H), 2.00 (dt, J= 10.8, 7.8 Hz, 1H), 1.91 - 1.68 (m, 3H), 1.49 (s, 9H), 1.35 (s, 3H). m / z (ESI): 326.1 [M+1], Step 4: To a solution of (3-((1-methylcyclobutyl)sulfon¡l)phen¡l)fert-butyl carbamate (1.8 g, 5.53 mmol) in 1,4-dioxane (20 ml), HCl ( 6.91 ml, 27.7 mmol, 4 M in dioxane) at 0 °C and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7-8 using 10% NaHCO3 aqueous solution. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether (100 ml), giving 3-((1-methylcyclobutyl)sulfonyl)anilline (1.05 g, 84% yield) as an off-white solid. Ή NMR (400 MHz, DMSO-d6) δ 7.34 - 7.21 (m, 1H), 7.00 (s, 1H), 6.93-6.79 QR7 Lnn / Zznz / E / YIAI -70(m, 2H), 5.66 (s, 2H), 2.73 - 2.59 (m, 2H), 2.07 - 1.93 (m, 1H), 1.85 - 1.76 (m, 3H), 1.35 (s, 3H). m / z (ESI): 226.1 [M+1], Intermediate compound 5: 3-((1,1,1-trifluoro-2-methylpropan-2-íl)sulfonyl)aníline TsCI, Et3N, DCM, TA, 6 p.m. Stage 1 Boc2O, TEA, THF, 6 p.m. Stage 3 Oxone, MeOH:Water, 18 h Stage 4 QR7 Lnn / Zznz / E / YIAI Intermediate compound 5 LDA. THF, HMPA,Fθ I 1. HCl in Dioxane Mel, -78 C, 30 min M Αθ 2. NaHCO3 Stage 5 Stage 6 Step 1: To a solution of 2,2,2-trifluoroethane-1-ol (5.0 g, 50.0 mmol) in DCM (300 ml), Et3N (4.64 ml, 33.3 mmol) and p-toluenesulfonyl chloride were added. (6.35 g, 33.3 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (200 ml) and extracted with DCM (2 x 500 ml). The combined organic extracts were washed with water, dried over Na3SO4, filtered and concentrated under reduced pressure to give 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (5 g, 59% yield) as an off-white solid. 1H NMR (400 MHz, Chloroform-d): δ 8.85 (d, J = 8.5Hz, 2H), 8.43 (d, J = 8.5 Hz, 2H), 5.38 (c, J = 10.2 Hz, 2H), 3.50 ( s, 3H). m / z (ESI): 255.1 [M+1], Step 2: To a solution of 3-aminobenzenethiol (4.43 g, 35.4 mmol) in DMF (225 ml), sodium hydride (1.77 g, 44.3 mmol) was added at 0 °C and stirred for 30 min followed by the addition of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (9.0 g, 35.4 mmol) and stirred for 18 h. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography through a silica gel column, eluting with a gradient of 5-10% EtOAc in hexanes, giving 3-((2,2,2-trifluoroethyl)thio)aniline ( 5.0 g, 68% yield) as a pale brown oil. 1H NMR (300 MHz, DMSO-de): δ 6.99 (d, J = 7.7 Hz, 1H), 6.66 - 6.58 (m, 2H), 6.47 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H ), 3.87 (c, J = 10.2 Hz, 2H). m / z (ESI): 208.2 [M+1], -71 Step 3: To a solution of 3-((2,2,2-trifluoroethyl)thio)aniline (5.0 g, 24.13 mmol) in THF (50 ml), Et3N (6.73 ml, 48.3 mmol) and Boc2O were added (8.40 ml, 36.2 mmol), and stirred at room temperature for 18 h. The reaction mixture was quenched with water (100 ml) and extracted with EtOAc (200 ml). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was absorbed onto a silica gel plug (60-120 mesh) and purified by flash chromatography through a silica gel column (50 g), eluting with a 5% to 8% gradient. of EtOAc in hexanes, giving (3-((2,2,2-trifluoroethyl)thio)phenyl)tert-butyl carbamate (4.2 g, 57% yield) as a white solid. 1H NMR (400 MHz, DMSO-c / e): δ 9.43 (s, 1H), 7.62 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.27 - 7.21 (m, 2H), 3.93 (c, J = 10.0 Hz, 2H), 1.48 (s, 9H). m / z (ESI): 308.1 [M+1], Step 4: To a solution of (3-((2,2,2-trifluoroethyl)thio)phenyl)tert-butylcarbamate (4.2 g, 13.67 mmol) in MeOH (40 ml) and water (20 ml), oxone (9.24 g, 30.1 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was neutralized with 10% aqueous NaHCO3 solution and extracted with EtOAc (3 x 200 ml). The combined organic extracts were washed with water (2 x 100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to give (3-((2,2,2trifluoroethyl)sulfon¡l)phen¡l)carbamate tert-butyl (3.2 g, 69% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.22 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.64-7.56 (m, 2H), 4.92 (c , J= 10.0 Hz, 2H), 1.49 (s, 9H). m / z (ESI): 338.0 [M-1], Step 5: To a solution of (3-((2,2,2-tnfluoroethyl)sulfonyl)phenyl)tert-butylcarbamate (8.5 g, 25.05 mmol) in dry THF (50 ml), methyl iodide was added (15.66 ml, 250 mmol) and HMPA (43.6 ml, 250 mmol) at 0 °C. The reaction mixture was cooled to -78 °C, and LDA (31.3 ml, 62.6 mmol, 2 M solution in THF) was added under nitrogen. The reaction mixture was stirred at −78 °C for 30 min and allowed to warm to room temperature. The reaction mixture was diluted with saturated aqueous NH4Cl solution (100 ml) and extracted with diethyl ether (3 x 250 ml). The organic layer was washed with brine solution (250 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography, eluting with 5-7% EtOAc in hexanes, giving (3-((1, 1,1-Trifluoro-2-methylpropan-2yl)sulfonyl)phenyl)tert-butyl carbamate (1.9 g, 21% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.15 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.62-7.58 (m, 1H), 7.50 (d, J = 7.9Hz, 1H), 1.58- 1.43 (m, 15H). m / z (ESI): 366.2 [M-1], Step 6: To a solution of (3-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)tert-butyl carbamate (1.8 g, 4.90 mmol) in 1,4-dioxane ( 20.0 ml), hydrochloric acid (12.3 ml, 49.0 mmol, 4 M in dioxane) was added at 0 °C and stirred at room temperature for 18 h. HE -72concentrated the reaction mixture under reduced pressure and adjusted to pH 7-8 using a 10% aqueous solution of NaHCOs. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography, eluting with 17-19% EtOAc in hexanes, giving 3-((1.1 ,1trifluoro-2-methylpropan-2-¡l)sulfon¡l)an¡line (0.9 g, 69% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 7.00 6.89 (m, 2H), 5.75 (s, 2H), 1.49 (s, 6H ). m / z (ESI): 268.1 [M+1]. Intermediate compound 6: 3-((3,3-difluoroc¡clopentyl)sulfonyl)aniline BOC2O, NaHCOa acetone Stage 1 Stage 2 Oxone, MeOH, H2O Stage 3 NHBoc Stage 4 F DAST, DCM, -78 °C-rt, 18 h NHBoc. HCI in NaHCO Stage 5 Dioxane F QR7 Lnn / Zznz / E / YIAI Intermediate compound 6 Step 1: Add 3-aminobenzenethiol solution (10.0 g, 80 mmol) in acetone (160 ml), Boc anhydride (37.1 ml, 160 mmol) and 10% aqueous sodium carbonate solution (20 ml, 160 mmol) were added. mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with water (250 ml) and extracted with EtOAc (3 x 250 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by flash chromatography through a silica gel column, eluting with a gradient of 1-15% EtOAc in hexanes, giving (3-mercaptophenyl)carbamate. tert-butyl (11 g, 61% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 13.1 (s, 1H), 7.56 (s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.31 (dd, J = 7.6, 7.2 Hz, 1H) , 7.19 (d, J = 7.6 Hz, 1H),6.54(s, 1H), 1.52 (s,9H). Step 2: A mixture of (3-mercaptophenyl)tert-butyl carbamate (10.0 g, 44.4 mmol) and cyclopent-2-enone (14.58 g, 178 mmol) was stirred at 120 °C for 24 h. The reaction mixture was absorbed directly onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography eluting with 9-12% EtOAc in hexanes, giving (3-((3- oxocyclopentyl)thio)phenyl)tert-butyl carbamate (10.0 g, 73% yield) as a colorless viscous oil. 1H NMR (300 MHz, Chloroform-d) δ 7.54 (s, 1H), 7.28 - 7.17 (m, -732Η), 7.07 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 3.94 (t, J = 8.0 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.45 2.20 (m, 4H ), 2.12-1.97 (m, 1H), 1.53 (s, 9H). m / z (ESI): 308.6 [M+1], Step 3: To a solution of (3-((3-oxocyclopentyl)thio)phenyl)fert-butyl carbamate (5.0 g, 16.27 mmol) in MeOH (100 ml), a solution of oxone (22 g, 35.8 mmol) in water (50 ml) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remove MeOH and the resulting aqueous solution was extracted with DCM (3 x 100 ml). The combined organic phases were washed with brine (50 ml), dried over Na2SÜ4, filtered and concentrated under reduced pressure, giving (3-((3oxocyclopentyl)sulfoníl)phenyl)fert-butyl carbamate (4.5 g, in crude) in the form of a pale yellow oil that was taken to the next stage as is. 1H NMR (400 MHz, DMSO-cfe) δ 9.84 (s, 1H), 8.14 (s, 1H), 7.71 (d, J = 7.92 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.48 (d, J = 7.7 Hz, 1H), 4.08 (t, J = 7.4 Hz, 1H), 2.45-2.16 (m, 6H), 1.50 (s, 9H). Step 4: To a solution of (3-((3-oxocyclopentyl)sulfonyl)phenyl)tert-butyl carbamate (1.65 g, 4.86 mmol) in DCM (20 ml), DAST (1.61 ml, 12.15 mmol) was added to - 78 °C under a nitrogen atmosphere and stirred at -78 °C for 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with 1 N aqueous NaOH solution (10 mL), diluted with water (25 mL), and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with 6-8% EtOAc in hexanes, giving (3-((3,3difluorocyclopentyl)sulfoníl)phení l)fert-butyl carbamate (0.95 g, 54% yield) as a colorless viscous oil. 1H NMR (300 MHz, DMSO-cfe): δ 9.84 (s, 1H), 8.14 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 -7.43 (m, 2H), 4.13-3.98 (m, 1H), 2.41 - 1.95 (m, 6H), 1.49 (s, 9H). m / z (ESI): 360.2 [M-1], Step 5: To a solution of (3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)tert-butyl carbamate (1.0 g, 2.77 mmol) in 1,4-dioxane (10 ml), HCl (10 ml, 40 ml) was added. mmol, 4 M in dioxane) at 0 °C and stirred at RT for 24 h. The reaction mixture was concentrated under low pressure. The crude residue was dissolved in water (15 ml) and the pH was adjusted to ~7 using 10% aqueous NaHCOs solution, diluted with water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic extracts were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was adsorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography, eluting with 20-25% EtOAc in hexanes, giving 3-((3,3-difluorocyclopentyl )sulfonyl)aniline (250 mg, 35% yield) as a viscous oil. 1H NMR (400 MHz, MeOD): 5 7.27 (t, J= 8.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.95 ( dd, J = 8. 