KIF18A inhibitor

Abstract

The present invention also provides compounds of formula (I) as defined herein, and their synthetic intermediates, which are capable of modulating KIF18A protein, thereby affecting the cell cycle and cell proliferation processes, for treating cancer and cancer-related diseases. The present invention also includes pharmaceutical compositions containing these compounds, and methods for treating disease conditions associated with the activity of KIF18A. TIFF2022514268000149.tif41170

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and more particularly to compounds and compositions useful for modulating KIF18A, and to uses and methods for controlling cell proliferation and treating cancer. [Background technology]

[0002] Cancer is one of the most widespread diseases afflicting humanity and is the leading cause of death worldwide. Over the past two decades or so, numerous groups have invested significant time, effort, and expense in efforts to find effective treatments or cures for one or more of the many different types of cancer. However, to date, only a few useful cancer treatments and cures have met with any degree of success.

[0003] Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes involved in cellular pathways that control the progression of proliferation through the cell cycle and centrosome cycle can cause loss of normal control of cell proliferation. These deregulated genes can encode various tumor suppressor or oncogene proteins that participate in a cascade of events, resulting in uncontrolled cell cycle progression and cell proliferation. It has become clear that various kinase and kinesin proteins play important roles in the control and progression of the cell cycle and cell division in normal dividing cells and cancer cells.

[0004] Kinesins are molecular motors that play an important role in cell division and intracellular vesicle and organelle transport. Cell division kinesins function in several aspects, including spindle assembly, chromosome segregation, centrosome separation, and dynamics (reviewed by O. Rath and F. Kozielski, Nature Review Cancer, 12:527-39, 2012). Human kinesins are classified into 14 subfamilies based on internal sequence homology in the so-called "motor domain," whose ATPase activity mediates unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are responsible for cargo attachment, and the "cargo" can include any one of a variety of membrane organelles, signal transduction systems, scaffolding systems, and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Therefore, kinesins are often referred to as "plus-end" or "minus-end" directed motors.

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is thought to regulate correct chromosome positioning and spindle tension by affecting the dynamics of the plus ends of kinetochore microtubules. Deficiency of human KIF18A results in spindle elongation, increased chromosome oscillations during metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology, 17, 488-98, 2007). KIF18A is considered a viable target for cancer treatment. KIF18A is overexpressed in various types of cancer, including, but not limited to, colon, breast, lung, pancreatic, prostate, bladder, head and neck, cervical, and ovarian cancers. Furthermore, genetic deletion, knockdown, or inhibition of KIF18A affects the organization of the mitotic spindle in cancer cell lines. Specifically, it has been found that inhibition of KIF18A induces cell cycle arrest of cell division, cell death in mitosis via apoptosis, cell division catastrophe, or lethality due to multipolarity, or known vulnerabilities that may promote apoptosis after cell division slippage at the interface. Therefore, there has been strong interest in discovering inhibitors of the KIF18A protein. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] O. Rath and F. Kozielski, Nature Review Cancer, 12:527~39, 2012 [Non-patent document 2] MI Mayr et.al,Current Biology,17,488~98, 2007 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, inhibiting the ATPase activity of KIF18A is a promising approach for developing novel anticancer drugs. [Means for solving the problem]

[0008] The present invention provides a new type of compound useful for modulating KIF18A protein alone or in the form of a complex in combination with microtubules to treat KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliopathology.

[0009] The compounds provided by the present invention have MT-based KIF18A modulating activity, particularly KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds in the form of formulations, as well as pharmaceutically acceptable salts thereof, and the production of pharmaceutical compositions or medicaments for the treatment, prevention, or management of acute or chronic diseases and disorders mediated by KIF18A, including, but not limited to, cancer. Thus, the compounds of the present invention are also useful in the production of anti-cancer drugs. The present invention also provides processes for making the compounds of Formula I, as well as intermediates useful in such processes.

[0010] In embodiment 1, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, X 1 is N or -CR 6 and; R 1 is the group -ZR 12 where Z is -C 0~4 alk-, -NR 11 -, -NR 11 SO2-C 0~4 alk-, -SO2NR 11 -C 0~4 alk-, -NR 11 SO2NR11 -, -NR 11 SO2NR 11 -C(=O)-O-, -C 0~4 alk-S(=O)(=NH)-, C 0~4 alk-NR 11 -S(=O)(=NH), -C 0~4 alk-S-, -C 0~4 alk-S(=O)-, -C 0~4 alk-SO2-, C 0~4 alk-O-, -P-, -P(=O), -P(=O)2, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)-, or -NR 11 (C=O); or Group-ZR 12 But -N=S(=O)-(R 12 )2, where the two R 12 may alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 2 is a halo or group -YR 13 where Y is -C 0~4 alk-, -N(C 0~1 alk)-C 0~4 alk-, -C(=O)NR a R a (C 1~4 alk)-, -OC 0~4 alk-, -S-, -S=O, -S(=O)2-, -SO2N(C 0~1 alk)-C 0~4 alk-, -N(C 0~1 alk)-SO2-C 0~4 alk-, -C 0~4 alk-S(=O)(=NH)-, -(C=O)-, -C 0~4 alk-(C=O)-O-; or Group-YR 13 But -N=S(=O)-(R 13 )2, where the two R 13may alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 3 is H, methyl, or ethyl; R 4 H, halo, CN, C 1~4 alk or C 1~4 It is haloalk; R 5 H, halo, C 1~8 alk or C 1~4 It is haloalk; R 6 H, halo, CN, C 1~8 alk, C 1~4 haloalk, -OC 0~6 alk- or R 6a and; R 7 H, halo, C 1~8 alk or C 1~4 It is haloalk; R 8 H, halo, C 1~8 alk or C 1~4 It is haloalk; R 9 H, halo, C 1~8 alk or C 1~4 It is haloalk; R x is selected from the group consisting of: [ka] R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j Each of these is H, halo, and R 10k , or R 10lor, alternatively, R 10a and R 10b Pair with R 10c and R 10d Pair with R 10e and R 10f Pair with R 10g and R 10h Pair with or R 10i and R 10j and each pair independently binds to the carbon atom to which it is bonded, forming R x wherein said 3-, 4-, 5-, 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein said 3-, 4-, 5-, 6-membered monocyclic ring is selected from F, Cl, Br, C 1~6 alk, C 1~4 haloalk, -OR a , -OC 1~4 haloalk, CN, -NR a R a substituted by 0, 1, 2, or 3 groups selected from: R 11 is H or C 1~8 alk; R 12 H, R 12a , or R 12b and; R 13 is R 13a or R 13b and; R 6a , R 10k , R 12a , and R 13a is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings, which in each instance contain 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and which are substituted by 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C1~6 alk、C 1~4 haloalk、-OR a 、-OC 1~4 haloalk、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2~6 alkNR a R a 、-OC 2~6 alkOR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-NR a C 2~6 alkNR a R a 、-NR a C 2~6 alkOR a 、-C 1~6 alkNR a R a 、-C 1~6 alkOR a 、-C 1~6 alkN(R a)C(=O)R b , -C 1~6 alkOC(=O)R b , -C 1~6 alkC(=O)NR a R a , -C 1~6 alkC(=O)OR a , R 14 , and oxo; R 10l , R 12b , and R 13b is independently, in each occurrence, F, Cl, Br, -C(=O)OR a , -OR a , -C 1~2 haloalk, -OC 1~4 C substituted by 0, 1, 2, 3, 4, or 5 groups selected from haloalk, CN, NH2, NH(CH3), or N(CH3)2 1~6 selected from the group consisting of alk; R 14 is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings, which in each instance contain 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and which are substituted by 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C 1~6 alk, C 1~4 haloalk, -OR a , -OC 1~4 haloalk, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2~6 alkNR a R a , -OC 2~6 alkORa , -SR a , -S(=O)R b , -S(=O)2R b , -S(=O)2NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O)2R b , -N(R a )S(=O)NR a R a , -NR a C 2~6 alkNR a R a , -NR a C 2~6 alkOR a , -C 1~6 alkNR a R a , -C 1~6 alkOR a , -C 1~6 alkN(R a )C(=O)R b , -C 1~6 alkOC(=O)R b , -C 1~6 alkC(=O)NR a R a , -C 1~6 alkC(=O)OR a , and oxo; R a is independently, in each occurrence, H or R b and R b are, independently, in each case, C 1~6 alk, phenyl, or benzyl, where C 1~6 Alkyl, halo, -OH, -OC1~4 alk, -NH2, -NHC 1~4 alk, -OC(=O)C 1~4 alk, or -N(C 1~4 alk)C 1~4 and the phenyl or benzyl is substituted by 0, 1, 2, or 3 substituents selected from halo, C 1~4 alk, C 1~3 haloalk, -OH, -OC 1~4 alk, -NH2, -NHC 1~4 alk, -OC(=O)C 1~4 alk, or -N(C 1~4 alk)C 1~4 substituted by 0, 1, 2, or 3 substituents selected from alk.

[0011] In embodiment 2, the present invention provides a compound comprising R x a compound having the formula: [ka]

[0012] In embodiment 3, the present invention provides a compound comprising X 1 Ga-CR 6 and a compound having the formula (Ia): [ka]

[0013] In embodiment 4, the present invention provides a compound comprising: X 1 is N, and the compound has the formula (Ib): [ka]

[0014] In embodiment 5, the present invention provides a compound comprising: 3 is H or methyl, or a pharmaceutically acceptable salt thereof.

[0015] In embodiment 6, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j Each of these is H, halo, and C. 1~6 alk or C 1~4 haloalk and R 10a and R 10b Each pair of R and R bonds to the carbon atom that is bonded to each of them. x and forming a saturated 3-, 4-, or 5-membered monocyclic ring spiro to the ring of wherein said ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S.