0, 2.0 Ηζ, 1 Η), 3.90-3.84 (m, 1 Η), 2.51 -2.05 (m, 6Η), NH2 protons were not visible, m / z (ESI): 262.1 [M+1 ], PREPARATION OF AR2 RING INTERMEDIATE COMPOUNDS Intermediate compound 7: 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2carboxylic acid Lnn / Zznz / E / YIAI Intermediate compound 7 Step 1: To a solution of 3,5-dichloropyrazine-2-carboxylic acid (3.25 g, 16.84 mmol, Frontier Scientific, Inc.) in MeOH (20 ml), 10 drops of conc. sulfuric acid were added. The reaction was stirred at reflux for 16 h, cooled to RT, and concentrated in vacuo. The material was taken up in EtOAc (25 ml) and washed with satd NaHCOs. (20 mi). The aqueous layer was extracted again with EtOAc (2 x 20 ml). The combined EtOAc layers were dried with MgSO4 and concentrated in vacuo, giving crude methyl 3,5-dichloropyrazine-2-carboxylate (3.15 g, 15.22 mmol, 90% yield) as a brown solid. The material was continued to be used without any further purification. 1H NMR (400 MHz, CHLOROFORM-c / ) δ ppm 8.58 (s, 1 H), 4.04 (s, 3 H). Step 2: To a solution of methyl 3,5-dichloropyrazin-2-carboxylate (2.02 g, 9.78 mmol) in DMSO (40 ml), DIPEA (3.41 ml, 19.56 mmol) and 2-amino -2-methyl-1-propanol (0.93 ml, 9.78 mmol, Aldrich). The solution was stirred at RT for 4 d and then treated with water (150 mL) and extracted with EtOAc (5 x 20 mL). The combined organic extracts were concentrated in vacuo and absorbed onto a plug of silica gel and chromatographed through a silica gel column eluting with 0-75% EtOAc in heptane, yielding 3-chloro-5-( Methyl (1-hydroxy-2-methylpropan-2-yl)amino)pyrazin-2-carboxylate (1.46 g, 5.63 mmol, 58% yield) as an orange solid . 1H NMR (400 MHz, DMSO-c / 6) δ ppm 7.94 (s, 1 H), 7.80 (s, 1 H), 4.84 (t, J = 5.9 Hz, 1 H), 3.78 (s, 3 H) , 3.55 (d, J = 5.9 Hz, 2 H), 1.31 (s, 6 H). m / z (ESI): 260.0 (M+H)+. Step 3: To a solution of methyl 3-chloro-5-((1-hydroxy-2-methylpropan-2-¡l)amino)pyrazin-2carboxylate (1.46 g, 5.62 mmol) in THF (40 ml) and MeOH (13 ml), LiOH (20 ml of a 1 M aqueous solution, 20.00 mmol) was added. The resulting dark brown solution was stirred at RT for 16 h and then concentrated in vacuo, removing organic solvents. HE -75neutralized the aqueous solution with HCl (2 N) to ~pH 7 and extracted with EtOAc (2x10 ml). The combined organic extracts were concentrated in vacuo, giving 3-chloro-5-((1-hydroxy¡-2methylpropan-2-yl)amino)pyrazín-2-carboxylic acid (1.15 g, 4.68 mmol, 83% yield) in the form QR7 Lnn / Zznz / E / YIAI of a yellow solid, m / z (ESI): 246.1 (M+H)+. Table 1: Intermediates 7-1 and 7-2 were prepared analogously to the preparation of intermediate 7: Ex. No. Chemical structure Name LRMS (Low Resolution Mass Spectrometry): (ESI, positive ion) m / z 7-1 0 Cl ΗΟ^'-γ^Ν H acid 3-chloro- 5-((1- (hydroxy¡methyl)cycloprop¡l)amino)pyrazine2-carboxylic 244.1 7-2 0 Cl / OTBS HO η Ν < ^K / OTBS N H acid 3-chloro-5- ((2,2,3,3,6,9,9,10,10- nonamethyl-4,8-dioxa-3,9- disilaundecan-6-yl)amino)pyrazine-2carboxylic 490.2 Intermediate compound 8: 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid. 1)SOCI2 2) BnOH Stage 1 tBuOK Stage 2 O Cl -76Lnn / Zznz / E / YIAI Intermediate compound 8 Step 1: A mixture of 3,5-dichloroprazine-2-carboxylic acid (17.0 g, 88 mmol) in thionyl chloride (50 ml, 820 mmol) was heated in an oil bath at 90 °C for 4 p.m. The dark solution was evaporated to dryness under reduced pressure. Benzyl alcohol (10 ml, 96 mmol) and EtaN (25 ml, 178 mmol) were dissolved in dry THF (100 ml) and cooled in an ice bath. The crude acid chloride was added slowly maintaining the internal temperature <35 °C. Once the addition was complete, the mixture was removed from the cold bath and stirred for another 10 min. Satd ammonium chloride was added. (75 ml), water (100 ml) and ETOAc (200 ml), and the phases were mixed and separated. The organic layer was evaporated to dryness under reduced pressure and purified on a silica gel column (10-40% EtOAc in heptane), giving benzyl 3,5dichloropyrazine-2-carboxylate (22.4 g, 79 mmol, 90%). performance), m / z (ESI): 304.8 (M+Na)+. Step 2: 4,4-Dimethyloxazolidin-2-one (4.1 g, 35.6 mmol) was dissolved in DMF (80 ml) in a jacketed reactor. The temperature was adjusted to 15 °C. Potassium tert-butoxide solution (35.5 ml, 35.5 mmol, 1 M in THF) was added and the mixture was converted into a thick gel. A solution of benzyl 3,5-dichloropyrazin-2-carboxylate (10.0 g, 35.3 mmol) in DMF (50 ml) was added in one portion, and the mixture was stirred for 2 h. Water (100 ml), satd ammonium chloride were added. (50 ml) and EtOAc (100 ml), and the mixture was stirred for 5 min. The aqueous layer was allowed to settle and then drained. The organic phase was washed with water (100 ml), then dried with Na2SO4 and evaporated to dryness under reduced pressure. Purification on silica gel column (0-100% EtOAc in heptane) gave 3-chloro-5-(4,4dimethyl-2-oxooxazol¡din-3-¡l)pyrazin-2 -Benzyl carboxylate (10.7 g, 29.6 mmol, 84% yield) as an off-white solid, m / z (ESI): 362.3 (M+H)+. Step 3: Benzyl 3-chloro-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)pyrazino-2-carboxylate (10.7 g, 29.6 mmol), 6-azaspiro[2.5]octane were combined. (3.5 g, 31.5 mmol) and cesium carbonate (12 g, 36.8 mmol) in DMF (75 mi) in nitrogen. The mixture was stirred at RT for 16 h. Water (200 ml) and EtOAc (200 ml) were added, and the phases were mixed and separated. The organic phase was washed with water (200 ml) and then evaporated to dryness under reduced pressure. -77The crude material was suspended in methyl tert-butyl ether (50 ml) and stirred for 10 min. Heptane (50 ml) was slowly added and the mixture was stirred for another 10 min. It was filtered through a sintered glass frit and the solid was washed with 2:1 heptane:methyl tert-butyl ether (10 ml). The solid was dried in vacuo, giving 5-(4,4-dimethyl-2-oxooxazol¡din-3-yl)-3-(6azaspiro[2.5]octan-6-¡l)pyrazine-2-carboxylate. Benzyl (12.2 g, 27.9 mmol, 95% yield) as a light yellow solid. The filtrate was evaporated to dryness under reduced pressure, giving a yellow oil (0.7 g). Purification using ISCO (heptane to EtOAc gradient) gave another 0.5 g. m / z (ESI): 437.2 (M+H)+. Step 4: 5-(4,4-dimethyl-2-oxooxazol¡din-3-¡l)-3-(6-azaspiro[2.5]octan-6yl)pyrazín-2-carboxylate was dissolved of benzyl (12.2 g, 27.9 mmol) in DCM:EtOH (1:1, 120 ml). Palladium on carbon (5 wt % Pd) (0.350 g, 0.082 mmol) was added and the suspension was hydrogenated at 275.79 kPa (40 psi) for 1 h. The suspension was filtered through a layer of CELITE® and the solids were washed with DCM (10 ml). The filtrate was evaporated to dryness under reduced pressure, giving 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octane-6 acid. -yl)pyrazine-2carboxylic (9.17 g, 26.5 mmol, 95% yield) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.1 (s a, 1 H) 8.60 - 8.78 (m, 1 H) 4.06 - 4.26 (m, 2 H) 3.49 - 3.63 (m, 4 H) 1.65 -1.81 ( m, 6 H) 1.49 -1.61 (m, 4 H) 0.34 - 0.50 (m, 4 H). m / z (ESI): 347.1 (M+H)+. QR7 Lnn / Zznz / E / YIAI Table 2: Intermediate 8-1 was prepared analogously to the preparation of intermediate 8: Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 8-1 And o. / Vz o^Xy 5-(5-oxo-6-oxa-4azaspiro[2.4]heptan-4-yl)-3-(6-azaspiro[2.5]octan-6yl)pyrazine-2-carboxylic acid 345.1 Intermediate compound 9: 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2hydroxy¡propan-2-¡l)pyrazine-2-carboxylic EtO^xSnBu3 AND PdCI2(AmPhos) Stage 1 HCI Stage 3 Lnn / Zznz / E / YIAI Intermediate compound 9 Step 1: A mixture of benzyl 3,5-dichloropyrazine-2-carboxylate (3.03 g, 10.70 mmol), thbutyl (1-ethoxyvinyl)tin (4.25 g, 11.77 mmol, Aldrich) and bis- was heated. (di-tert-butyl(4dimethylaminophenyl)phosphin)dichloropalladium (0.30 g, 0.42 mmol) in toluene (1 mi) at 80 °C in 2 h. The reaction mixture was cooled to RT and treated with 15 ml of 1 M aqueous KF and stirred for 30 min. The mixture was diluted with t-butyl methyl ether and the precipitated solid was collected by filtration. The filtrate was separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified on a silica gel column (10% EtOAc in heptane), giving a mixture of benzyl 3-chloro-5-(1-ethoxyvinyl)pyrazín-2-carboxylate and 5-chloro3-( Benzyl 1-ethoxyvinyl)pyrazin-2-carboxylate (3.03 g). m / z (ESI): 319.5 (M+H)+. Step 2: a mixture of benzyl 3-chloro-5-(1-ethoxyvinyl)pyrazin-2-carboxylate and 5-chloro-3-(1-ethoxyvinyl) was heated. Benzyl pyrazine-2-carboxylate (2.81 g, 8.82 mmol), DIPEA (4.62 ml, 26.4 mmol) and 6-azaspiro[2.5]octane (1.18 g, 10.58 mmol, Wuxi Apptec) in DMSO (10 mi) at 70 °C for 3 h. The reaction mixture was cooled to RT, diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were concentrated and the residue was purified on an ISCO column (0-20% EtOAc in heptane), giving 5-(1-ethoxyvinyl)-3-(6Lnn / Zznz / E / YIAI Benzyl -79azaspiro[2.5]octan-6-yl)pyrazín-2-carboxylate (1.33 g, 3.40 mmol, 38% yield): 1H NMR (CHLOROFORM-d) δ: 8.30 (s, 1H), 7.45 -7.51 (m, 2H), 7.31-7.40 (m, 3H), 5.42 (s, 2H), 5.40 (d, J= 1.8 Hz, 1H), 4.41 (d, J = 2.0 Hz, 1H), 3.96 ( c, J=7.0 Hz, 2H), 3.413.47 (m, 4H), 1.43 (t, J = 6.9 Hz, 3H), 1.38 (dd, J = 6.5, 4.7 Hz, 4H), 0.33 (s, 4H ). m / z (ESI): 394.1 (M+H)+. Step 3: to a stirred solution of benzyl 5-(1-ethoxyvinyl)-3-(6-azaspiro[2.5]octan-6-íl)pyrazino2-carboxylate (1.33g, 3.38 mmol) in THF (15 ml), 5N HCl (3.38 ml, 16.90 mmol) was added. After addition, the mixture was stirred at RT for 3 h. The mixture was diluted with EtOAc and slowly neutralized with satd aqueous NaHCOs. The organic layer was separated, dried over MgSO4 and concentrated to provide benzyl 5-acetyl-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2carboxylate. 