[0016] In embodiment 7, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j is H, methyl, or ethyl, and R 10a and R 10b Each pair of R and R bonds to the carbon atom that is bonded to each of them. x to form a cyclopropyl, cyclobutyl, or cyclopentyl ring which is spiro to the ring.

[0017] In embodiment 8, the present invention provides a compound comprising: x

[0023] The present invention provides a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein is selected from: [ka]

[0018] In embodiment 9, the present invention provides a compound comprising: x

[0023] Provided is a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein: [ka]

[0019] In embodiment 10, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: Z is absent and is NH—, —NHSO—(CH) 0~4 -, -N(CH3)-SO2-(CH2) 0~4 -, -NCH3SO2NH, -NHSO2NH-C(=O)-O-, -SO2NH-(CH2) 0~4 -, -(CH2) 0~2 -S(=O)(=NH)-, -(CH2) 0~2 -S-, -(CH2) 0~2 -S(=O)-, (CH3CH)-S(=O)-, -(CH2) 0~2 -SO2-, -O-, -P(=O), -(C=O)-, or -NH(C=O)-.

[0020] In embodiment 11, the present invention provides compounds according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 12 But -N=S(=O)-(R 12 )2, where two R 12 can alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and selected from: [ka]

[0021] In embodiment 12, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 1 Ga-ZR 12 Z is absent, NH-, -NHSO2-(CH2) 0~4 -, -N(CH3)-SO2-(CH2) 0~4 -, -NCH3SO2NH, -NHSO2NH-C(=O)-O-, -SO2NH-(CH2) 0~4 -, -(CH2) 0~2 -S(=O)(=NH)-, -(CH2) 0~2 -S-, -(CH2) 0~2 -S(=O)-, (CH3CH)-S(=O)-, -(CH2) 0~2 -SO2-, -O-, -P(=O), -(C=O)-, or -NH(C=O)-; and R 12 is selected from the following: (a)H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, [ka] wherein each of said rings is selected from 0, 1, 2, or 3 groups selected from OH, F, methyl, -CHOH, -C(=O)OCH, -C(=O)OC(CH), NH, CN, and oxo, or a C(=O) group substituted by 0, 1, 2, or 3 groups selected from OH, F, -C(=O)OCH, -NH, -NH(CH), or -N(CH). 1~6 replaced by alk].

[0022] In embodiment 13, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 1 Base-ZR 12 where Z is -NHSO2- or -SO2NH-, and R 12is oxetanyl, cyclopropyl, or R 12 is substituted by 0, 1, 2, or 3 OH groups 1~6 It is alk.

[0023] In embodiment 14, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, as follows: 1 Base-ZR 12 where Z is -NHSO2-, and R 12 is -CH2-CH2-OH.

[0024] In embodiment 15, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein: R 2 is a halo or group -YR 13 where Y is absent and -SO2NH-(CH2) 0~4 -, NH-, -NH-SO2-(CH2)2) 0~4 -, -O-(CH2) 0~4 , -O-(CH(CH3))-, -(CH2) 0~4 -S(=O)(=NH)-, -(C=O)-, -(CH2) 0~4 -(C=O)-O-, or -(CH2) 1~4 and; R 13 is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or an 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 selected from F, Cl, Br, C 1~6 alk, C 1~4 haloalk, -OH, -OC 1~4 haloalk, CN, R 14 and oxo, or R 13 F, Cl, Br, -OH, -OC 1~4C substituted by 0, 1, 2, 3, 4, or 5 groups selected from haloalk, or CN 1~6 It is alk.

[0025] In embodiment 16, the present invention provides a compound according to any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each said ring is selected from the group consisting of F, Cl, Br, C 1~6 alk, C 1~4 Haloalk, -OH, -OCH3, -OC 1~4 haloalk, CN, R 14 and oxo.

[0026] In embodiment 17, the present invention provides a compound comprising: 2

[0023] Provided is a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein: (a) F, Br; (b) Group -YR 13 [where Y is absent and R 13 morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, 3,6-dihydro-2H-pyranyl, [ka] wherein each said ring is substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF, CHOH, CH(CH)OH, C(CH)OH, —OH, —OCHF, CN, oxo, or cyclopropyl; or (c) Group -YR 13wherein Y is absent, —SO2NH—, NH, —O—, S(═O)(═NH)—, —O—(CH2), —O—(CH(CH3))—, C(═O)—, C(═O)—O—, —CH2C(═O)—O—, or —CH2—, and wherein R 13 but, [ka] wherein each ring is substituted with 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, methyl, CF, —OH, or CN, or R 13 is H or C substituted by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, methyl, CF3, —OH, or CN; 1~6 alk].

[0027] In embodiment 18, the present invention provides a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 is: (a) halo; (b) a group -YR 13 [where Y is absent and R 13 morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, [ka] wherein each said ring is substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF, —OH, —OCHF, CN, and oxo; or (c) a group —YR 13 wherein Y is NH, —O—, —O—(CH)—, —O—(CH)—(CH)—, or —O—(CH)—(CH)—(CH)—, and wherein R 13 but, [ka] or R 13is substituted by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, methyl, CF3, —OH, or CN; 1~6 alk].

[0028] In embodiment 19, the present invention provides a compound comprising: 2

[0023] Provided is a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein: [ka]

[0029] In embodiment 20, the present invention provides a compound comprising: 2 is morpholinyl or piperidinyl substituted by 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF, —OH, —OCHF, CN, or oxo. Provided are compounds according to any of the above embodiments, or a pharmaceutically acceptable salt thereof.

[0030] In embodiment 21, the present invention provides a compound comprising: 2 is morpholinyl substituted by 1, 2 or 3 methyl groups; or a pharmaceutically acceptable salt thereof.

[0031] In embodiment 22, the present invention provides a compound comprising: 4 is selected from H, F, methyl, CN, or Br, or a pharmaceutically acceptable salt thereof.

[0032] In embodiment 23, the present invention provides a compound comprising: 4 is H, or a pharmaceutically acceptable salt thereof.

[0033] In embodiment 24, the present invention provides a compound comprising: 5is H, or a pharmaceutically acceptable salt thereof.

[0034] In embodiment 25, the present invention provides a compound comprising: 6 is H, methyl, cyclopropyl, CN, CF3, or azetidinyl, or a pharmaceutically acceptable salt thereof.

[0035] In embodiment 26, the present invention provides a compound comprising: 7 is H, or a pharmaceutically acceptable salt thereof.

[0036] In embodiment 27, the present invention provides a compound comprising: 8 is H or F, or a pharmaceutically acceptable salt thereof.

[0037] In embodiment 28, the present invention provides a compound comprising: 9 is H or F, or a pharmaceutically acceptable salt thereof.

[0038] In embodiment 29, the present invention provides a compound selected from the following table, or a pharmaceutically acceptable salt thereof:

[0039] [Table 1]

[0040] [Table 2]

[0041] [Table 3]

[0042] [Table 4]

[0043] [Table 5]

[0044] In embodiment 30, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0045] In embodiment 31, the present invention provides a method for treating a condition treatable with a KIF18a inhibitor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described in embodiments 1 to 29 or a composition described in embodiment 30.

[0046] In embodiment 32, the present invention provides the method of embodiment 31, wherein the condition is a cancer selected from the group consisting of: (a) a tumor of solid or hematological origin selected from cancer of the bladder, endometrial, squamous cell lung, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gallbladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; (b) leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and / or thyroid cancer. (c) hematopoietic tumors of the lymphoid system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) malignant melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0047] In subembodiment 32a, the invention provides the method of embodiment 31, wherein the condition is a cancer selected from the group consisting of malignant melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia. See: Zhang C., et.al., "Kif18A is involved in human breast carcinogenesis", 2010 Sep;31(9):1676-84. doi:10,1093 / carcin / bgq134. Epub 2010 Jul 1. See also: (1) https: / / www.proteinatlas.org / ENSG00000121621-KIF18A / pathology; (2) Nagahara, M., et. al., "Kinesin 18A expression: clinical relevance to colorectal cancer progression," Int. J. Cancer: 129, 2543-2552 (2011) VC 2011 UIC; and (3) Yu. Y., et. al., "The Role of Kinesin Family Proteins in Tumorigenesis and Progression - Potential Biomarkers and Molecular Targets for Cancer Therapy," Cancer 2010; 116: 5150-60., VC 2010 American Cancer Society.

[0048] In embodiment 33, the present invention provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in embodiments 1 to 29 or a composition described in embodiment 30.

[0049] In embodiment 34, the present invention provides a method of treating a cell proliferation disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in embodiments 1 to 29 or a composition described in embodiment 30.

[0050] In embodiment 35, the present invention provides a method for inhibiting KIF18A in a cell, the method comprising contacting the cell with a compound described in embodiments 1 to 29 or a pharmaceutically acceptable salt thereof, or a composition described in embodiment 30.

[0051] In embodiment 36, the present invention provides a method for preparing a compound of formula (I) described herein.

[0052] In embodiment 37, the present invention provides intermediate compounds used in the methods of preparing compounds of formula (I) described herein. DETAILED DESCRIPTION OF THE INVENTION

[0053] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0054] Examples of isotopes suitable for incorporation into compounds of the invention include, but are not limited to, isotopes of hydrogen such as: 2 H and 3 H, carbon, for example, 11 C. 13 C and 14 C, chlorine, for example, 38 Cl, fluorine, for example, 18 F, iodine, for example, 123 I and 125 I, nitrogen, for example, 13 N and 15 N, oxygen, for example 15 O. 17 O, and 18 O, phosphorusFor example, 32 P, as well as sulfur, for example, 35 S.