1H NMR (CHLOROFORM-d) δ: 8.51 (s, 1H), 7.46-7.50 (m, 2H), 7.317.41 (m, 3H), 5.44 (s, 2H), 3.42-3.52 (m, 4H), 2.62 (s, 3H), 1.33-1.41 (m, 4H), 0.36 (s, 4H). m / z (ESI): 366.1 (M+H)+. Step 4: to a stirred mixture of benzyl 5-acetyl-3-(6-azaspiro[2.5]octan-6-yl)pyrazino-2carboxylate (1.21 g, 3.31 mmol) and cesium fluoride (2.01 g, 13.23 mmol) In THF (2 ml), trimethyl(trifluoromethyl)silane (0.59 ml, 3.97 mmol, Aldrich) was added. After addition, the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on a silica gel column (0-30% EtOAc in heptane), giving 3-(6-azaspiro[2.5]octan-6-yl)-5-(1, Benzyl 1,1-trifluoro-2-hydroxypropan-2yl)pyrazine-2-carboxylate (1.21 g, 2.78 mmol, 84% yield) 1H NMR (CHLOROFORM-d) δ: 8.10 (s, 1H), 7.49 (dd, J=7.8, 1.4 Hz, 2H), 7.37 (dd, J = 7.5, 1.9 Hz, 3H), 5.44 (s, 2H), 5.21 (s, 1H), 3.40-3.47 (m, 4H), 1.74 (s, 3H), 1.39 (dd, J = 6.5, 4.7 Hz, 4H), 0.36 (s, 4H). m / z (ESI): 436.3 (M+H)+. Step 5: a solution of 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2hydroxypropan-2-!l)pyrazino-2- was hydrogenated Benzyl carboxylate (1.2 g, 2.76 mmol) in ethanol (15 ml) at 344.7 kPa (50 psi) in the presence of Pd / C (0.293 g of 10 wt%, 0.276 mmol) for 2 h. The catalyst was removed by filtration through a short pad of CELITE® and the solids were rinsed with EtOH. The filtrate was concentrated, yielding 3-(6-azaspiro[2.5]octan-6-yl)5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazino acid. 2-carboxylic (0.90 g, 95% yield) as a yellow solid, m / z (ESI): 346.3 (M+H)+. Coupling of Intermediate Compounds of Ar1 and Ar2 Intermediate compound 10: n-(3-(n-(tert-but¡l)sulfamo¡l)phen¡l)-3,5-dichloropyraz¡n-2carboxamide -80OH Cl DMTMM, DMF, ta, 24 h Intermediate compound 10 QR7 Lnn / Zznz / E / YIAI To a stirred mixture of 3,5-dichloropyrazine-2-carboxylic acid (2.19 g, 11.35 mmol), 3amino- / V-(tert-butyl)benzenesulfonamide (2.85 g, 12.48 mmol) in DMF (20 ml) at rt, 4-(4,6-dimethoxy-1,3,5-tñazin-2-íl)-4-methylmorpholynio chloride (DMTMM) (4.71 g) was added. , 17.02 mmol). The reaction mixture was stirred at RT for 24 h and water was added to the mixture. The precipitate obtained was separated by filtration, washed with water and dried. N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2,6-dichloronicotinamide (4.10 g, 90% yield) was obtained as a white solid, m / z (ESI): 425.0 (M+Na)+. Table 3: Intermediate 10-1 was prepared analogously to the preparation of intermediate 10: Comp. int. No. Chemical structure LRMS name: (ESI, positive ion) m / z 10-1 / —i O Cl Ti n 0 0 N Cl 3,5-dichloro- / \ / -(3- (cyclopentylsulfonyl)pheníl )p¡r azine-2-carboxamide 401.2 Intermediate compound 11: 3-chloro-n-(3-(cyclopentylsulfonyl)phenyl)-5-((1-hydroxy-2methylpropan-2-yl)amino)pyrazin-2-carboxamide O Cl HATU, DIPEA DCM Intermediate compound 11 To a solution of 3-chloro-5-((1-hydroxy¡-2-methylpropan-2-¡l)amino)pyraz¡n-2carboxylic acid (0.15 g, 0.60 mmol, Intermediate 7), 3-(cyclopentylsulfonyl)aniline (0.16 g, 0.72 mmol, Combi-Blocks Inc.), DIPEA (0.367 ml, 2.11 mmol, Sigma-Aldrich) and DCM (5 ml) in a vial fitted with a red pressure relief cap , HATU (344 mg, 0.904 mmol, Sigma-Aldrich) was added. The solution was stirred at room temperature for 3 h and diluted with DCM. -81 (10 mi) and water (20 mi). The organic layer was collected and the aqueous layer was re-extracted with DCM (10 ml). The combined organic extracts were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a silica gel column, eluting with 0-50% EtOAc in heptane, yielding the title compound (112 mg , 0.247 mmol, 41% yield), as a light yellow solid, m / z (ESI): 453.0 (M+H)+. QR7 Lnn / Zznz / E / YIAI Table 4: Intermediates 11-1 to 11-5 were prepared analogously to the preparation of Intermediate 11: Com Pint. No. Chemical structure LRMS name: (ESI, positive ion) m / z 11-1 O. / / W o IZ X IZ O I 3-chloro-5-((1 -hydroxy¡-2methylpropan-2-yl)amino )A / -(3-(piperidín-1ylsulfonyl)phenyl)pyrazine-2carboxamide 468.0 11-2 / —1 o Cl Ν'γ, 'Ν ' / η II | \ / OO >\ / OH N H 3-chloro- / V-(3- (cyclopentylsulfonyl)phenyl)- 5-((1- (hydroxymethyl)cyclopropíl)amino)pyrazine-2carboxamide 451.0 11-3 ΖΞΕ O. / O IZ IZ O I N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3chloro-5-((1 -hydroxy¡-2methylpropan-2yl)amino)pyraz¡n-2-carboxamide 456.1 11- 4 T o ZI / 2 o=\ ZI Q. cnC / xo IZ N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3- chloro-5-((1- (hydroxymethyl)cycloprop¡l )a mino)pyrazine-2carboxamide 454.1 Com Pint. No. Chemical structure LRMS name: (ESI, positive ion) m / z 11-5 H A ? ? ^OTBS 1 o O M N / V .OTBS H M-(3-( / V-(tertbutyl)sulfamoyl)pheníl)-3chloro-5((2,2,3,3,6,9,9,10, 10- nonamethyl-4,8-dioxa-3,9disilaundecan-6yl)amino)pyrazín-2carboxamide 701.2 Example 100: n-(3-(n-(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-l)amino)-3(6-azaspiro[2.5 ]octane-6-l)pyrazine-2-carboxamide. QR7 Lnn / Zznz / E / YIAI Step 1: A mixture of A / -(3-(A / -(fert-butyl)sulfamoyl)phenyl)-3,5-dichloroprazin-2carboxamide (3.71 g, 9.20) was stirred. mmol, Intermediate compound 10), DIPEA (2.12 ml, 11.96 mmol) and 2amino-2-methyl-1-propanol (0.97 m., 10.12 mmol) in ACN:DMSO (4:1.50 ml) at RT for 16 h . Water was then added and extracted with DCM (2 x 20 ml). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-30% EtOAc / EtOH (3:1) in heptane, giving A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl) -5-chloro-3-((1-hydroxy-2-methylpropan-2yl)amino)pyrazín-2-carboxamide (1.50 g, 3.29 mmol, 36% yield). 1H NMR (DMSOd6) δ: 10.85 (s, 1H), 9.03 (s, 1H), 8.44 (s, 1H), 7.87-7.94 (m, 2H), 7.50-7.61 (m, 3H), 5.05 (t, J = 5.5 Hz, 1H), 3.53 (d, J = 5.5 Hz, 2H), 1.39 (s, 6H), 1.11 (s, 9H). m / z (ESI): 456.0 (M+H)+. Step 2: to a solution of A / -(3-(A / -(ert-butyl)sulfamoyl)phenyl)-3-chloro-5-((1-hydroxy-2methylpropan-2-yl)amino)p Reason-2-carboxamide (60 mg, 0.13 mmol) and DMSO (1.5 ml) were -83added DIPEA (0.046 ml, 0.26 mmol) and 6-azaspiro[2.5]octane (26 mg, 0.23 mmol). The solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2x15 ml). The combined organic extracts were concentrated in vacuo and adsorbed onto a plug of silica gel and subjected to chromatography through a silica gel column eluting with 0-60% EtOAc in heptane, yielding A / -(3 -( / V-(tert-butyl)sulfamo¡l)phenyl)-5-((1-hydroxy¡-2-methylpropan-2-¡l)amino)-3-(6azaspiro[2.5 ]octan-6-yl)pyrazín-2-carboxamide (39 mg, 0.073 mmol, 55% yield) as a light yellow solid. 1H NMR (DMSO-d6) δ: 10.29 (s, 1H), 8.42 (s, 1H), 7.87 (d, J = 5.9 Hz, 1H), 7.40-7.51 (m, 4H), 6.99 (s, 1H) , 4.74 (t, J = 4.8 Hz, 1H), 3.58 (d, J = 4.5 Hz, 2H), 3.36 - 3.45 (m, 4H), 1.42 (s a, 4H), 1.34 (s, 6H), 1.11 ( s, 9H), 0.32 (s, 4H). m / z (ESI): 531.2 (M+H)+. Table 5: Examples 100-1 to 100-17 were prepared analogously to the preparation of example 100: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 100-1 c \n, XX X S N X , ' / J l-l I \ / 1 o O H N X (ferc- butyl )su Ifamoyl )pheni 1 )-5-(( 1 hydroxy-2-methylpropan-2yl)amino)-3-(4-methylpiperidin- 1-yl)pyrazín-2-carboxamide 519.1 100-2 X H A Η Ϊ / \ / / Λ μ ι \ / 1 o 0 H Ν -((1 hydroxy-2-methylpropan-2yl)amino)pyrazine-2carboxamide 541.2 100-3 cf3 C. 19 \.n„ XX XX X 's; n X^n , , 1 o O H Ν 3-(4-(trifl uorometi I)p¡ perid i n-1 yl)pyrazin-2-carboxamide 573.1 Ex. No. Chemical Structure LRMS Name: (ESI, positive ion) m / z 100-4 Η Π íí^ \ .Nx A ^A. Jk A. A N yj N x , ' ' / Y H II | \ / 1 o 0 M N.Á -2yl)amino)pyrazine-2carboxamide 533.2 100-5 n ¿ X.X. XX X ,s^ N Y N \ / ' / i-i II i \ / 1 0 0 H Ν.Χ I p¡ peri d in-1 -i I )-5-(( 1 hydroxy-2-methylpropan-2¡l)amino)pyrazín-2carboxamide 533.1 100-6 Y xO A X S N YY*N , , ' / \ ' H II 1 \ / 1 o 0 M N. 2yl)amino)-3-(4isopropylpiperidin-1 yl)pyrazine-2-carboxamide 547.1 100-7 - c í \^NX J\xA A A χχ N γγ^ χ / 1 θΑ H IX .A AYH N H 3-(4 -(tert-butyl)piperid in-1yl)-N-(3-(N-(tert-butyl)suIfamoyl)pheni I)-5-((1 hydroxy-2-methylpropan-2yl)amino)pyrazin- 2- carboxamide 561.1 100-8 - c Q \ ^nx A A A A A< a N Ti N \ / 1 o'b H Yx X nH H 3-(4-(sec-butyl)piper¡din-1 -yl)N- (3-(N-(tert-butyl)su Ifamoyl )pheni I )-5-(( 1 hydroxy-2-methylpropan-2yl)amino)pyrazine-2carboxamide 561.1 QR7 ίηη / 77η7 / Ε / ΥΙΛΙ Ex. no. Chemical structure LRMS name: (ESI, positive ion) m / z 100-9 C ¿ / Y )pheni 1 )-5-(( 1 hydroxy-2-methylpropan-2yl)amino)-3-(4- propylpiperidin-1 -yl)pyrazine-2carboxamide 547.1 100-10 • C 7 - Λ X n a a, X N li N \ / 1 o'b H XX -methylpropan-2yl)amino)pyrazine-2carboxamide 545.1 100-11 .. V xV ΛΓ N ii N \ / 1 o'b H XX X .OH \x- N H N-(3-(N-(tert-butyl) su Ifamoyl )pheni I )-5-(( 1 hydroxy-2-methylpropan-2yl)amino)-3-(4(methoxymethyl)piperidín-1yl)pyrazine-2-carboxamide 549.1 100- 12 H A II \ .n. XX. X X n Y, , I o'b H N.X 3-(2-azaspiro[3.3]heptan-2yl)pyrazine-2-carboxamide 517.1 100-13 H A ? ? 1 ¿''Ó H ν' -(2- azaspiro[3.5]nonan-2yl)pyrazine-2-carboxamide 545.1 QR7 ίηη / 77η7 / Ε / ΥΙΛΙ Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 100-14 NnΛΛn \ / । o / xo h n 2 y oh H N-(3-(N-(tert-butyl)su Ifamoyl )pheni 1 )-5-(( 1 hydroxy-2-methylpropan-2yl)amino)-3-(3 -oxa-9- azaspiro[5.5]undecan-9yl)pyrazín-2-carboxamide 575.1 100-15 phenyl)-5-((1 hydroxy-2-methylpropan-2yl)amino)-3-(7azaspiro[3.5]nonan-7yl)pyrazín-2-carboxamide 545.1 100-16 F F u A 0 XA-A v 1 o 0 M N AklX / OH N H N-{3-(N-(tertbutyl)sulfamoyl)phenyl)-3-(2,2difluoro-7-azaspiro[3.5]nonan-7-yl)-5((1 -hydroxy- 2-methylpropan-2yl)amino)pyrazin-2- carboxamide 581.1 100-17 \ / N^ ΛΑ A A A X N Ti N \ / z z / i-ι II i \ / 1 o O M m A X / OH v N H N-( 3-(N-(tert-butyl)suIfamoyl)pheni I)-5-((1 hydroxy-2-methylpropan-2yl)amino)-3-(8-azaspiro[4.5]decan-8yl)pyrazin-2- carboxamide 559.2 Example 101: n-(3-(n-(tert-butyl)sulfamo¡l)-5-methylphen¡l)-5-((1-hydroxy-2-methylpropan-2yl) amino)-3-(6-azaspiro[2.5]octan-6-¡l)pyrazín-2-carboxamide. QR7 Lnn / Zznz / E / YIAI Step 1 Η QR7 Lnn / Zznz / E / YIAI Step 1: To a 50 ml round bottom flask, 5-(4,4-dimethyl-2oxooxazolidin-3-yl) acid was added. -3-(6-azaspiro[2.5]octan-6-¡l)pyrazín-2-carboxylic acid (111 mg, 0.320 mmol, Intermediate 8) and DCM (4 ml). Oxalyl chloride (0.24 ml, 0.48 mmol, 2 M in DCM) was then added, followed by a couple of drops of DMF. The reaction mixture was stirred at RT for 30 min and the solvent was removed in vacuo. The residue was redissolved in DCM (4 ml), and treated with 3-amino-A / -(tert-butyl)-5-methylbenzenesulfonamide (78 mg, 0.32 mmol, Intermediate 1) and DIPEA (0.17 ml, 0.96 mmol). The reaction mixture was stirred for 18 h at RT and the solvent was removed in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column, eluting with a gradient of 0-50% EtOAc in heptane, providing N-(3-{N- (tertbut¡l)sulfamo¡l)-5-methylphen¡l)-5-(4,4-dimethyl-2-oxooxazol¡din-3-¡l)-3-(6-azaspiro [2.5]octan-6yl)pyrazine-2-carboxamide (117 mg, 0.205 mmol, 64% yield) as a light yellow solid, m / z (ESI): 571.3 (M+H)+. Step 2: To a 15 ml reaction vial, A / -(3-(A / -(tert-butyl)sulfamoyl)-5methylphenyl)-5-(4,4-dimethyl-2-oxooxazole) was added. d¡n-3-¡l)-3-(6-azaspiro[2.5]octan-6-íl)pyrazín-2carboxamide (117 mg, 0.205 mmol), sodium hydroxide (0.410 ml, 2.050 mmol, 1 N) and MeOH (3 ml). The reaction mixture was heated to 70 °C for 1.5 h, cooled to rt, and the solvent was removed in vacuo. HCl (2N) was added and extracted with EtOAc. The organic extract was washed with satd NaHCOs. and water, and dried over Na2SO4. A / -(3-(N-(tert-Butyl)sulfamoyl)-5methylphenyl)-5-((1-hydroxy-2-methylpropan-2-¡l)amino)-3- was obtained. (6-azaspiro[2.5]octan-6-¡l)pyrazín-2carboxamide (86 mg, 0.16 mmol, 77% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.41 (s, 1H), 7.29 -88(s, 1Η), 6.98 (s, 1 Η), 4.79 (t, J = 5.77 Hz, 1H), 3.59 (d, J = 5.67 Hz, 2H), 3.35-3.48 (m, 4H), 2.35 (s, 3H), 1.38-1.47 (m, 4H), 1.34 (s, 6H), 1.13 (s, 9H), 0.33 (s, 4H). m / z (ESI): 545.3 (M+H)+. Table 6: Examples 101-1 to 101-8 were prepared analogously to the preparation of example 101: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 101-1. n - OO H ,1 -trifluoro-2methylpropan-2yl)sulfonyl)phenyl)pyrazine-2carboxamide 570.2 101-2 3 n · 5 OO H N X -methylpropan2-yl)amino)-3-(6azaspiro[2.5]octan-6¡l)pyraz¡n-2-carboxamide 516.2 101-3 o A / W x 'o ΞΖ IZ 0 T 5-((1 -hydroxy -2-methylpropan2-yl)amino)- / \ / -(3-((1-methylcyclobutyl)sulfonyl)phenyl)3-(6-azaspiro[2.5]octan-6¡l)pyraz¡n-2-carboxamide 528.2 101-4. Λ AaA ... 1 0 Ο H N. yl)amino)-3-(6- azaspiro[2.5]octan-6- ¡l)pyraz¡n-2-carboxamide 549.2 101-5 V Η |Π Η 1 \ A. A / A A A JA ,s; r n n x , ' O^O F H -(6- 549.2 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z azaspiro[2.5]octan-6- yl)pyrazine-2-carboxamide 101-6 r * 1 i H H 1 \ / o=s^J ν,,ΑΧ ,oh / z V N V 0 H / 7-(3-(1,1- dioxidothiomorpholino)phenyl)-5((1 -hydroxy-2-methylpropan-2yl)amino)-3- (6-azaspiro[2.5]octan-6yl)pyrazine-2-carboxamide 529.3 101-7 - í 1 1 H 11 1 \ / 0. J X / OH v N H 5-((1 -hydroxy-2-methylpropan- 2- yl)amino)-A / -(3morpholinophenyl)-3-(6azaspiro[2.5]octan-6yl)pyrazine-2-carboxamide 481.2 101-8 1 O IZ or ¿Cv IZ or I 5-((1 -hydroxy -2-methylpropan2-yl)amino)-A / -(3-((1 -hydroxy2-methylpropan-2yl)amino)phenyl)-3-(6azaspiro[2.5]octan-6¡l)pyraz¡n-2- carboxamide 483.3 Examples 102-1 and 102-2: (s)-n-(3-((3,3-difluorocyclopentyl)sulfoníl)phenyl)-5-((1-hydroxy-2methylpropan-2-yl)amino )-3-(6-azaspiro[2.5]octan-6-yl)pyrazin-2-carboxamide and (r)-n-(3-((3,3difluoroc¡clopentyl)sulfonyl) phen¡l)-5-((1-hydroxy¡-2-met¡lpropan-2-¡l)amino)-3-(6azaspiro[2.5]octan-6-yl)pyraz¡n-2 -carboxamide. -90Lnn / Zznz / E / YIAI Step 1: to a solution of 5-(4,4-dimethyl-2-oxooxazolidín-3-yl)-3-(6azaspiro[2.5]octan-6-yl)pyraz acid n-2-carboxylic acid (71 mg, 0.21 mmol, Intermediate 8) and DMF (2 ml), 3-((3,3-difluorocyclopentyl)sulfonyl)aniline (54 mg, 0.21 mmol, Intermediate) was added 6) and 4-(4,6-dimethoxy-1,3,5-tr¡az¡n-2-yl)-4-methylmorphol¡n-4-io chloride (86 mg, 0.31 mmol). The solution was stirred at room temperature for 16 h. The reaction was treated with more 4-(4,6-dimethoxy¡-1,3,5-triaz¡n-2-¡l)-4-methylmorphol¡n-4-¡o chloride (50 mg). After another 24 h, the reaction was diluted with water (40 ml) and stirred for 20 min. The aqueous solution was filtered and the yellow solids were dried under vacuum while on the filter. The material was adsorbed onto a plug of silica gel and chromatographed through a silica gel column, eluting with 0-50% EtOAc in heptane, yielding Λ / -(3-((3,3difluorocyclopentyl )sulfon¡l)phen¡l)-5-(4,4-dimethyl-2-oxooxazol¡din-3-¡l)-3-(6-azaspiro[2.5]octan- 6yl)pyrazin-2-carboxamide (88 mg, 0.15 mmol, 72% yield) as a light yellow solid. Step 2: to a solution of A / -(3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)-5-(4,4-dimethyl-2oxooxazolidin-3-yl)-3-(6-azaesp ¡ro[2.5]octan-6-¡l)pyrazin-2-carboxamide (88 mg, 0.15 mmol) and THF (2 ml):MeOH (0.5 ml), 1 M aqueous LiOH (0.45 ml) was added , 0.45 mmol). The solution was stirred at room temperature. After 2 h, the reaction was diluted with water and extracted with EtOAc (2x15 ml).The combined organic extracts were concentrated in vacuo, adsorbed onto a silica gel plug, and chromatographed through a silica gel column, eluting with 0-100% EtOAc in heptane, yielding Λ / -( 3-((3,3difluorocyclopentyl)sulfonyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazin -2-carboxamide (61 mg, 0.11 mmol, 73% yield) as an off-white solid, m / z (ESI): 590.2 (M+H)+. This material was separated by chiral preparative SFC-91 using an OX column (250 x 21 mm, 5 pm) with a mobile phase of 60% liquid CO2 and 40% MeOH, and a flow rate of 75 ml / min, giving : Example 102-1: (S)- / \ / -(3-((3,3-difl uorocyclopentyl)sulfonyl )phenyl )-5-(( 1 -hydroxy-2methylpropan-2-yl)amino )-3-(6-azaspiro[2.5]octane-6-l)pyrazine-2-carboxamide. First elution maximum; ee > 99%, 1H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (s, 1 H), 8.43 (t, J = 1.8 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H) , 7.59 (t, J = 7.9 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.45 (s, 1 H), 7.03 (s, 1 H), 4.72 - 4.89 (m, 1 H), 4.01 - 4.11 (m, 1 H), 3.56 - 3.60 (m, 2 H), 3.38 - 3.44 (m, 4 H), 2.37 - 2.46 (m, 1 H), 1.99 - 2.24 (m, 4 H), 1.76 (dt, J = 6.8, 3.2 Hz, 1 H), 1.37 - 1.47 (m, 4 H), 1.34 (s, 6 H), 0.33 (s, 4 H). 19F NMR (376 MHz, DMSO-d6) δ ppm -92.52 - -90.43 (m, 2 F). m / z (ESI): 564.2 (M+H)+. Example 102-2: (R)-W-(3-((3,3-difluoroc¡clopent¡l)sulfon¡l)phen¡l)-5-((1-hydroxy-2methylpropan-2-yl)am ¡no)-3-(6-azaspiro[2.5]octane-6-¡l)pyrazín-2-carboxamide. Second elution maximum; 98% ee, 1H NMR (400 MHz, DMSO-d6) δ ppm 10.42 (s, 1 H), 8.43 (t, J=1.8 Hz, 1 H), 8.13 (d, J= 8.4 Hz, 1 H) , 7.58 (t, J = 7.9 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.44 (s, 1 H), 7.03 (s, 1 H), 4.79 (s a, 1 H) , 4.05 (t a, J = 8.2 Hz, 1 H), 3.58 (s a, 2 H), 3.38 - 3.45 (m, 4 H), 2.35 - 2.47 (m, 2 H), 1.98 - 2.24 (m, 4 H ), 1.37 - 1.45 (m, 4 H), 1.33 (s, 6 H), 0.32 (s, 4 H). m / z (ESI): 564.2 (M+H)+. Stereochemistry was assigned arbitrarily. QR7 Lnn / Zznz / E / YIAI Example 103: r)-(3-(cyclopentylsulfon¡I)pheniI)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-yl pyrazin-2-carboxamide To a solution of 3-chloro-A / -(3-(cyclopentylsulfonyl)phenyl)-5-((1-hydroxy-2-methylpropan-2yl)amino)pyrazine-2-carboxamide (110 mg, 0.243 mmol, Intermediate compound 11), DIPEA (0.085 ml, 0.486 mmol, Sigma-Aldrich) and DMSO (2 ml), 6-azaspiro[2.5]octane (45 mg, 0.405 mmol, AstaTech, Inc.) was added. The solution was stirred at 50 °C for 16 h. After cooling to rt, water was added and the solids were filtered, adsorbed onto a plug of silica gel and chromatographed through a silica gel column, eluting with 0-50% EtOAc in heptane. providing the title compound (104 mg, 0.20 mmol, 81% yield), as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.80 (s, 1 H), 8.15 (d a, J = 8.2 Hz, 1 H), 8.08 (s, 1 H), 7.56 - 7.60 (m, 1 H) , 7.52 (d, J = 8.0 Hz, 1 H), 7.25 (s, 1 H), 4.90 (s, 1 H), 3.76 (d, J = 5.7 Hz, 2 H), 3.69 (d a, J = 5.9 Hz, 1 H), 3.55 (ta, J= 5.5 Hz, 5 H), 2.06-2.15 (m, 2 H), 1.74- 1.96 (m, 4 H), 1.59-1.64 -92(m, 2 Η), 1.53 - 1.55 (m, 4 H, obscured by aqueous maximum), 1.45 (s, 6 H), 0.38 (s, 4 H). m / z (ESI): 528.2 (M+H)+. Table 7: 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.Oaa / / \' lj I \ / 00 A. X oh H 5-((1 -hydroxy-2-methylpropan -2yl)amino)-A / -(3-(perídin-1ylsulfonyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide 543.2 103-2 o c · θ Ti n w OO M N. X. 6-yl)pyraz¡n2-carboxamide 526.1 103-3 ....... í H í¡^ 9 z 'k H II I \ / 1 o O M N / AX.0H N H A / -(3-( / \ / -(ert-butyl)sulfamoyl)phenyl)- 5-((1- (hydroxymethyl)cyclopropyl)amino)-3(6-azaspiro[2.5]octan-6-yl)pyrazine2-carboxamide 529.1 103-4 , , ... . δ ΛΑ A A N ii N O'b H N A N [2.5]octan-6-yl)pyrazín2-carboxamide 543.2 Example 104: n-(3-(n-(fert-butyl)sulfamo¡l)phen¡l)-3-(4-chlorophen¡l)-5-((1-hydroxy¡-2methylpropan-2-yl) amino)pyrazin-2-carboxamide. ci Lnn / Zznz / E / YIAI -93A mixture of A / -(3-(A / -(tert-butyl)sulfamo¡l)pheníl)-3-chloro-5-((1-hydroxy¡-2methylpropan-2-yl) was stirred )amino)pyrazín-2-carboxamide (137 mg, 0.302 mmol, Intermediate 113), (4-chlorophenyl)boronic acid (71 mg, 0.45 mmol), potassium carbonate (125 mg, 0.91 mmol ) and PdCl2(PPh3)2 (42 mg, 0.06 mmol) in dioxane (2 ml) / water (0.4 ml) at 90 °C for 3 h. The reaction mixture was cooled, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, concentrated and purified by silica gel chromatography (0-50% EtOAc:EtOH (3:1) in heptane), giving A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-3-(4-chlorophenyl)-5-((1hydroxy-2-methylpropan-2-yl)amino) pyrazine-2-carboxamide (84 mg, 0.16 mmol, 53% yield). 