[0055] Certain isotopically labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose due to their ease of incorporation and ready means of detection.

[0056] Heavier isotopes, such as deuterium, i.e. 2 Substitution with H may confer certain therapeutic advantages from increased metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances.

[0057] Positron-emitting isotopes, for example: 11 C. 18 F, 15 O, and 13 Substitution with N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0058] Isotopically labeled compounds of the 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" section, substituting appropriate isotopically labeled reagents for the unlabeled reagents previously employed.

[0059] Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0060] Included in certain embodiments of the present invention are the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof.

[0061] Unless otherwise stated, the following definitions apply to terms found in the specification and claims.

[0062] "C α~β "Alk" means an alkyl group containing a minimum of α and a maximum of β carbon atoms, in a branched or linear relationship, or any combination of the three, where α and β represent integers. The alkyl groups described in this section may contain one or two double or triple bonds. The notation COalk suggests a direct bond. 1~6 Examples of alkyl include, but are not limited to: [ka]

[0063] The term "benzo", alone or in combination, means the divalent group CH=, one designation of which is CH=CH-CH=CH, which, when closely attached to another ring, forms a benzene-like ring (e.g., tetrahydronaphthylene, indole, etc.).

[0064] The terms "oxo" and "thioxo" refer to the groups =O (e.g., in carbonyl) and =S (e.g., in thiocarbonyl), respectively.

[0065] "Halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0066] "C α~β "Haloalk" means an alk group, as described above, in which any number (at least one) of the hydrogen atoms attached to the alk chain have been replaced by F, Cl, Br, or I.

[0067] Group N(R a )R a For example, the two R aIncluded are substituents where the groups combine to form a ring, optionally containing an N, O, or S atom, such as, for example, groups such as: [ka]

[0068] Group N(C α~β alk)C α~β alk (where α and β are defined above) has two C α~β Included are substituents in which alk groups combine to form a ring, optionally containing an N, O, or S atom, such as, for example, groups such as: [ka]

[0069] "Bicyclic ring" means a group characterized by two connected rings. A bicyclic ring may be carbocyclic (the ring atoms are all carbon) or heterocyclic (the ring atoms consist of, in addition to carbon atoms, e.g., one, two, or three heteroatoms, such as N, O, or S). The two rings may be aliphatic (e.g., decalin and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include the following: (a) Spirocyclic compounds, in which two rings share only one single atom, the spiroatom (usually a quaternary carbon). Spirocyclic compounds include, but are not limited to: [ka] (b) Fused bicyclic compounds, in which two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., their bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic rings include, but are not limited to, the following: [ka] (c) Bridged bicyclic compounds, in which two rings share three or more atoms and a bridge containing at least one atom separates the two bridgehead atoms. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings each sharing their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to: [ka]

[0070] "Carbocycle" or "carbocyclic" means a ring, alone or in combination with other terms, and unless otherwise specified, includes "C α~β It represents the cyclic version of "alk." Examples of carbocycles include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene, and the like.

[0071] "Heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Heterocycles that may be found in the claims include, but are not limited to: [ka]

[0072] "Pharmaceutically acceptable salt" refers to a salt prepared by conventional means and is well known to those skilled in the art. "Pharmacologically acceptable salts" include, but are not limited to, base salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, and mandelic acid. When the compounds of the present invention contain an acidic functional group, such as a carboxy group, suitable pharmaceutically acceptable cation pairs for the carboxy group are known to those skilled in the art, and include, for example, alkali, alkaline earth, ammonium, and quaternary ammonium cations. For further examples of "pharmacologically acceptable salts," see below and Berge et al., J. Pharm. Sci., 66:1 (1977).

[0073] "Saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogen, substituents that are not completely saturated with hydrogen, and substituents that are partially saturated with hydrogen.

[0074] A "leaving group" generally refers to a group that can be readily displaced by a nucleophile, such as an amine, a thiol, or an alcohol. Such leaving groups are well known to those skilled 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 described elsewhere herein.

[0075] The term "protecting group" generally refers to a group known to those skilled in the art that is used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto, and the like, from undergoing undesired reactions, such as nucleophilic reactions, electrophilic reactions, oxidation reactions, reduction reactions, and the like. Preferred protecting groups are described elsewhere herein. 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 aralkyls include, but are not limited to, benzyl, ortho-methylbenzyl, trityl, and benzhydryl (which may optionally be substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl, and the like, as well as salts, such as phosphonium and ammonium salts). Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl, and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl groups, preferably having 6 to 10 carbon atoms, include, but are not limited to, cyclohexenylmethyl, and the like. Suitable acyl, alkoxycarbonyl, and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, and the like. Mixed protecting groups can also be used to protect the same amino group; for example, a primary amino group can be protected with both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also use their nitrogen to form heterocyclic rings with those to which they are attached, such as 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl, and the like, and these heterocyclic groups can also incorporate aryl and cycloalkyl rings.In addition, heterocyclic groups may be mono-, di-, or trisubstituted, such as nitrophthalimidyl. Amino groups may be further protected from undesired reactions, such as oxidation, by forming addition salts with, for example, hydrochlorides, toluenesulfonic acid, trifluoroacetic acid, and the like. Many amino-protecting groups are also suitable for protecting carboxy, hydroxy, and mercapto groups, such as aralkyl groups. Alkyl groups, such as tert-butyl, are also suitable groups for protecting hydroxy and mercapto groups.

[0076] A silyl protecting group is a silicon atom optionally substituted with one or more alkyl, aryl, and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane, and diphenylmethylsilyl. Silylation of an amino group provides a mono- or di-silylamino group. Silylation of an amino alcohol compound provides an N,N,O-trisilyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment, for example, with a metal hydroxide or ammonium fluoride reagent, either as a separate reaction step or in situ during the reaction with the alcohol group. Suitable silylating agents include, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their reaction products in combination with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods for preparing amine derivatives thereof from the corresponding amino acids, amino acid amides, or amino acid esters, including amino acid / amino acid ester or amino alcohol chemistry, are also well known to those skilled in the art of organic chemistry.

[0077] Protecting groups are removed under conditions that do not affect the remaining portion of the molecule. These methods are well known to those skilled in the art and include acid hydrolysis, hydrogenolysis, and the like. A preferred method involves the removal of protecting groups, for example, by hydrogenolysis using palladium on carbon in a suitable solvent system, such as alcohol, acetic acid, or a mixture thereof, to remove benzyloxycarbonyl groups. A t-butoxycarbonyl protecting group can be removed using an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The amino salt thus obtained can be readily neutralized to give the free amine. Carboxy protecting groups, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0078] It should be noted that the compounds of the present invention may contain groups that can exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted heteroaryl groups (Y' = O, S, NR), etc., as illustrated in the following examples: [ka] And, even if one form is called out, described, shown or claimed herein, all tautomeric forms are intended to be inherently included in such name, description, showing and / or claim.

[0079] Prodrugs of the compounds of the present invention are also contemplated by the present invention. A prodrug is an active or inactive compound that is chemically modified by in vivo physiological action, such as hydrolysis, metabolism, etc., to yield a compound of the present invention after administration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known to those skilled in the art. For reviews of prodrugs, including esters, see Svensson and Tunek, Drug Metabolism Reviews, 165 (1988), and Bundgaard, Design of Prodrugs, Elsevier (1985). Examples of masked carboxylate anions 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 have been masked as arylcarbonyloxymethyl-substituted derivatives, which are cleaved in vivo by esterases to release the free drug and formaldehyde (Bungaard, J. Med. Chem., 2503 (1989)). Furthermore, drugs containing acidic NH groups, such as imidazole, imide, and indole, have been masked using N-acyloxymethyl groups (Bungaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. European Patent No. 039,051 (Sloan and Little, April 11, 1981) discloses hydroxamic acid prodrugs of Mannich bases, their preparation, and uses.

[0080] The specification and claims contain lists of chemical species (sometimes called Markush groups) using the phrases "selected from ... and ..." and "is ... or ...." When this phrase is used in the art, unless otherwise specified, it means that the group as a whole, or various single members thereof, or various subgroups thereof are included. The use of this phrase is merely for shorthand purposes and is not meant in any way to limit the elimination of individual elements or subgroups, where appropriate.

[0081] Pharmaceutical Compositions, Dosages, and Routes of Administration Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein in association with a pharmaceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those that allow the compound to be administered in an effective amount to achieve its intended purpose. Administration of the compounds is described in more detail below.

[0082] Depending on the route of administration and the desired dose, the appropriate pharmaceutical formulation can be determined by one skilled in the art. See, for example, Remington's Pharmaceutical Sciences, pp. 1435-712 (18th ed., Mack Publishing Co., Easton, Pennsylvania, 1990). The formulation may affect the physical properties, stability, in vivo release rate, and in vivo excretion rate of the administered drug. Depending on the route of administration, the appropriate dosage can be calculated based on body weight, body surface area, or organ size. Further refinement of the calculations required to determine the appropriate therapeutic dosage can be performed routinely by one skilled in the art without undue experimentation, taking into account the dosage information and assays disclosed herein, as well as pharmacokinetic data available through animal or human clinical trials.

[0083] The terms "pharamaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable excipients" include any or all of the following: solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such excipients for pharmaceutically active substances is well known to those skilled in the art. Except insofar as any conventional media or agent is incompatible with the therapeutic composition, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In an exemplary embodiment, the formulation may include the following: corn syrup solids, high oleic safflower oil, palm oil, soybean oil, L-leucine, tribasic calcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (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-glutamine, L-valine, dibasic potassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, L-glutamine, L-valine, dibasic potassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine mono Supplement: glutamic acid, L-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, cupric sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0084] The compounds may be present in the pharmaceutical composition as pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" includes, for example, base addition salts and acid addition salts.

[0085] Pharmaceutically acceptable base addition salts are preferably formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium, and quaternary ammonium cations. Carbonate or bicarbonate salts are also possible. Examples of metals used as cations include sodium, potassium, magnesium, ammonium, calcium, or ferric iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0086] Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, and phosphates. Other suitable pharmaceutically acceptable salts will be known to those skilled in the art and include, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; organic carboxylic acids, sulfonic acids, sulfo- or phosphonic acids, or N-substituted sulfamic acids, such as 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, salts with amino acids, such as the 20 alpha amino acids involved in the synthesis of natural proteins, 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, N-cyclohexylsulfamic acid (with the formation of cyclamate), or organic compounds of other acids, such as ascorbic acid.

[0087] Pharmaceutical compositions containing the compounds disclosed herein can be produced by conventional methods, such as by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen.

[0088] Suitable compositions for oral administration can be easily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known to those skilled in the art. Such excipients and carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by the patient receiving treatment. Formulations for oral use can be obtained by adding the compounds disclosed herein to solid excipients, optionally grinding the resulting mixture, and, if desired, processing the granular mixture after adding suitable excipients to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can also be added if desired. Pharmaceutically acceptable ingredients for various types of formulations are known and may include, for example: binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavorings, coating agents, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various types of formulations.

[0089] When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition will typically be in the form of a solid dosage form (e.g., a tablet, capsule, pill, powder, or lozenge) or a liquid formulation (e.g., an aqueous suspension, solution, elixir, or syrup).

[0090] When administered in tablet form, the composition may further contain a functional solid and / or solid carrier, such as gelatin or an adjuvant. The tablet, capsule, or powder may contain about 1% to about 95% of the compound, preferably about 15% to about 90% of the compound.

[0091] When administered in solution or suspension form, a functional liquid and / or liquid carrier, such as water, petroleum, or oils of animal or plant origin, may be added. Liquid forms of the composition may further comprise saline solution, a sugar alcohol solution, a glucose or other sugar solution, or a glycol. When administered in solution or suspension form, the composition may contain from about 0.5 to about 90% by weight of a compound disclosed herein, preferably from about 1 to about 50% by weight of a compound disclosed herein. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in solution form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0092] When a therapeutically effective amount of a compound disclosed herein is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into due consideration pH, isotonicity, stability, and the like, is within the skill of those in the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compound disclosed herein. Such compositions can be prepared for administration as a solution of a free base or pharmacologically acceptable salt in water, admixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may optionally contain a preservative to prevent the growth of microorganisms.

[0093] Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for extemporaneous preparation for the preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, the form must be sterile and must be fluid to the extent that easy inhalation into a syringe is possible. It must be stable under the conditions of manufacture and storage and must resist the contaminating action of microorganisms, such as bacteria and fungi, by the inclusion of an optional preservative. The carrier may be a solvent or dispersion medium, including, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), and vegetable oils, suitable for mixtures thereof. In one contemplated embodiment, the carrier is non-aqueous or substantially non-aqueous. Such proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size of the compound in the dispersion embodiment, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0094] Sterile injectable solutions are prepared by incorporating the compound of the active ingredient in the required amount in a suitable solvent with the various ingredients listed above, followed by filtration sterilization, if necessary. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the other ingredients listed above as required. In the embodiment of sterile powders for preparing sterile injectable solutions, the preferred methods for preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredients (previously sterile filtered from their solutions).

[0095] Slow- or sustained-release formulations may be prepared to achieve controlled release of the active ingredient compound in contact with body fluids in the gastrointestinal tract and to provide a substantially constant and effective level of the active ingredient compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. In addition, the sustained-release approach can enhance absorption through saturable or restricted pathways within the gastrointestinal tract. For example, for this purpose, the compound may be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, and optionally, a suitable surfactant. "Embedding," in this context, means incorporating microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using known dispersion or emulsion coating techniques.

[0096] For administration by inhalation, the compounds of the present invention are conveniently administered in the form of an aerosol spray composition from pressurized packs or nebulizers using a suitable propellant. In pressurized aerosol embodiments, the dosage unit can be determined by providing a valve to deliver a predetermined amount. Capsules and cartridges, for example, of gelatin, for use in inhalers or insufflators can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0097] The compounds disclosed herein can also be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection can be provided in unit dosage form (e.g., in ampoules or in multi-dose containers) with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents.

[0098] Pharmaceutical preparations for parenteral administration include aqueous solutions of the compound in water-soluble form. Furthermore, suspensions of the compound can also be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles 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 further contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, the present compositions may be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) immediately before use.

[0099] The compounds disclosed herein can also be formulated in rectal compositions, for example, 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 depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0100] Specifically, the compounds disclosed herein can be administered orally, bucally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules, alone or in combination with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid formulations can be prepared with pharmaceutically acceptable excipients, such as suspending agents. The compounds can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution, which may contain other substances to make the solution isotonic with blood, such as salts, sugar alcohols, e.g., mannitol, or glucose.

[0101] For veterinary use, the compounds disclosed herein are administered in a suitably acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosage and route of administration for a particular animal.

[0102] In some embodiments, all of the components necessary to treat a KIF18A-associated disorder may be packaged into a kit, using the compounds disclosed herein, alone or in combination with other drugs or interventions traditionally used to treat such disorders. Specifically, the present invention provides kits for use in disease treatment interventions, comprising a packaged set of drugs containing the compounds disclosed herein, as well as buffers and other ingredients for formulating the drugs into a deliverable form, and / or equipment for administering such drugs, and / or various drugs used in combination therapy with the compounds disclosed herein, and / or instructions for treating the disease packaged with the drugs. The instructions may be contained on various tangible media, such as printed paper or computer-readable magnetic or optical media, or may be instructions referencing a remote computer database, e.g., via the Internet, such as a World Wide Web page.

[0103] A "therapeutically effective amount" refers to an amount effective to treat, prevent the progression of, or alleviate existing symptoms in the subject being treated. Determining the effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective dose" refers to the amount of the compound that results in achieving the desired effect. For example, in one preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KIF18A activity by at least 5%, 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% compared to a control.

[0104] The amount of compound administered will depend on the subject being treated and may be dependent on the subject's age, health, sex, and weight, type of concurrent treatment (if any), the severity of the disease, the nature of the desired effect, the mode and frequency of treatment, and the judgment of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen tension. While individual needs vary, determining optimal ranges for effective amounts of the compound is within the skill of one of ordinary skill in the art. Such dosages may be administered as a single dose or divided into multiple administrations.

[0105] The terms "cancer" or "cancerous," as used herein, refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, sarcoma, blastoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, ovarian cancer, and endometrial cancer. The term "cancer," as used herein, is not limited to any one specific form of disease, and it is believed that the methods of the present invention will be particularly effective against cancers that are found to be associated with unregulated levels of KIF18A or dependent on KIF18A for proper chromosome segregation and survival in mammals.

[0106] The terms "treat," "treating," and "treatment," as used herein, refer to therapy, including, but not limited to, curative therapy and prophylactic therapy. Prophylactic therapy generally consists of either preventing the onset of a disorder altogether or delaying the onset of a pre-clinically evident stage of a disorder in an individual.

[0107] The terms "patient," "subject," or "mammal," as used herein, refer to any of human, bovine, equine, canine, and feline "patients," "subjects," or "mammals." In one embodiment of the invention, the mammal is a human.

[0108] The term "comprising" is intended to be open-ended and inclusive, including the listed elements but not excluding other elements.

[0109] The term "Formula I" also includes various subformulas.

[0110] How to use KIF18A inhibitors The present disclosure provides compounds that generally have MT-based KIF18A modulatory activity, particularly inhibitory activity. In one embodiment of the present invention, a method for regulating KIF18A protein in a subject is provided, comprising administering to the subject an effective dose of a compound of Formula I. As such, the compounds of the present invention can be used to treat cell proliferation disorders, including uncontrolled cell proliferation, abnormal cell cycle regulation, and centrosome abnormalities (structural and / or numerical fragmentation). Other diseases or disorders associated with the accumulation of extra centrosomes (>2) include human papillomavirus (HPV) infection (including HPV-associated neoplasia). These compounds are also useful for cilia-related disorders and for the ablation of haploid germ cell populations, potentially as a male contraceptive.

[0111] In addition, the compounds of the present invention are useful for the prevention and treatment of, but not limited to, cancer and other KIF18A-mediated diseases or disorders. For example, the compounds of the present invention may be useful for the treatment of various solid and hematologically derived tumors, such as: carcinomas, including but not limited to, cancers of the bladder, breast, colon, kidney, liver, lung (including squamous cell and small cell lung cancer), esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair follicle, and bladder); hematopoietic tumors of the myeloid lineage (including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including malignant melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma).

[0112] The compounds of the present invention are further useful in the treatment of cancer-related indications such as, for example, solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic malignancies (including leukemia and lymphoma), tumor-induced pleural or pericardial effusion, and malignant ascites.

[0113] Based on their ability to regulate kinesin-induced angiogenesis, the compounds of the present invention are also useful in the treatment and therapy of proliferative diseases. In particular, these compounds can be used to treat inflammatory diseases such as: various inflammatory rheumatoid diseases, especially those affecting the locomotor system, including rheumatoid arthritis, juvenile arthritis, or chronic polyarthritis, including psoriatic arthropathy; paraneoplastic syndromes or tumor-induced inflammatory diseases, cloudy exudates, collagen diseases such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic ligamentous sclerosis, or mixed collagen diseases; post-infectious arthritis (when no living pathogenic microorganisms are found at or in the infected body part), seronegative spondylitis, such as ankylosing spondylitis; vasculitis, sarcoidosis, or arthropathy; or various combinations thereof.