1H NMR (DMSO-d6) δ: 10.60 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H), 7.83 (d a, J = 7.3 Hz, 1H), 7.54-7.62 (m, 2H) , 7.44-7.53 (m, 5H), 7.37 (s, 1H), 4.86 (t, J = 5.7 Hz, 1H), 3.61 (d, J = 5.8 Hz, 2H), 1.36 (s, 6H), 1.10 ( s, 9H). m / z (ESI): 532.1 (M+H)+. Table 8: Examples 104-1 to 104-4 were prepared analogously to the preparation of example 104: Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 104-1 -Ύ 0. O ΙΣ I ZY / =\ yxx IZ 0 / V-(3-(A / -(tert-butyl )sulfamoyl)phenyl)3-(4-fluorophenyl)-5-((1-hydroxy-2methylpropan-2-yl)amino)pyrazín-2carboxamide 516.2 104-2 T 0 ZI 0— \== / / =z o =\ ΣΙ 0. Ό Y A / -(3-(A / -(tert-butyl)sulfamoyl)pheníl)5-((1 -hydroxy-2-methylpropan-2yl)amino)-3-(4 (trifluoromethyl)pheniI)pyrazine-2carboxamide 566.2 104-3 or h Yíi ? Y X S N T N , / 1 0 O H N A amino)pyrazine-2carboxamide 526.1 Ex. No. Chemical structure LRMS name: (ESI, positive ion) m / z 104-4 or H lí \ Λ A A As AA χ n A n , , 1 o O H nX X .OH N H A / -(3-( A / -(fert-butyl)sulfamoyl)phenyl)5-((1-hydroxy-2-methylpropan-2yl)amino)-3-(4isopropylphenyl)pyrazine-2carboxamide 540.2 Examples 105-1 and 105-2: (r)-n-(3-(n-(ferc-butyl)sulfamo¡l)phen¡l)-3-(6-azaspiro[2.5]octan6-yl) -5-(1,1,1-trifluoro-2-hydroxypropan-2-¡l)pyrazin-2-carboxamide and (s)-n-(3-(n-(tert-butyl)sulfamoyl)phen¡ l)-3-(6-azaspiro[2.5]octan-6-íl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazín2-carboxamide . QR7 Lnn / Zznz / E / YIAI DIPEA, HATU, DMF, ta, 24 h To a mixture of 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan2-¡l)pyrazine-2-carboxylic acid (150 mg, 0.434 mmol, Intermediate 9), 3-amino-A / -(tert-butyl)benzenesulfonamide (119 mg, 0.52 mmol) and DIPEA (0.19 ml, 1.09 mmol) in DMF (2 ml), HATU (0.21 g, 0.56) was added mmol). The reaction mixture was stirred at room temperature for 18 h and diluted with water. The precipitated solid was collected by filtration, washed with water and dried. The crude material was purified by silica gel chromatography (030% EtOAc:EtOH (3:1) in heptane), giving A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-3 -(6azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-l)pyrazine-2-carboxamide (192 mg, 0.346 mmol, 80% yield) in the form of a white solid. 1H NMR (DMSO-de) δ: 10.98 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.87 (dt, J = 6.9, 2.1 Hz, 1H), 7.51-7.61 (m, 3H), 6.94 (s, 1H), 3.50-3.59 (m, 4H), 1.69 (s, 3H), 1.34-1.41 (m,4H), 1.11 (s, 9H), 0.32 (s, 4H).) . m / z (ESI): 556.1 (M+H)+. This racemic material was separated by chiral preparative SFC using a -95Chiralpack AD column (250 x 20 mm, 5 pm) with a mobile phase of 75% liquid CO2 and 25% MeOH, and a flow rate of 60 ml / min, giving: Example 105-1: (R)-A / -(3-(A / -(ferc-butyl)sulfamoyl)pheníl)-3-(6-azaspiro[2.5]octan-6-íl)-5( 1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazín-2-carboxamide. First elution maximum; ee > 99%, 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.87 (dt, J = 6.9, 2.1 Hz, 1H), 7.51 -7.61 (m, 3H), 6.94 (s, 1H), 3.50-3.59 (m,4H), 1.69 (s, 3H), 1.34-1.41 (m, 4H), 1.11 (s, 9H), 0.32 (s , 4H). ). m / z (ESI): 556.1 (M+H)+. Example 105-2: (S)-A / -(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)-5(1,1 ,1-trifluoro-2-hydroxypropan-2-l)pyrazin-2-carboxamide. Second elution maximum; ee > 99%, 1H NMR (DMSO-d6) δ: 10.98 (s, 1H), 8.37 (s, 1H), 8.26 (s, 1H), 7.87 (dt, J = 6.9, 2.1 Hz, 1H), 7.51 -7.61 (m, 3H), 6.94 (s, 1H), 3.50-3.59 (m, 4H), 1.69 (s, 3H), 1.34-1.41 (m, 4H), 1.11 (s, 9H), 0.32 (s , 4H). m / z (ESI): 556.1 (M+H)+. Stereochemistry was assigned arbitrarily. Example 106: n-(3-(n-(fert-butyl)sulfamoyl)phenyl)-5-((1,3-dihydroxy-2-methylpropan-2¡l)amino)-3-(6-azaspiron [2.5]octan-6-yl)pyrazin-2-carboxamide. Stage 1: to a solution of A / -(3-(A / -(te / 'c-butyl)sulfamo¡l)pheníl)-3-chloro-5((2,2,3,3,6 ,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)amino)pyrazín-2-carboxamide (240 mg, 0.343 mmol, Intermediate 11 -5) and DMSO (2 ml), 6azaspiro[2.5]octane (46 mg, 0.41 mmol, AstaTech, Inc.) and DIPEA (0.119 ml, 0.685 mmol, Sigma-Aldrich) were added. The reaction mixture was stirred at room temperature for 96 h, diluted with water and stirred for 20 min, then filtered, giving a yellow solid. The yellow solid was taken up in EtOAc, dried over MgSO4 and concentrated in vacuo, giving N-(3-(N-(tertbutyl)sulfamoyl)phenyl)-5-((2,2,3,3,6 ,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-l)amino)3-(6-azaspiro[2.5]octan-6 -yl)pyrazine-2-carboxamide (285 mg, 0.368 mmol), as a yellow solid, m / z (ESI): 775.4 (M+H)+, which was continued to be used without further purification. -96Stage 2: to a solution of A / -(3-(A / -(tert-butyl)sulfamo¡l)phen¡l)-5-((2,2,3,3,6,9,9, 10,10nonamethyl-4,8-dioxa-3,9-d¡s¡laundecan-6-¡l)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyraz¡n-2carboxamide (266 mg, 0.257 mmol) in THE (5 ml), TBAF (1.6 ml, 1.6 mmol, 1 M in THE) was added. The reaction mixture was stirred at RT for 16 h. The crude mixture was then adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column eluting with 0-100% EtOAc in heptane, giving A / -( 3-( / V(tert-butyl)sulfamoyl)phenyl)-5-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan6-íl) pyrazine-2-carboxamide (23.5 mg, 0.043 mmol, 17% yield), as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.30 (s, 1 H), 8.43 (s, 1 H), 7.84 - 7.90 (m, 1 H), 7.43 - 7.50 (m, 4 H), 6.79 ( s, 1 H), 4.67 (t, J = 5.7 Hz, 2 H), 3.59 - 3.71 (m, 4 H), 3.35 3.43 (m, 4 H), 1.38 - 1.46 (m, 4 H), 1.30 ( s, 3 H), 1.11 (s, 9 H), 0.33 (s, 4 H). m / z (ESI): 547.1 (M+H)+. ADDITIONAL EXAMPLES QR7 Lnn / Zznz / E / YIAI The following compounds can be prepared according to a procedure similar to the previous examples using commercially available starting materials or can be prepared according to a procedure familiar to those skilled in the art. Ex. No. Chemical structure Name 107 V Y y 1 o O o N. methylpropan-2-yl)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazin-2¡l)benzamide 108 * ύ ίι i h Ϊ OO o N. Xx. x 2¡l)benzam¡da 109 rz 0 H ll 1 H ? .N. XK1 1-trifluoro-2-hydroxypropan-2-yl)pyrazín2-yl)-3-(M-(tert-butyl)sulfamoyl)benzamide Ex. No. Chemical structure Name 110 ri C h Γ i h 7 Y s γ Y n Y II II i 1 o 0 0 N^Y»0H CF3 (F?)- / V-(3-(6-azaspiro[ 2.5]octan-6-yl)-5- (1,1,1-tnfluoro-2-hydroxy¡propan-2-¡l)p¡razin2-¡l)-3-( / V-(te / 'c-but¡l)sulfamoyl)benzamide 111 A, 0 íi 1 h 7 / \ AYzN. Y < N γ H N \ / fYY 0 N. A Y ,OH / 'x / N F H 3-(4,4-Difluoropiperidin-1 -yl)-A / -(5-((1 hydroxy-2-methylpropan-2- yl)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazín-2-íl)-5methylbenzamide 112 Λ °ύ Y'^Y YA 1 H ii 1 \ / Yk xA Y / OH / N F H A / -(3-(4,4-Difluoropiperidin-1 -yl)-5methylpheníl)-5-((1-hydroxy¡-2-methylpropan-2¡l)amino)-3 -(6-azaspiro[2.5]octan-6¡l)pyrazine-2-carboxamide 113 / a p A p„O FY^ N'^'n'Sx' / xOH F H A / -(3-(4,4-Difluoropiperid ¡n-1-yl)-5methylphenyl)-5-((2-hydroxy¡ethyl)sulfonamido)-3(6-azasp¡ ro[2.5]octa η-6-i I) pi razi n- 2carboxamide 114 X il)-3-(6azaspiro[2.5]octan-6-yl)pyrazin-2carboxamide QR7 ίηη / 77η7 / Ε / ΥΙΛΙ -98Lnn / Zznz / E / YIAI Ex. No. Chemical structure Name 115 τ T O / O W' ° ZE (S)- / V-(3-( / \ / -(tert-Butyl)sulfamo¡l)phen¡l)-5(1,2 -dihydroxypropan-2-yl)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide 116 % \ .o ωζ / o A / -(3-(4,4-D¡fluoropiper¡din-1 -yl)-5methylphenyl)-5-((methylsulfonyl)methyl)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2carboxamide BIOLOGICAL EXAMPLES For the compounds in Table A, the following assay conditions were used: 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 MgCl2 (JT Baker Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 pM 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 room temperature, then ATP is added (at Km, 75 pM) to the reaction mixture and incubate for a further 15 minutes at room temperature. Mix 5 pl of ADP-Glo™ reagent and 2.5 pl of the reaction mixture and incubate for 40 minutes at room temperature. Add 10 pl of ADP-Glo™ Detection Reagent and incubated for 40 minutes at room temperature. Luminescence is read using an EnVision microplate reader with an ultraluminescence module (Perkin Elmer Inc). Cho determination and adjustment are performed of the concentration response curve using the -99Genedata Screener software (Standard 15.0.1, Genedata Inc) with a four-parameter logistic regression fitting model. TABLE A: BIOLOGICAL DATA QR7 Lnn / Zznz / E / YIAI Ex. No. Compound name KIF18A ATPase IC50 (pM) 100 A / -(3-(A / -(tert-butyl)sulfamo¡l)phenyl)-5-((1 -hydroxy-2methylpropan-2-yl )amino)-3-(6-azaspiro[2.5]octan6-yl)pyrazin-2-carboxamide 0.082 100-1 M-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-5-((1 -hydroxy-2methylpropan-2-yl)amino)-3-(4-methylpiperidin-1¡l)pyrazine-2-carboxamide 0.177 100-2 A / -(3-(A / - (tert-butyl)sulfamoyl)phen¡l)-3-(4,4difluoropiper¡din-1-yl)-5-((1-hydroxy-2-methylpropan2-yl)amino)pyraz¡n-2- carboxamide 0.342 100-3 A / -(3-(W-(7ert-butyl)sulfamoyl)phenyl)-5-((1-hydroxyl-2methylpropan-2-yl)amino)-3-(4 - (trifluoromethyl)piperidin-1-l)pyrazin-2-carboxamide 0.455 100-4 A / -(3-(A / -(tert-butyl)sulfamoyl )pheníl)-3-(4ethylpiperidin-1 -yl )-5-((1 -hydroxy-2-methylpropan-2yl)amino)pyrazín-2-carboxamide 0.133 100-5 A / - (3-(A / -(tert-butyl)sulfamoyl)pheníl)-3-(4,4dimethylpiperidin-1 -yl)-5-((1 -hydroxy-2-methylpropan2-íl)amino)p¡ ration-2-carboxamide 0.190 100-6 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1 -hydroxy-2methylpropan-2-yl)am ¡no)-3-(4-¡sopropylpipendin-1¡l)pyrazin-2-carboxamide 0.319 100-7 3-(4-(tert-butyl)piperidin-1 -i\)-N-( 3-(N-(tert-butyl)sulfamo¡l)phenyl)-5-((1-hydroxy¡-2-methylpropan-2yl)amino)pyrazín-2-carboxamide 0.788 100-8 3 -(4-(sec-butyl)p¡peridin-1 -ü)-N-(3-(N-(tert-butyl)sulfamo¡l)phen¡l)-5-((1-hydroxy-2- methylpropan-2-yl)amino)pyrazin-2-carboxamide 0.163 100-9 N-(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1 - hydroxy-2methylpropan-2-¡l)amino)-3-(4-propylp¡peridin-1¡l)pyrazín-2-carboxamide 0.118 -100- Ex. No. Compound name KIF18A ATPase IC50 (pM) 100- 10 W-(3-(A / -(tert-butyl)sulfamoyl)pheníl)-3-(4cyclopropylpiperidin-1 -yl)-5- ((1-hydroxy-2methylpropan-2-yl)amino)pyrazine-2-carboxamide 0.221 