[0114] The compounds of the present invention can also be used as active agents for the treatment of disease conditions such as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer disease, Helicobacter-associated disease, bone fractures, cat-scratch fever, rubeosis, neovascular glaucoma, and retinopathies (e.g., those associated with diabetic retinopathy or macular degeneration). In addition, some of these compounds can be used as active agents for solid tumors, malignant ascites, cancers of the hematopoietic system, and hyperproliferative disorders such as thyroid hyperplasia (particularly Graves' disease), cysts (e.g., hypervascularity of the ovarian stroma, characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)), because such diseases require vascular cell proliferation for growth and / or metastasis.

[0115] In addition to being useful in human treatment, the compounds are also useful in the veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats can be treated with the compounds provided by the present invention.

[0116] Combination therapy Although the compounds of the present invention can be dosed or administered as the sole active pharmaceutical agent, they can also be combined with one or more compounds of the present invention or used simultaneously with other drugs. When administered as a combination, the therapeutic agents can be formulated as separate compositions and administered simultaneously or sequentially at different times, or the therapeutic agents can be given as a single composition.

[0117] The term "co-therapy" (or "combination therapy"), in defining the use of a compound of the invention with another pharmaceutical agent, is intended to encompass administration of each agent in the therapy in a sequential manner to achieve the beneficial effect of the combined drugs, as well as co-administration of the agents in a substantially simultaneous manner, e.g., in the form of a single capsule containing a fixed ratio of the active agents, or in the form of separate capsules for each agent.

[0118] In particular, the administration of the compounds of the invention can be combined with additional therapies known to those skilled in the art in the prevention or treatment of cancer, such as radiation therapy, small molecule targeted drugs (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies (e.g., naked drug conjugates) in combination with oncological or cytotoxic agents, immunotherapeutic antibodies (checkpoint inhibitors, bispecific T cell inducers).

[0119] If formulated as a fixed dose, such combination formulations employ the compounds of the present invention within their acceptable dosage range. When a combined formulation is inappropriate, the compounds of Formula I may be administered sequentially with known anticancer or cytotoxic agents. The present invention does not limit the order of administration, and the compounds of the present invention may be administered before, simultaneously with, or after the administration of known anticancer or cytotoxic agents.

[0120] There are many anti-cancer drugs available in commercial use, clinical evaluation, and preclinical development that may be selected for the treatment of neoplasia by combination drug chemotherapy. Such drugs fall into several major categories: antibiotic-type agents, alkylating and alkylating-like agents, mitotic inhibitors, targeted small molecule agents, antimetabolites, hormonal agents, immunological agents, anti-angiogenic agents, interferon-type agents, and miscellaneous categories of agents.

[0121] The present disclosure also provides methods for combination therapy in which agents known to regulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes, are used in combination with compounds of the present disclosure, or pharmaceutically acceptable salts thereof. In one embodiment, such therapy includes, but is not limited to, combining one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, targeted small molecule agents, and radiation therapy to provide synergistic or additive therapeutic effects.

[0122] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present 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, antiangiogenic agents, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include: alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, methyledopa, and uredopa; ethyleneimines and methylameramines such as altretamine, triethylenemelamine, triethylenephosphoramide, trimethylameramine ... Ethylenethiophosphoramide and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics such as aclacinomycin, actinomycin, austramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, pupromycin, thromycin, chelamycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine , doxifluridine, enocitabine, floxuridine, androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenameth; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxanes such as paclitaxel and docetaxel, Nab-paclitaxel; retinoic acid; esperamycin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0123] Suitable chemotherapeutic cell conditioners include antihormonal agents that act to regulate or inhibit the action of hormones on tumors, such as antiestrogens such as tamoxifen, (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, luprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin, carboplatin; etoposide (VP-16); ifosfamide; and mitomycin. C; mitoxantrone; vinblastine; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; topotecan; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO).

[0124] If desired, the compounds or pharmaceutical compositions of the present disclosure can also be used in combination with commonly prescribed anti-cancer drugs, such as, for example, Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Abraxane, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumab, 17-N-arylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, amonafod, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW. 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agents, dichloroacetic acid, discodamolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, orapa Ribociclib, talazoparib, niraparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapatitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegaflu-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar, CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, quisqali; abemaciclib, velzenio).

[0125] The present disclosure also relates to methods for using the compounds or pharmaceutical compositions provided herein in combination with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in mammals, although techniques for administering radiation therapy are known to those skilled in the art and can be used in the combination therapies described herein. The administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0126] Radiation therapy can be administered by one or a combination of several methods, including, but not limited to, external beam therapy, internal radiation therapy, implant radiation therapy, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy," as used herein, refers to radiation therapy delivered by spatially confined radioactive materials inserted inside the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell conditioners of the present disclosure include both solid and liquid sources. By way of non-limiting example, the radiation source may be a radionuclide, such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic radiation. The radioactive material may also be a fluid made from various solutions of the radionuclide, e.g., a solution of I-125 or I-131, or a radioactive fluid may be made using a slurry of a suitable fluid containing small particles of a solid radionuclide, e.g., Au-198, Y-90. Furthermore, the radionuclide may be embodied in the form of a gel or radioactive microspheres.

[0127] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0128] Antiangiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can also be used in combination with the compounds of the present disclosure and the 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 the following patents: WO 96 / 33172, WO 96 / 27583, EP 0818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 606046, European Patent Application See, for example, Publication No. 931788, WO 90 / 05719, WO 99 / 52910, WO 99 / 52889, WO 99 / 29667, WO 1999007675, EP 1786785, EP 1181017, U.S. Patent Application Publication No. 20090012085, U.S. Patent No. 5863949, U.S. Patent No. 5861510, and EP 0780386 (all of which are incorporated herein by reference). Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1.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, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0129] The compounds of the present invention can also be used in co-therapy with other anti-cancer agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, and cetroleri. ox, cladribine, clotrimazole, cytarabine ocphosphate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, efornithine, emiteflu, epirubicin, Epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fudrabin phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumabzogamicin, dimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, interferon alfa, natural, interferon alfa) Lufa-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha-n3, interferon alphacon-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult),Leflunomide, lenograstim, lentinan sulfate, letrozole, leucocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melasoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamivir Do, noscapine, novel erythropoiesis-stimulating protein, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, raltitrexed, rasbriemboment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramotim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimec s, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, barbican, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL532 (Elan), EM800 (Endorecherche), eniluracil,Etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering) Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital), or Valspodar.

[0130] The compounds of the present invention can also be used in combination with VEGFR inhibitors. Other compounds described in the following patents and patent applications can also be used in combination therapy: U.S. Pat. No. 6,258,812, U.S. Pat. No. 2003 / 0105091, WO 01 / 37820, U.S. Pat. No. 6,235,764, WO 01 / 32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat. No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, WO 02 / 68406. brochures, 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, U.S. Pat. No. 5,990,141, WO 00 / 12089, and WO 00 / 02871.

[0131] In some embodiments, the combination includes a composition of the present invention in combination with at least one anti-angiogenic agent. Agents include, but are not limited to, in vitro synthetically prepared compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Agents may be agonists, antagonists, allosteric modulators, toxins, or, more generally, may exert an inhibitory or stimulatory effect on their target (e.g., activation or inhibition of a receptor or enzyme), thereby promoting cell death or arresting cell proliferation.

[0132] Examples of anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind to VEGF, or soluble VEGF receptors, or their ligand-binding regions) such as AVASTIN™ or VEGF-TRAP™, and anti-VEGF receptor drugs (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto) such as Vectibix (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind thereto, or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the present invention may further include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that bind to and inhibit the activity of growth factors, such as hepatocyte growth factor (HGF, also known as "scatter factor"), and antibodies or antigen-binding regions that specifically bind to its receptor "c-met."

[0133] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen-binding regions, or soluble TWEAK receptor antagonists; see Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains that antagonize integrin binding to its ligands (Fanslow et al., U.S. Patent Application Publication No. 2002 / 0042368), and specific binding Anti-eph receptor and / or anti-ephrin antibodies or antigen binding regions thereof (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124, and members of those patent families), as well as anti-PDGF-BB antagonists (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., antibodies or antigen binding regions that specifically bind thereto).

[0134] Additional anti-angiogenic / anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EP 770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); m-PGA (Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat (Arriva, USA, U.S. Pat. No. 5,892,112); emaxanib (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab, (Amgen, USA); CEP-7055, (Cephalon, USA); Anti-Vn Mab, (Crucell, Netherlands) DAC: Antiangiogenic, (ConjuChem, Canada); Angiosidin, (InKine Pharmaceutical, USA); KM-2550, (Kyowa Hakko, Japan); SU-0879, (Pfizer, USA); CGP-79787, (Novartis, Switzerland, European Patent No. 970070); ARGENT technology, (Ariad, USA); YIGSR-Stealth, (Johnson & Johnson, USA); Fibrinogen-E fragment, (BioActa, UK); Angiogenesis inhibitor, (Trigen, UK); TBC-1635, (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbot, USA); metastatin, (EntreMed, USA); angiogenesis inhibitor, (Tripep, Sweden); maspin, (Sosei, Japan); 2-methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA); Tz-93, (Tsumura, Japan);TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02-233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, alpha 5 beta 3 integrin, second generation (Applied Molecular Evolution, USA, and MediImmune, USA); gene therapy, retinopathy (Oxford BioMedica, UK); 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, (Regeneron, USA); rBPI 21 and BPI-derived antiangiogenic, (XOMA, USA); PI 88, (Progen, Australia); cilengitide (pINN), (Merck KGaA, German; 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 Children's Hospital, USA); ATN 161, (Attenuon, USA); ANGIOSTATIN, (Boston Children's Hospital, USA); 2-methoxyestradiol, (Boston Children's Hospital, USA);ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD9935, (AstraZeneca, UK); AZD2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizole, (Yonsei University, South Korea); gene-based VEGF-2 vaccine, (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-guanidine, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); 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-1 alpha inhibitor, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA);KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); Drug delivery system, intraocular, 2-methoxyestradiol, (EntreMed, USA); Anginex, (Maastricht University, Netherlands, and University of Minnesota, USA); ABT 510, (Abbot, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitor (National Institute on Aging, USA); SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518 (Abbot, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5beta1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB 116 (University of South Florida, 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, UK); CKD 732, (Chong Kun Dang, South Korea); MAb, vascular endothelial growth factor, (Xenova, UK); 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 inhibitor, (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 modulator, (Pharmacopeia, USA); VE-cadherin-2 antagonist, (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 Ligand (Regeneron, USA); and Thrombospondin 1 Inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0135] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and agents that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA inhibitors that inhibit the expression of proteins, including but not limited to ATG5 (which is involved in autophagy), may also be used.

[0136] Additional pharmaceutically active compounds / drugs that can be used to treat cancer and that can be used in combination with one or more compounds of the present invention include: epoetin alfa; darbepoetin alfa; 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.

[0137] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitexel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, and enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically, depriving cells that do not have the ability to synthesize their own asparagine). asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB 286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazene-dacarbazine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalipsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF-neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38 MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), Aurora kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torc1 / 2-specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib, talazoparib, niraparib, veliparib (ABT-888)), BCL-2 antagonists. Other chemotherapeutic agents include: mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or analogs or derived variants thereof.

[0138] The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0139] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate ... Ruprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, [triamcinolone acetonide / triamcinolone acetonide], triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In certain embodiments, the compounds of the present invention may also be used in combination with an additional pharmaceutically active agent for treating nausea. Examples of drugs that can be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0140] The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more agents selected from the following: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and immune agents such as anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0141] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently, lapatinib (TykerB). See, for example, the following references: Yan L., et. al., "Pharmacogenetics and Pharmacogenomics in Oncology Therapeutic Antibody Development," BioTechniques, 2005;39(4):565-8, and Paez JG, et. al., "EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy," Science, 2004;304(5676):1497-500.

[0142] Non-limiting examples of small molecule EGFR inhibitors include the various EGFR inhibitors described in the following published patents, including all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: EP 520722 (published December 30, 1992); EP 566226 (published October 20, 1993); WO 96 / 33980 (published October 31, 1996); U.S. Pat. No. 5,747,498 (issued May 5, 1998); WO 96 / 33980 (published May 5, 1998); No. 0347 (Publication Date: October 3, 1996); European Patent Application Publication No. 787772 (Publication Date: August 6, 1997); International Publication No. WO 97 / 30034 (Publication Date: August 21, 1997); International Publication No. WO 97 / 30044 (Publication Date: August 21, 1997); International Publication No. WO 97 / 38994 (Publication Date: October 23, 1997); International Publication No. WO 97 / 49688 (Publication Date: December 31, 1997); European Patent Application Publication No. 837063 (Publication Date: April 1998) 22); WO 98 / 02434 (Publication Date: January 22, 1998); WO 97 / 38983 (Publication Date: October 23, 1997); WO 95 / 19774 (Publication Date: July 27, 1995); WO 95 / 19970 (Publication Date: July 27, 1995); WO 97 / 13771 (Publication Date: April 17, 1997); WO 98 / 02437 (Publication Date: January 22, 1998); WO 98 / 02438 No. WO 97 / 32881 (Publication Date: September 12, 1997); German Patent Application Publication No. 19629652 (Publication Date: January 29, 1998); German Patent Application Publication No. WO 98 / 33798 (Publication Date: August 6, 1998); German Patent Application Publication No. WO 97 / 32880 (Publication Date: September 12, 1997); German Patent Application Publication No. WO 97 / 32880 (Publication Date: September 12, 1997); European Patent Application Publication No. 682027 (Publication Date: November 15, 1995);International Publication No. 97 / 02266 (Publication Date: January 23, 1997); International Publication No. 97 / 27199 (Publication Date: July 31, 1997); International Publication No. 98 / 07726 (Publication Date: February 26, 1998); International Publication No. 97 / 34895 (Publication Date: September 25, 1997); International Publication No. 96 / 31510 Lett (Publication Date: October 10, 1996); WO 98 / 14449 (Publication Date: April 9, 1998); WO 98 / 14450 (Publication Date: April 9, 1998); WO 98 / 14451 (Publication Date: April 9, 1998); WO 95 / 09847 (Publication Date: April 13, 1995) WO 97 / 19065 (Publication Date: May 29, 1997); WO 98 / 17662 (Publication Date: April 30, 1998); U.S. Patent No. 5,789,427 (Issue Date: August 4, 1998); U.S. Patent No. 5,650,415 (Issue Date: July 22, 1997); U.S. Patent No. 5,656,643 (Issue Date: Publication No. WO 99 / 35146 (Publication Date: August 12, 1997); WO 99 / 35132 (Publication Date: July 15, 1999); WO 99 / 07701 (Publication Date: February 18, 1999); and WO 92 / 20642 (Publication Date: November 26, 1992). Further non-limiting examples of small molecule EGFR inhibitors include the various EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents, 8(12):1599-1625.

[0143] Antibody-based EGFR inhibitors include various anti-EGFR antibodies or antibody fragments that can partially or completely block EGFR activation by natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following documents: 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. et al., 1999, Cancer Res., 15:59(8):1935-40; and Yang, X. et al., 1999, Cancer Res., 59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0144] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0145] PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxywortmannin analogs (described in WO 06 / 044453), 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941, described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235 and described in WO 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride (available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide (available from Axon Medchem), GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate (available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-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). (Available from Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxyviridine, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0146] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al., (2005) Biochem. J., 385(Pt.2), 399-408); Akt-1-1,2 (inhibits AK1 and 2) (Barnett et al., (2005) Biochem. J., 385(Pt.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., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963); Sarkar and Li, (2004) J. Nutr., 134(12 suppl), 3493S-3498S); perifosine (e.g., disrupts Akt membrane localization); Dasmahapatra et. al., (2004) Clin. Cancer Res., 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis, (2004) Expert. Opin. Investig. Drugs, 13, 787-97); and triciribine (TCN or API-2, or NCI identifier: NSC 154020; Yang et. al., (2004) Cancer Res., 64, 4394-9).

[0147] TOR inhibitors include, but are not limited to, inhibitors including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Torin 1). Other TOR inhibitors at the FKBR12 enhancer include rapamycin and its derivatives, including CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010), and AP23573; rapalogs, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, e.g., AP23573, AP23464, or AP23841; 40-(2-hydroxybenzoates)-4-hydroxybenzoates; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin, and other derivatives disclosed in WO 05005434; derivatives disclosed in the following patents: U.S. Pat. 389, WO 94 / 090101, WO 92 / 05179, U.S. Pat. No. 5,118,677, U.S. Pat. No. 5,118,678, U.S. Pat. No. 5,100,883, U.S. Pat. No. 5,151,413, U.S. Pat. No. 5,120,842, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO Nos. WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and U.S. Pat. No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0148] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Examples of anti-PD-1 antibodies and their methods of use are described in the following documents: Goleberg 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. JP 2006 / 309606 (= WO 2006 / 121168A1), which are expressly incorporated herein by reference. Further examples include Yervoy™ (ipilimumab) or tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3475 (against PD-1), AMP224 (against B7DC), BMS-936559 (against B7-H1), MPDL3280A (against B7-H1), MEDI-570 (against ICOS), AMG557 (against B7H2), MGA271 (against B7H3), IMP321 (against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (vs. OX40L), atacicept (vs. TACI), CP-870893 (vs. CD40), lucatumumab (vs. CD40), decatuzumab (vs. CD40), muromonab-CD3 (vs. CD3), ipilumumab (vs. CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0149] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as those described in U.S. Pat. No. 6,111,090 box.c, EP 090505 B1, U.S. Pat. No. 8,586,023, WO 2010 / 003118, and WO 2011 / 090754, or anti-GITR antibodies, such as those described in the following patents: U.S. Pat. No. 7,025,962, EP 1947183 B1, U.S. Pat. No. 7,812,135, and U.S. Pat. No. 8,388,967. No. 8,591,886, European Patent No. 1866339, International Publication No. WO2011 / 028683, International Publication No. WO2013 / 039954, International Publication No. WO2005 / 007190, International Publication No. WO2007 / 133822, International Publication No. WO2005 / 055808, International Publication No. WO99 / 40196, International Publication No. WO2001 / 03720, International Publication No. WO99 / 20758, International Publication No. WO2006 / 083289, International Publication No. WO2005 / 115451, U.S. Patent No. 7,618,632, and International Publication No. WO2011 / 051726.

[0150] The compounds described herein can be used in combination with other agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with other agents, as described above. When used in combination therapy, the compounds described herein can be administered simultaneously or separately with the second agent. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and the various agents described above can be administered simultaneously in the same dosage form. Alternatively, the compounds of the present disclosure and the various agents described above can be administered simultaneously, with both agents present in separate formulations. Alternatively, the compounds of the present disclosure can be administered followed by the various agents described above, or vice versa. In some embodiments of the separate administration protocol, the compounds of the present disclosure and the various agents described above are administered minutes, hours, or days apart.