100- 11 A / -(3-(A / -(tert-butyl)sulfamo¡l)phen¡l)-5-( (1-hydroxyl-2methylpropan-2-yl)amino)-3-(4-(methoxymethyl)pyridin-1-yl)pyrazine-2-carboxamide 1.39 100- 12 A / -(3- (A / -(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2methylpropan-2-yl)amino)-3-(2-azaspiro[3.3]heptan-2-yl)p¡raz¡ n-2-carboxamide 0.931 100- 13 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxyl-2methylpropan-2-yl)amino) -3-(2-azaspiro[3.5]nonan-2-yl)pyrazin-2-carboxamide 0.410 100- 14 A / -(3-(W-(ferc-butyl)sulfamoyl)phenyl)-5-((1- hydroxy-2methylpropan-2-yl)amino)-3-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrazin-2-carboxamide 1.38 100- 15 A / -(3-( A / -(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxyl-2methylpropan-2-yl)amino)-3-(7-azaspiro[3.5]nonan-7-yl)pyrazin- 2-carboxamide 0.077 100- 16 W-(3-(M-(tert-butyl)sulfamoyl)phenyl)-3-(2,2-difluoro-7-azaspiro[3.5]nonan-7-yl)-5 -((1-hydroxy-2-methylpropan-2-yl)amino)pyrazín-2-carboxamide 0.215 100- 17 A / -(3-(A / -(ert-butyl)sulfamoyl )phenyl)-5-((1 -hydroxy-2methylpropan-2-yl)amino)-3-(8-azaspiro[4.5]decan-8-yl)pyrazine-2-carboxamide 0.129 101 N-(3-( / V-(tert-Butyl)sulfamoyl)-5-methylphenyl)-5-((1hydroxy-2-methylpropan-2-¡l)amino)-3-(6azaspiro[2.5]octan-6-yl) pyrazín-2-carboxamide 0.231 101-1 5-((1 -hydroxy-2-methylpropan-2-íl)amino)-3-(6azaspiro[2.5]octan-6-yl) -N-(3-((1,1,1 -trifl uoro-2- methylpropan-2-yl)sulfonyl)phenyl)pyrazine-2-carboxamide 0.108 QR7 ίηη / 77η7 / Ε / ΥΙΛΙ - 101 Lnn / Zznz / E / YIAI Ex. No. Compound name KIF18A ATPase IC50 (pM) 101-2 W-(3-(tert-butylsulfoníl)phenyl)-5-((1 -hydroxy-2methylpropan-2-yl)amino)-3 -(6-azaspiro[2.5]octan6-yl)pyrazine-2-carboxamide 0.218 101-3 5-((1 -hydroxy-2-methylpropan-2-yl)amino)- / V-(3 -((1-methylcyclobutyl)sulfonyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide 0.204 101-4 A / -(3-(A / -(tert-butyl )sulfamoyl)-5-fluorophenyl)-5-((1hydroxy-2-methylpropan-2-¡l)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazín- 2-carboxamide 0.172 101-5 A / -(3-(A / -(tert-butyl)sulfamo¡l)-2-fluorophenyl)-5-((1hydroxy-2-methylpropan-2-yl)am¡ no)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide 0.527 101-6 Λ / -(3-(1,1-dioxydothiomorpholino)phenyl)-5-((1-hydroxy - 2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazín-2-carboxamide 0.545 101-7 5-((1-hydroxy- 2-methylpropan-2-yl)amino)- / \ / -(3morpholinophenyl)-3-(6-azaspiro[2.5]octan-6yl)pyrazine-2-carboxamide 0.768 101-8 5-((1 -hydroxy-2 -methylpropan-2-¡l)am¡no)- / \ / -(3-((1 hydroxy¡-2-methylpropan-2-yl)am¡no)phen¡l)-3-(6- azaspiro[2.5]octan-6-yl)pyrazín-2-carboxamide 0.240 102-1 (S)-A / -(3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)-5- ((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide 0.067 102-2 (R)-A / -(3 -((3,3-difluorocyclopentyl)sulfonyl)phenyl)-5- ((1-hydroxy-2-methylpropan-2-l)amino)-3-(6-azaspiro[2.5]octan -6-yl)pyrazin-2-carboxamide 0.111 103 N-(3-(Cíclopentylsulfoníl)pheníl)-5-((1 -hydroxy¡-2methylpropan-2-yl) amino)-3-(6-azaspiro[2.5]octan6-yl)pyrazin-2-carboxamide 0.077 103-1 5-((1-hydroxy-2-methylpropan-2-¡l)amino)- / \ / -(3-(piperidin-1-ylsulfonyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazin-2-carboxamide 0.135 - 102- Ex. No. Compound name KIF18A ATPase IC50 (pM) 103-2 N-(3-(cyclopentylsulfonyl)phenyl)-5-(( 1 - (hydroxymethyl)cyclopropyl)amino)-3- (6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide 0.143 103-3 A / -(3-(A / -(tert-butyl)sulfamoyl)pheníl)-5-((1 ( hydroxymethyl)cyclopropyl)amino)-3-(6azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide 0.139 103-4 5-((2-hydroxymethylpropyl)amino)-A / - (3-(piperidin1-¡lsulfonyl)phenyl)-3-(6-azaspiro[2.5]octan-6¡l)pyrazine-2-carboxamide 0.406 104 A / -(3-(A / -(tert -butyl)sulfamoyl)phenyl)-3-(4-chlorophenyl)5-((1-hydroxyl-2-methylpropan-2-l)amino)pyrazine-2carboxamide 0.135 104-1 A / -( 3-(W-(tert-butyl)sulfamoyl)phenyl)-3-(4fluorophenyl)-5-((1-hydroxy-2-methylpropan-2¡l)amino)pyraz¡n-2-carboxamide 0.418 104-2 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1-hydroxyl-2methylpropan-2-yl)amino)-3-(4(trifluoromet ¡l)phenyl)pyrazín-2-carboxamide 0.168 104-3 N-(3-(N-(ert-butyl)sulfamo¡l)phen¡l)-3-(4-ethylphenyl)-5((1 -hydroxy¡-2-methylpropan-2-¡l)amino)pyrazine-2carboxamide 0.146 104-4 A / -(3-(A / -(tert-butyl)sulfamoyl)phenyl)-5-((1 -hydroxy- 2methylpropan-2-yl)amino)-3-(4-isopropylphenyl)pyrazine2-carboxamide 0.141 105-1 (R)-N-(3-( / V-(ferc-butyl)sulfam azaspiro[2.5]octan-6- il)-5-(1,1,1-trifluoro-2hydroxypropan-2-yl)pyrazin-2-carboxamide 0.174 105-2 (S)-A / -(3-(A / -( tert-butyl)sulfamoyl)phenyl)-3-(6azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2hydroxypropan-2-yl)pyrazine-2-carboxamide 0.356 106 N-(3-( / V-(tert-butyl)sulfamoyl)phenyl)-5-((1,3dihydrox¡-2-methylpropan-2-yl)amino)-3-(6azaspiro[2.5] octan-6-yl)pyrazin-2-carboxamide 0.103 QR7 ίηη / 77η7 / Ε / ΥΙΛΙ - 103The above invention has been described in some detail by way of illustration and as an example, for the purposes of better understanding and clarity. The person skilled in the art understands that it is possible to implement certain changes and modifications 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 should be determined not with reference to the above description but, on the contrary, should be determined with reference to the claims appended below, together with the full scope of the equivalents to which they are entitled. said 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: QR7 Lnn / Zznz / E / YIAI or any pharmaceutically acceptable salt thereof, wherein: L is -(C=O)-NR8- or -NR8-(C=O)-; R1 is a -Z-R9 group; where Z is absent, or is -NR11-, -NR11SO2-alkyl Cm-, NR11SO2NR11, -NR11SO2NR11-C(=O)-O-, -N=S(=O)<, -SO2NR11-alkyl C0.4-, alkyl C0.4S(=O)-(=NH), Co-4-S(=0)(=N,(CH3)2)-, alkyl Cm-, alkyl C0-4-S-, alkyl Co-4-S(=0)-, alkyl C0-4-SO2-, -O-, -P-, -P(=O), -P(=O)2, -(C=O)-, -(OH,(OH) -NR11(CO); R2 is a group -Y-R10, where Y is absent, or is alkyl Co-4-S-, alkyl Co-4-S=0, alkyl C0-4-S(=O)2, -CO2NR10c-alkyl C0-4-, -NR10c-, -NR10c-CO2-alkyl C0-4-, -Calkyl-4- Cu_4S(=O)(=NH)-, -O-alkyl C0-4-, -(C=O)-, -alkyl Co-4-(C-0)-0- or -NS(-O)<; R3 is H, halo, alkyl Cm or haloalkyl Cm; R4 is H, halo, alkyl Cm or haloalkyl Cm; R5 is H, halo, alkyl Cm or haloalkyl Cm; R6 is H, halo, alkyl Cm or haloalkyl Cm; R7 is H, halo, alkyl Cm or haloalkyl Cm; R8 is H or alkyl Cm;R9 is H, R9a or R9b; R10is halo, R10a or R10b; - 105RXa QR7 Lnn / Zznz / E / YIAI or Rxis a C2-8 alkyl substituted with 0, 1,2, 3, 4 or 5 group(s) selected from F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl Cm, CN, NH2, NH(CH3), N(CH3)2 or RXm; or Rxes phenyl or unsaturated 5-membered monocyclic ring substituted with 0, 1, 2, 3, 4 or 5 group(s) selected from F, Cl, Br, C1.6-alkyl, C1.6-haloalkyl, -C(=O)ORa, -ORa, Cm-haloalkyl, CN, NH2, NH(CH3), N(CH3)2 or RXm; wherein said 5-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S; each of RXa, RXb, RXc, RXd, RXe, RXf, RXg, RXh, RXi, RXk and RXI is H, halo, RXn or RXo;or, alternatively, each of the pair RXa and RXb, pair RXcy 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 3, 4, 5, 6-membered monocyclic ring saturated or partially saturated spiro with the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or azepanyl ring; wherein said 3, 4, 5, 6-membered monocyclic ring contains 0, 1, 2 or 3 atoms of N and 0 or 1 atom selected from 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;each RXm and RXn is selected independently, in each case, from the group consisting of a monocyclic ring of 3, 4, 5, 6 or 7 members or a bicyclic ring of 8, 9, 10, 11 or 12 members saturated, partially saturated or unsaturated containing 0, 1.2 or 3 atoms of N y 0 or 1 atom selected from O and S, which is substituted with 0, 1, 2, 3 or 4 group(s) selected from F, Cl, Br, C1.6 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-C2-6alkyl-NRaRa, -O-C2.6alkyl-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-C2-6alkyl-NRaRa, -NRa-C26alkyl-ORa, -Ci-salkyl-NRaRa, -Ci6alkyl-ORa, -C1.6 alkyl-N(Ra)C(=O)Rb, -C1.6 alkyl-OC(=O)Rb, -alkyl C1.6-C(=O)NRaRa, -alkyl Ci.6C(=O)ORa y oxo;RXose independently selects, in each case, from the group consisting of C1-8 alkyl substituted with 0, 1, 2, 3, 4 or 5 group(s) selected from F, Cl, Br, -CH2F, CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl CM, CN, NH2, NH(CH3) or N(CH3)2;R9a and R10a are selected independently, in each case, from the group consisting of a monocyclic ring of 3, 4, 5, 6 or 7 members or a bicyclic ring of 8, 9, 10, 11 or 12 members saturated, partially saturated or unsaturated containing 0, 1, 2 or 3 atoms of N y 0 o 1 atom selected from O and S, which 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, -C(=O)Rb, C(=O)ORa, -C(=O)NRaRa, -C(=NRJNRaRa, -OC(=O)Rb, -OC(=O)NRaRa, -O-C2-6alkyl-NRaRa, O-alkyl C2.6-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-C2-6alkyl-NRaRa, -NRa-C2-6alkyl-ORa, -Ci-6alkyl-NRaRa, -Ci6alkyl-ORa, -Ci.6alkyl-N(Ra)C(=O)Rb, -alkyl Ci.6-OC(=O)Rb, -alkyl Ci.6-C(=O)NRaRa, -alkyl Ci-6C(=O)ORa, R11 and oxo;R9t and RWbse are selected independently, in each case, from the group consisting of C1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 group(s) selected from F, Cl, Br, -CH2F, CHF2, -CF3, -C(=O)ORa, -ORa, -O-haloalkyl CM, CN, NH2, NH(CH3) or N(CH3)2; R10c is H or Ci-4 alkyl; R11 is Ho Ci-s alkyl; Ra is independently, in each case, H or Rb; and -107Rb is independently, in each case, C1-6 alkyl, phenyl or benzyl, wherein the Ci-e alkyl is substituted with 0, 1, 2 or 3 substituents selected from halo, -OH, -O-C1.4 alkyl, -NH2, -NH-Cm alkyl, -OC(=O)-C1.4 alkyl, or -N-(C1-4 alkyl)-C1.4 alkyl; and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from halo, C1-3 alkyl, -OH, -O-C1.4 alkyl, -NH2, -NH-C1-4 alkyl, -OC(=O)-C1-4 alkyl, or -N-(C1-4 alkyl)-C1-4 alkyl.

2. The compound of any one of the preceding claims, wherein L is -NR8-(C=O); having the formula (a): Lnn / Zznz / E / YIAI (a); wherein said pair RXa and RXb can be combined with the carbon atom attached to each of them to form a saturated or partially saturated spiro 3, 4, 5, or 6-membered monocyclic ring with the piperidinyl ring; wherein said 3, 4, 5, or 6-membered monocyclic ring contains 0 atoms of N, O, and S, and further wherein said 3, 4, 5, or 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.

3. The compound of any one of the preceding claims, wherein L is-(C=O)-NR8-; having the formula (Ib): (Ib); wherein said pair RXa and RXb can be combined with the carbon atom attached to each of them to form a saturated or partially saturated spiro 3, 4, 5, 6-membered monocyclic ring with the piperidinyl 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, C1-6 haloalkyl, -ORa, -O-C1-4 haloalkyl, CN, NRaRa or oxo.

4. The compound of any one of the preceding claims, wherein R8 is H or methyl.

5. The compound of any one of the preceding claims, wherein each of RXc, RXd, RXc, RXf, RXg, RXh, RXi, RXj, RXk and RXI is H, halo, C1-6 alkyl or C1.4 haloalkyl; and each of the pair RXa and RXb combines with the carbon atom attached to each of them to form a spiro-saturated 3, 4 or 5-membered monocyclic ring with the piperidinyl ring; wherein said ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S.

6. The compound of any one of the preceding claims, wherein each of RXc, RXd, RXe, RXf, RX9, RXh, RXi, RXj, RXk and RXI is H, methyl or ethyl; and each of the pair RXa and RXb combines with the carbon atom attached to each of them to form a cyclopropyl, cyclobutyl or cyclopentyl spiro ring with the piperidinyl ring.

7. The compound of any one of the preceding claims, wherein Rx is selected from (a) ethynyl substituted with isobutyl or cyclopentyl; (b) phenyl substituted with 0, 1, 2 or 3 F, Cl, CF3, CH2OCH3, methyl, ethyl, propyl, isopropyl, tert-butyl or cyclopropyl groups; (c) or pyrazolyl substituted with 0, 1, 2 or 3 F, Cl, CF3, CH2OCH3, methyl, ethyl, propyl, isopropyl, tert-butyl or cyclopropyl groups; QR7 Lnn / Zznz / E / YIAI - 109- is A . QR7 Lnn / Zznz / E / YIAI 9. The compound of any one of the preceding claims, wherein Z is absent, or is -NH-, -NHSO2-, -SO2NH- or -CH2SO2-.

10. The compound of any one of the preceding claims, wherein R9 is selected from: (a) H; (b) C1-6 alkyl substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, CF3 or -OH; or (c) 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, Cl, Br, methyl, ethyl, -CF3, CH2OH, -OH, -OCH3, -NH2 or oxo.

11. The compound of any one of the preceding claims, wherein R9 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxethanyl, azetidinyl, diazirinyl, oxazolidinyl, isothiazolidinyl, pyrazolyl or pyrrolidinyl.

12. The compound of any one of the preceding claims, wherein R1 is a -Z-R9 group, wherein Z is absent, or is -NH-, -NHSO2-, -SO2NH- or -CH2SO2-; and R9 is cyclopropyl or oxazolinyl substituted with 0, 1, 2 or 3 OH, -CH2OH, methyl or oxo group(s), or R9 is C1-6 alkyl substituted with 0, 1, 2 or 3 OH or CF3 group(s).

13. The compound of any one of the preceding claims, wherein R1 is a -Z-R9 group, wherein Z is -NHSO2- and R9 is -CH2-CH2-OH.

14. The compound of any one of the preceding claims, wherein R2 is a -Y-R10 group, wherein Y is absent, or is -NH-, -NHSO2-, SO2NH- or SO2-; and -110R10 is 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, Cl, Br, methyl, ethyl, CF3, CH2OH, -OH, -OCH3, -NH2, -NH(CH3) and oxo; or; R10 is C1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 group(s) selected from F, Cl, Br, -OH or -CF3.

15. The compound of any one of the preceding claims, wherein R2 is a morpholinyl, thiomorpholinyl, cyclobutyl, cyclopentyl or piperidinyl ring, wherein each of said rings is substituted with 0, 1, 2 or 3 group(s) selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2 or oxo.

16. The compound of any one of the preceding claims, wherein R2 is morpholyl or piperidinyl substituted with 0, 1, 2 or 3 selected from F or methyl.

17. The compound of any one of the preceding claims, wherein R3 is H or F.

18. The compound of any one of the preceding claims, wherein R4 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, F or methyl.