[0151] While one embodiment of the present invention contemplates the treatment of diseases using a combination of pharmaceutically active compounds that may be administered separately, the present invention also relates to combinations in the form of kits of separate pharmaceutical compositions. The kit includes two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes containers containing the separate compositions, for example, in separate bottles or separate foil pouches. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. Such kits are particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0152] experiment

[0153] [Table 6]

[0154] [Table 7]

[0155] [Table 8]

[0156] Unless otherwise noted, all raw materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in °C unless otherwise noted. All microwave-assisted reactions were performed using a Smith Synthesizer™ manufactured by Biotage™. All compounds exhibited NMR spectra consistent with their assigned structures. Melting points were determined on a Buchi instrument and are uncorrected. Mass spectral data were obtained by electrospray ionization. All examples were purified to greater than 90% purity as determined by high-performance liquid chromatography. Unless otherwise noted, reactions were performed at room temperature.

[0157] In synthesizing the compounds of the present invention, it is desirable to use certain leaving groups. The term "leaving group (LG)" generally refers to a group that can be displaced by a nucleophile. Such leaving groups are known to those skilled 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., SCH), N-hydroxysuccinimide, N-hydroxybenzotriazole, etc. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), etc.

[0158] The following examples illustrate specific embodiments of the present invention and are intended to be representative and not to limit the scope of the claims in any way.

[0159] When used in reference to a liquid, a percentage (%) refers to the volume percent of the solution. When used in reference to a solid, a percentage refers to the composition of the solid. Materials obtained from commercial suppliers were typically used without further purification. Reactions involving air- or moisture-sensitive reactants were typically performed under a nitrogen or argon atmosphere. Purity was measured using a high-performance liquid chromatography (HPLC) system (System A: Agilent Zorbax Eclipse XDB-C8, 4.6 × 150 mm, 5 μm, 5–100% CH3CN in HO, 0.1% TFA, 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6 × 75 mm, 10–90% CH3CN in HO, 0.1% formic acid, 1.0 mL / min for 12 min) with UV detection at 254 nm and 215 nm (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed using prepackaged silica gel cartridges (Biotage, Uppsala, Sweden, or Teledyne-Isco, Lincoln, Nebr.). 1 H NMR spectra were recorded at ambient temperature on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. All observed protons are expressed as parts per million (ppm) below tetramethylsilane (TMS) or other internal standard in the appropriate solvent indicated. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data were obtained using an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS in low-resonance electrospray mode (ESI) with UV detection at 254 nm and 215 nm.

[0160] For clarity in this general synthesis section, compounds of formula (I) as defined in the Summary of the Invention may be synthesized schematically as follows: 1 and Ring Ar 2 and can be depicted as including: [ka] where the group -NR 3 -(C=O)- is a linker, and Ring Ar 1 is located to the left of the linker, and Ring Ar 2 is located to the right of the linker. Generally, compounds of formula (I) can be synthesized via three general steps:

[0161] Step 1: Ring Ar 1 Compound preparation.

[0162] Step 2: Ring Ar 2 Compound preparation.

[0163] Step 3: Ring Ar 1 Compound Ring Ar 2 Coupling to compounds.

[0164] The general Schemes A-E shown below are intended to provide guidance to a synthetic chemist of ordinary skill, who will readily be able to determine and modify, if necessary, the solvents, concentrations, reactants, protecting groups, order of synthetic steps, times, temperatures, and the like, within the skill and judgment of the ordinary artisan.

[0165] Scheme A In Scheme A, in one embodiment, compounds of formula (I) disclosed herein can be synthesized as follows:

[0166] Step 1a: Ring Ar 1 Compound preparation: [ka] Step 1a: Ring Ar 1 Compound preparation: Compound A-1 (wherein, W 1 is halogen, such as fluoro, chloro, or bromo) in the presence of a suitable base in a suitable organic solvent, such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., by reacting R 2 The compound A-1 can be reacted with a reactant containing a group to form compound A-2. 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, 6-fluoropyridin-2-amine, 6-fluoro-4-methylpyridin-2-amine, 6-chloro-5-methylpyridin-2-amine, 6-bromo-5-methylpyridin-2-amine, or 6-chloropyrazine-2-amine. R 2 Examples of reactants include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0167] Step 1b: Ring Ar 1 Compound preparation: [ka] Alternatively, compound A-1 as defined in step 1a may be reacted with an appropriate organoboron R 2 Reactant (R 2-Y B -Y2, ​​where Y is an organic functional group) can be converted to compound A-2, defined in step 1a, via a Suzuki cross-coupling reaction using, for example, 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-(4-fluorocyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and a suitable palladium catalyst and base, for example, PdCl(dppf)-DCM adduct and tribasic potassium phosphate. This step is followed by reduction to form compound A-2 using a suitable palladium catalyst and a hydrogen source, for example, Pd / C in the presence of hydrogen gas. This alternative Suzuki reaction can be carried out by reacting the group R 2 However, Ar is bonded to the 1 It can be used when it is attached to a ring.

[0168] Step 2a: Ring Ar 2 Compound preparation: [ka] In step 2a, compound A-3 (wherein W 2 and W 3 wherein each is independently a halogen, such as fluoro, chloro, bromo, or iodo, in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO, or the like, with R x Compound A-4 can be formed by reaction with a reagent such as (1) 6-azaspiro[2.5]octane hydrochloride, (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.

[0169] Step 3a: Ring Ar 1 Compound Ring Ar 2 Coupling to the compound followed by R 1 Introduction: [ka] In step 3a, compound A-4 (obtained in step 2a) can be reacted with an activating agent, such as an acid chloride (COCl) or SOCl, in a suitable organic solvent, such as tetrahydrofuran, methylene chloride, etc., to form an acid chloride derivative, which can then be reacted with compound A-2 to form compound A-5. Alternatively, compound A-2 can be directly coupled with compound A-4 (obtained from step 2a) in the presence of a coupling agent, such as N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyldiimidazole, and polyphosphonic anhydride, in a suitable organic solvent, such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc. A synthetic chemist of ordinary skill will readily recognize that other coupling agents can also be used. The conversion reaction can be carried out, for example, in a suitable organic solvent, such as DMSO, acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., in the presence of a metal catalyst and R 1 a halogen group W using a metal-catalyzed sulfamidation, sulfination, or sulfonylation in the presence of a reactant such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethan-1-ol, or (11) cyclopropanethiol; 3can be further treated to form compound (I). A chemist of ordinary skill will readily appreciate that coupling reactions such as those shown in step 3a can be carried out under a variety of known conditions.

[0170] Scheme B Step 1a or 1b: Ring Ar 1 Preparation of Compounds: See Scheme A above Step 2b: Ring Ar 2 Compound preparation: [ka] Scheme B provides an alternative method for forming compounds of formula (I) disclosed herein. After step 1a or step 1b described in Scheme A, alternatively, instead of step 3a in Scheme A, in step 2b, a group R 1 Ring Ar 2 In step 2b, compound B-1 (wherein W 4 and W 5 wherein each is independently a halogen, such as fluoro, chloro, bromo, or iodo), can be reacted with an appropriate carboxylic acid protecting group (PG1 reactant), such as methyl iodide, in the presence of a base, such as potassium carbonate, to form a methyl ester, or with other appropriate protecting groups in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., to form other esters, such as benzyl esters, or to form compound B-2, where W 4 and W 5 are as defined in Compound B-1. Compound B-2 is then dissolved in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO, etc., with R x can be reacted with a reagent such as 6-azaspiro[2.5]octane to form compound B-3, where W 5is as defined in Compound B-1. Compound B-3 is then reacted with R in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF, etc., in the presence of a metal catalyst such as copper iodide, Pd2(dba)3. 1 Compound B-4 can be formed by reaction with a reactant, such as a metal-catalyzed sulfamidation, sulfination, or sulfonylation, which can then be further reacted with an appropriate carboxylic acid deprotecting agent to form compound B-5. Suitable carboxylic acid protecting groups and deprotecting agents are known to those skilled in the art and are discussed, for example, in "Greene's Protective Groups in Organic Synthesis."

[0171] Step 3b: Ring Ar 1 Compound Ring Ar 2 Coupling to compounds: [ka] Step 3b is a coupling reaction similar to that described above in Step 3a.

[0172] Scheme C Scheme C provides yet another method for forming compounds of Formula (I) disclosed herein. In Scheme C, step 1a can be carried out as described in Scheme A, followed by step 2b as described in Scheme B.

[0173] Step 3c: Ring Ar 1 Compound Ring Ar 2 Coupling to compounds: [ka] Step 3c, Compound A-1a (Compound A-1 in Scheme A, where X 1 But N or CR 6 And W 1is halogen, for example, fluoro or chloro) is reacted with compound B-5 obtained from step 2b of Scheme B in the presence of an activating agent under conditions similar to steps 3a and 3b above to give compound C-1 (where W 1 is defined as compound A-1a), which can then be reacted with R 2 The compound of formula (I) can be formed by reacting with a reactant containing a group such as (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol.

[0174] Scheme D Scheme D provides yet another method for forming compounds of Formula (I) disclosed herein. In Scheme D, step 1a or 1b can be carried out as described in Scheme A, followed by step 2b as described in Scheme B.

[0175] Step 3d: Ring Ar 1 Compound Ring Ar 2 Coupling to compounds: [ka] In step 3d, compound A-1a (compound A-1 in Scheme A, where X 1 is N or CR 6 And W 1 is halogen, e.g., fluoro or chloro), can be reacted with compound B-5 obtained from step 2a of Scheme A in the presence of an activating agent under conditions similar to those described above in steps 3a and 3b to form compound D-1, where W 1 is defined as in compound A-1a, and W3 is defined in Compound B-5), which is then reacted with R 2

[0044] Compound A-5a can be formed by reacting compound A-5 with a reactant containing a group such as (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol, optionally in the presence of a suitable base such as diisopropylethylamine, potassium carbonate, or sodium hydride, in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, and the like, to form compound A-5a (which is compound A-5, where X 1 is N and W 3 is defined as Compound B-5), which is then converted into R by a conversion reaction, such as a metal-catalyzed sulfamidation, sulfination, or sulfonylation reaction, in the presence of a metal catalyst in a suitable organic solvent, such as DMSO, dioxane, acetonitrile, tetrahydrofuran, or DMF. 1 The compound of formula (I) can be formed by reacting with a reactant containing a group.