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

22. The compound of claim 1, or any pharmaceutically acceptable salt thereof, selected from the group comprising: A / -(3-(A / -(terc-butyl)sulfamo¡l)phenyl)-5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-2-carboxam¡da; A / -(3-(A / -(terc-but¡l)sulfamoyl)phenyl)-5-((1-hydrox¡-2-methylpropan-2-yl)am¡no)-3-(4methylp¡peridin-1-yl)p¡raz¡n-2-carboxamide; A / -(3-(A / -(terc-but¡l)sulfamoyl)phen¡l)-3-(4,4-d¡fluoropipendin-1-¡l)-5-((1-hydrox¡-2methylpropan-2-yl)am¡no)p¡raz¡n-2-carboxam¡da; / V-(3-(N-(?erc-butyl)sulfamo¡l)phen¡l)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4(tr¡fluoromet¡l)piperidin-1-yl)pyraz¡n-2-carboxam¡da; A / -(3-( / V-(terc-butyl)sulfamoyl)phenyl)-3-(4-ethylp¡peridin-1-yl)-5-((1-hydroxy-2-methylpropan-2yl)amino)pyrazine-2-carboxam¡da; A / -(3-(A / -(terc-but¡l)sulfamoyl)phen¡l)-3-(4,4-d¡met¡lp¡per¡d¡n-1 -yl)-5-((1 -hydroxy-2methylpropan-2-yl)am¡no)pyraz¡n-2-carboxam¡da;QR7 Lnn / Zznz / E / YIAI Lnn / Zznz / E / YIAI -111 / V-(3-( / V-(terc-butyl)sulfamo¡l)phenyl)-5-((1 -hydroxy-2-methylpropane-2-yl)am¡no)-3-(4¡sopropylpiperidine-1-¡l)p¡raz¡n-2-carboxaxam¡da; 3-(4-(terc-but¡l)p¡d¡n-1-yl)-A / -(3-(M-(tefc-butyl)sulfamo¡l)phen¡l)-5-((1-hydrox¡-2methylpropan-2-yl)amino)pyrazine-2-carboxamide; 3-(4-(sec-butyl)piper¡din-1-yl)- / V-(3-(A / -(terc-but¡l)sulfamoyl)phenyl)-5-((1-h¡droxy-2methylpropan-2-yl)amino)pyrazin-2-carboxxam¡da; N-(3-(A / -(ferc-butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropane-2-yl)amino)-3-(4prop¡lp¡peridin-1-yl)pyrazin-2-carboxamide; / V-(3-( / V-(terc-but¡l)sulfamo¡l)phen¡l)-3-(4-c¡cloprop¡lp per¡d¡n-1 -yl)-5-((1 -hydroxy-2methylpropan-2-yl)am¡no)pyraz¡n-2-carboxam¡da; / V-(3-(W-(ferc-butyl)sulfamoyl)phen¡l)-5-((1-h¡drox¡-2-met¡lpropane-2-yl)am¡no)-3-(4(methoxymethyl)p¡per¡d¡n-1-l)pyrazin-2-carboxaxam¡da; A / -(3-(A / -(ferc-but¡l)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropane-2-yl)amino)-3-(2azaesp¡ro[3.3]heptan-2-yl)p¡razin-2-carboxamide; / V-(3-(W-(tert-butyl)sulfamoyl)phen¡l)-5-((1-h¡droxy-2-methylpropan-2-yl)am¡no)-3-(2azaespiro[3.5]nonan-2-yl)pyrazine-2-carboxamide; A / -(3-( / V-(ferc-butyl)sulfamo¡l)phenyl)-5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3-(3-oxa-9azaespiro[5.5]undecan-9-yl)pyrazine-2-carboxam¡da; A / -(3-(A / -(tert-butyl)sulfamoyl)phen¡l)-5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3-(7azaespiro[3.5]nonan-7-yl)pyrazine-2-carboxamide; / V-(3-(W-(terc-but¡l)sulfamoyl)phenyl)-3-(2,2-difluoiO-7-azaesp¡ro[3.5]nonan-7-yl)-5-((1h¡drox¡-2-methylpropan-2-yl)am¡no)pyraz¡n-2-carboxylate; A / -(3-( / V-(ierc-butyl)sulfamoyl)phen¡l)-5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3-(8azaespiro[4.5]decan-8-yl)pyrazine-2-carboxam¡da; A / -(3-(A / -(terc-butyl)sulfamoyl)-5-methylphenyl)-5-((1-hydrox¡-2-methylpropan-2-yl)am¡no)-3-(6azaespiro[2.5]octan-6-yl)pyrazine-2-carboxamide; 5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3-(6-azaespiro[2.5]octane-6-yl)-N-(3-((1,1,1trifluoro-2-methylpropan-2-¡l)sulfonyl)phen¡l)p¡raz¡n-2-carboxamide;A / -(3-(terc-butylsulfon¡l)phenyl)-5-((1-h¡droxy-2-methylpropan-2-¡l)amino)-3-(6azaespiro[2.5]octane-6-yl)pyrazine-2-carboxam¡da; 5-((1 -h¡drox¡-2-methylpropan-2-¡l)amino)-N-(3-((1-met¡lc¡clobutyl)sulfonyl)phen¡l)-3-(6azaespiro[2.5]octane-6-yl)pyrazine-2-carboxam¡da; A / -(3-(A / -(terc-butyl)sulfamoyl)-5-fluorophenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6azaespiro[2.5]octane-6-¡l)pyrazine-2-carboxam¡da; A / -(3-(A / -(terc-but¡l)sulfamo¡l)-2-fluorophen¡l)-5-((1-h¡droxy-2-met¡lpropan-2-¡l)am¡no)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-carboxam¡da; -112Λ / -(3-(1,1 -dioxythiomorpholino)phenyl)-5-((1 -hydroxy-2-methylpropan-2-yl)amino)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-2-carboxam¡da; 5-((1 -h¡drox¡-2-methylpropan-2-¡l)am¡no)- / V-(3-morpholinophen¡l)-3-(6-azaespiro[2.5]octane-6yl)pyrazine-2-carboxamide; 5-((1 -h¡drox¡-2-methylpropan-2-¡l)am¡no)-N-(3-((1-h¡drox¡-2-meth¡lpropan-2-¡l)am¡no)phen¡l)3-(6-azaespiro[2.5]octane-6-raz)p¡-caramine-2-carmine;(S)-A / -(3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)-5-((1-hydroxy-2-met¡lpropan-2-yl)amino)-3(6-azaespiro[2.5]octane-6-yl)p¡razin-2-carboxamide; (R)-A / -(3-((3,3-d¡fluorooc¡clopentyl)sulfon¡l)phen¡l)-5-((1-h¡drox¡-2-met¡lpropan-2-¡l)am¡no)-3(6-azaespiro[2.5]octane-6-yl)pida-carp-2; / V-(3-(c¡clopent¡lsulfonyl)phen¡l)-5-((1-h¡droxy-2-methylpropan-2-¡l)amino)-3-(6azaespiro[2.5]octane-6-yl)pyrazine-2-carboxamide; 5-((1-hydroxy-2-methylpropan-2-yl)amino)-A / -(3-(piperidin-1-ylsulfonyl)phenyl)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-2-carboxamide; A / -(3-(cyclopentylsulfon¡l)phenyl)-5-((1-(h¡drox¡methyl)cycloprop¡l)am¡no)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-2-carboxam¡da; A / -(3-(A / -(ferc-butyl)sulfamo¡l)phenyl)-5-((1-(hydroxymet¡l)c¡chlopropyl)am¡no)-3-(6azaespiro[2.5]octane-6-yl)pyrazine-2-carboxam¡da; 5-((2-h¡droxy-2-methylpropyl)amino)-A / -(3-(piperidin-1 -ylsulfonyl)phenyl)-3-(6azaespiro[2.5]octan-6-yl)pyrazine-2-carboxamide; / V-(3-(W-(terc-butyl)sulfamoyl)phenyl)-3-(4-chlorophenyl)-5-((1-h¡drox¡-2-met¡lpiOpan-2yl)amino)pyrazine-2-carboxam¡da; / V-(3-(W-(ferc-butyl)sulfamo¡l)phen¡l)-3-(4-fluorophen¡l)-5-((1-h¡drox¡-2-methylpropan-2yl)amino)p¡raz¡n-2-carboxam¡da; A / -(3-(A / -(terc-butyl)sulfamoyl)phen¡l)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(4(trifluoromethyl)phenyl)pyrazine-2-carboxamide; / V-(3-(W-(terc-but¡l)sulfamoyl)phenyl)-3-(4-ethylphen¡l)-5-((1-hydrox¡-2-met¡lpiOpan-2yl)amino)pyrazine-2-carboxam¡da; / V-(3-(W-(ferc-but¡l)sulfamoyl)phen¡l)-5-((1-h¡droxy-2-methylpiOpan-2-yl)amino)-3-(4isopropylphen¡l)p¡raz¡n-2-carboxamide; (R)-A / -(3-(A / -(terc-butyl)sulfamo¡l)phen¡l)-3-(6-azaesp¡ro[2.5]octane-6-¡l)-5-(1,1,1-trifluoro-2hydroxypropan-2-yl)pyrazine-2-carboxamide; (S)- / V-(3-(N-(tert-butyl)sulfamoyl)phen¡l)-3-(6-azaespiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2hydroxy¡propan-2-yl)pyrazine-2-carboxamide;or A / -(3-(A / -(tert-butyl)sulfamo¡l)phen¡l)-5-((1,3-dih¡drox¡-2-methylpropan-2-yl)am¡no)-3-(6azaespiro[2.5]octane-6-yl)pyraz¡n-2-carboxam¡da. QR7 Lnn / Zznz / E / YIAI -113QR7 Lnn / Zznz / E / YIAI; 23. The compound of claim 1, selected from the group consisting of: Example No. Chemical Structure Name 100 A o. / ZI A IZ vio IZ o I N-(3-(A / -(tert-Butyl)sulfamoyl)phenyl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)prazin-2-carboxamide 100-1 I o ZI - <M x— / Az O=( ZI ά ωζ A / -(3-(W-(terc-Butil)sulfamo¡l)fen¡l)-5-((1hidroxi-2-met¡lpropan-2-¡l)amino)-3-(4met¡lp¡per¡d¡n-1-il)pirazin-2-carboxamida 100-15 T o ZI «Μ \--f (=Z o=\ ZI ά ω5 IZ ° A / -(3-(A / -(terc-butil)sulfamoil)fenil)-5-((1hidrox¡-2-met¡lpropan-2-il)am¡no)-3-(7azaespiro[3.5]nonan-7-il)p¡raz¡n-2carboxamida 101 V h MI ? Ϊ A A N íi N \ / 1 0 0 H νΟ / Χ^οη N H / V-(3-( / V-(terc-Butil)sulfamoil)-5-metilfenil)5-((1 -hidroxi-2-met¡lpropan-2-¡l)am¡no)-3(6-azaespiro[2.5]octan-6-il)pirazin-2carboxamida 101-3 & n . 0 H II 1 \ / 0 0 M N X X / OH N H 5-((1-H¡drox¡-2-metilpropan-2-¡l)am¡no)- / \ / (3-((1-met¡lc¡clobutil)sulfon¡l)fen¡l)-3-(6azaespiro[2.5]octan-6-il)pirazin-2carboxamida 101-4 ó.15 ASN Ti N \ / NV 1—1 I \ / 1 o 0 H mX X / OH HA / -(3-(W-(ferc-Butyl)sulfamoyl)-5fluorophenyl)-5-((1-hydroxy-2-methylpropane-2¡l)amino)-3-(6-azaespiro[2.5]octane-6¡l)pyrazine-2-carboxamide -114- Example Structure n.01-8-Chemical Name x(A' ho. X ΛΑ AANN < N , HH n^a 5C°h NH 5-((1-Hydrox¡-2-methylpropane-2-¡l)amino)- / \ / (3-((1 -hydroxy-2-methylpropane-2- ¡l)amino)phenyl)-3-(6-azaesp¡ro[2.5]octane-6- ¡l)pyrazin-2-carboxam¡da 102-1 o.. 'ó IZ ko tfo IZ o I (S)-N-(3-((3,3- Difluorocyclopentyl)sulfon-l(l)(l)(l) hydroxy-2-met¡lpropan-2-yl)amno)-3-(6azaespiro[2.5]octane-6-yl)p¡raz¡n-2carboxamide 102-2 VF ΛΊ XA 0 Ms^n^n oX HV^OH NH (R)- / V-(3,3-(3-(3) Difluorocyclopentyl)sulfon¡l)phenyl)-((1 hydroxy-2-methylpropan-2-yl)am¡no)-3-(6azaespiro[2.5]octan-6-yl)p¡raz¡n-2carboxamide 103 o δ δ PspAAA \ \ \ _ I \ 0 H. N_AK1AAoH HA / -(3-(Cyclopentylsulfonyl)phen¡l)-5-((1 hydroxy-2-meth¡lpropan-2-¡l)am¡no)-3-(6azaespiro[2.5]octan-6-yl)pyrazin-2carboxamide 103-1 O P O 9 H O Φ H.Α,Α,ΌΗ NH 5-((1-Hydrox¡-2-methylpropane-2-yl)am¡no)- / \ / (3-(p¡per¡din-1-ylsulfon¡l)phen¡l)-3-(6azaespiro[2.5]octan-6-yl-c.120carrabox-amidane \ AA >T wy / \x U-Ι I \ / ' O 0 HN JA JDH v N v HA / -(3-(M-(terc-But¡l)sulfamoyl)phenyl)-5-((1(hydroxymethyl)aminopropyl)amino)-3-(6azaespirotan)cda[car6-box-o Q«7 ίηη / 77η7 / Ε / ΥΙΛΙ -115- Example no.° Chemical structure Name 104 -Ύ O. / ZT XA IZ w QO IZ or I / V-(3-(A / -(terc-But¡l)sulfamoyl)phen¡l)-3-(4chlorophenyl)-5-((1-hydroxy-2-met¡lpropan-2yl)amide)pyrazine-2-carboxamide 105-1 AA XX XAN XX 1 OOM nX-oh (R)-A / -(3-( / \ / -(terc-But¡l)sulfamo¡l)phen¡l)-3(6-azaespiro[2.5]octan-6-yl)-5-(1,1,1tr¡fluoro-2-h¡droxypropane-2-l)pyrase Ε2-amide V¡n-Ϊ5carbox XNNX| NXO / XO HN^X^OH cf3 (S)-A / -(3-(A / -(terc-But¡l)sulfamoyl)phenyl)-3(6-azaespiro[2.5]octan-6-yl)-5-(1,1,1trifluoro-2-hydroxy¡propan-2-¡l)pyrazín-2carboxamide 106 VH Pl N 1 χχΡΡΛΑ rOH AOOH tX' X°HNHA / -(3-(A / -(terc-Butil)sulfamoil)fenil)-5-((1,3dihidroxi-2-metilpropan-2-¡l)amino)-3-(6azaespiro[2.5]octan-6-il)piraz¡n-2carboxamida ; or any pharmaceutically acceptable salt thereof. QR7 Lnn / Zznz / E / YIAI.

24. 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.

25. 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 23, or the composition according to claim 24.

26. The method of claim 25, 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, Sjogren'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.

27. 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 23, or the composition according to claim 24.

28. 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 23, or the composition according to claim 24.

29. A method for inhibiting KIF18A in a cell, comprising contacting the cell with a compound, or pharmaceutically acceptable salts thereof, according to any one of claims 1 to 23, or the composition according to claim 24.

30. The method of claim 25, 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, follicular thyroid cancer or Kaposi sarcoma.