[0176] Scheme E Scheme E provides yet another method for forming compounds of formula (I) disclosed herein. In Scheme E, steps 1a or 1b can be carried out as described in Scheme A to prepare compound A-2. Compound E-1 (where W 6 is halogen, e.g., fluoro or chloro, and includes, but is not limited to, 2-fluoro-4-nitrobenzoic acid, 2,5-difluoro-4-nitrobenzoic acid, or 2,6-difluoro-4-nitrobenzoic acid, which are commercially available or can be synthesized by methods known to those skilled in the art.

[0177] Step 3e: Ring Ar 1 Compound Ring Ar 2 Coupling to compounds [ka] In step 3e, compound A-2 can be reacted with compound E-1 in the presence of an activating agent under conditions similar to those in steps 3a and 3b above to form compound E-2, which can then be converted to R in a manner similar to that described in step 2a. x The nitro group on compound E-4 can then be converted to an amino group by reaction with a reducing agent (including, but not limited to, palladium on carbon and hydrogen gas) to form compound E-4, which can then be converted to R by a transformation reaction such as metal-catalyzed sulfamidation, sulfination, or sulfonylation in the presence of a metal catalyst in a suitable organic solvent such as DMSO, dioxane, acetonitrile, tetrahydrofuran, DMF, etc. 1 Compound (I) can be formed by reaction with a reagent such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethan-1-ol, or (11) cyclopropanethiol.

[0178] Example Preparation of synthetic intermediates Ring Ar 1 Intermediates: Intermediate 1: 6-amino-N-(tert-butyl)pyridine-2-sulfonamide [ka] Step 1: To an ice-cooled solution of 6-bromopyridine-2-sulfonyl chloride (0.50 g, 1.9 mmol, Suzhou sibian, China) in dichloromethane (10 mL), triethylamine (0.543 mL, 3.90 mmol) and tert-butylamine (0.310 mL, 2.92 mmol) were added in that order under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1.5 h. Upon completion of the reaction, the reaction mixture was quenched with water (10 mL), and the biphasic mixture was extracted with dichloromethane (3 × 15 mL). The combined organic extracts were washed with saturated brine solution (15 mL) and dried over anhydrous NaSO. The solution was filtered and concentrated under reduced pressure to give the crude product as a pale yellow oil. The crude material was absorbed onto a plug of silica gel and purified by Isolera-Biotage eluting with 17% to 22% ethyl acetate in petroleum ether to give 6-bromo-N-(tert-butyl)pyridine-2-sulfonamide (0.35 g, 1.19 mmol, 61% yield) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.98 (dd, J = 7.6, 0.9 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.65 (dd, J = 8.0, 0.9 Hz, 1H), 4.96 (s, 1H), and 1.27 (s, 9H).

[0179] Step 2: A mixture of 6-bromo-N-(tert-butyl)pyridine-2-sulfonamide (14.5 g, 49.5 mmol), N1,N2-dimethylethane-1,2-diamine (0.436 g, 4.95 mmol), K2CO3 (1.367 g, 9.89 mmol), and copper(I) iodide (0.471 g, 2.47 mmol) was added to aqueous ammonia (21%, 100 mL, 970 mmol) and ethylene glycol (100 mL) in a 500 mL sealed tube. The tube was sealed with a screw cap under a nitrogen atmosphere. The resulting reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (150 mL), and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with saturated brine solution (50 mL) and dried over anhydrous NaSO. The solution was filtered and concentrated under reduced pressure to give the crude product as a pale yellow oil. The crude product was absorbed onto a plug of silica gel and purified by Isolera-Biotage eluting with 5% to 6% methanol in chloroform to give 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (6.94 g, 30.3 mmol, 61% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.54(ddd,J=8.4,7.2,1.3Hz,1H),7.21(s,1H),7.03(dt,J=7.3,0.9Hz,1H),6.59( dt,J=8.4,1.0Hz,1H),6.33(s,2H),and 1.12(d,J=1.3Hz,9H).m / z(ESI):230.1(M+H) + .

[0180] Intermediate 2: 4-methyl-6-morpholinopyridin-2-amine [ka] To a 250 mL pressure tube were added 6-fluoro-4-methylpyridin-2-amine (10.0 g, 79 mmol, Sibian Chemicals, China), morpholine (8.29 g, 95 mmol), and DIPEA (41.5 mL, 238 mmol). The mixture was heated at 150 °C for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 × 250 mL). The organic extracts were combined, washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluted with a gradient of 1% to 15% EtOAc in hexane to afford the title compound (8.5 g, 44.0 mmol, 56% yield) as a brown semi-solid. 1 H NMR(400MHz,DMSO-d6)δ 5.75(s,1H),5.67(s,1H),5.44(s,2H),3.65(t,J=8.4Hz,4H),3.30(t,J=8.4Hz,4H),2.06(s,3H).m / z(ESI):194.2(M+H) + .

[0181] Intermediate 3: (R)-6-(2-methylmorpholino)pyridin-2-amine [ka] To a 500 mL pressure tube was added 6-fluoropyridin-2-amine (30.0 g, 268 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine hydrochloride (44.2 g, 321 mmol, F chemicals, China), and DIPEA (140 mL, 803 mmol) in water (60 mL). The mixture was heated at 180 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (2 × 250 mL) and washed with brine (200 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (330 g) eluted with a gradient of 1% to 20% EtOAc in hexanes to afford the title compound (38.0 g, 197 mmol, 74% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 7.20-7.14(m,1H),5.89(d,J=8.0Hz,1H),5.79(d,J=7.8Hz,1H),5.53(s,2H),4.07-3.97(m,1H),3.98-3.82( m,2H),3.55-3.45(m,2H),2.71-2.58(m,1H),2.35-2.29(m,1H),1.13(d,J=6.2Hz,3H).m / z(ESI):194.2(M+H) + .

[0182] Intermediate 4: (R)-4-methyl-6-(2-methylmorpholino)pyridin-2-amine [ka] A mixture of 6-fluoro-4-methylpyridin-2-amine (75.0 g, 595 mmol) and (R)-2-methylmorpholine hydrochloride (84 g, 832 mmol) in DIPEA (312 mL, 11.78 mol) was heated in an autoclave (600 mL) at 150 °C for 48 h. The reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (2 × 2500 mL). The combined organic layers were washed with brine solution (1000 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 30-100% ethyl acetate in hexanes to afford the title compound (62 g, 50% yield) as an off-white solid. 1 H NMR(300MHz,DMSO-d6):δ 5.74(s,1H),5.63(s,1H),5.43(s,2H),3.98(dt,J=12.8,2.5Hz,1H),3.90-3.80(m,2H),3.53-3.44(m,2H),2.62(ddd,J =15.9,8.0,3.7Hz,1H),2.29(ddd,J=13.4,10.5,3.1Hz,1H),2.04(s,3H),1.11(d,J=6.3Hz,3H).m / z(ESI):208.1(M+H) + .

[0183] [Table 9]

[0184] Intermediate 5: 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine [ka] Step 1: To an autoclave was added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4-difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180 °C for 24 h. The reaction mixture was cooled to room temperature and basified to pH 9 using 10% aqueous NaHCO solution. The reaction mixture was extracted with ethyl acetate (2 × 1500 mL), washed with water (1500 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (60-120 mesh) using 5-10% ethyl acetate in hexane to give a 1:3 mixture (102 g) of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine as a light brown oil. This mixture (102 g) was further purified by reverse-phase chromatography using 60% acetonitrile in water as eluent to give 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58% yield) as a light brown liquid. 1 H NMR(400MHz,DMSO-d6):δ 6.76(s,1H),6.57(s,1H),3.66(t,J=5.6Hz,4H),2.22(s,3H),2.03-1.91(m,4H).m / z(ESI):247.1(M+H) + .

[0185] Step-2: To a solution of 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (30.0 g, 122 mmol) in 1,4-dioxane (300 mL) was added (4-methoxyphenyl)methanamine (23.8 mL, 182 mmol) and CsCO (79 g, 240 mmol). The reaction mixture was degassed and purged with nitrogen for 30 min. BINAP (7.57 g, 12.2 mmol) and palladium(II) acetate (2.73 g, 12.2 mmol) were added to the reaction mixture and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a bed of CELITE®, washing with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was extracted with EtOAc (2 x 500 mL) and washed with water (500 mL) and then brine (500 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 5-8% ethyl acetate in hexanes to afford 6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (48 g, 76% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ 7.22(d,J=7.2Hz,2H),6.85(d,J=7.2Hz,2H),6.64(t,J=6.0Hz,1H),5.84(s,1H),5.68(s,1H),4.31(d,J =6.0Hz,2H),3.71(s,3H),3.56(t,J=5.6Hz,4H),2.05(s,3H),1.90-1.80(m,4H).m / z(ESI):348.1(M+H) + .

[0186] Step-3: To a solution of 6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (48.0 g, 138 mmol) in dry dichloromethane (480 mL) was added anisole (30.2 mL, 276 mmol) and TFA (240 mL, 3120 mmol). The reaction mixture was stirred at 55° C. for 4 h and concentrated under reduced pressure. The residue was dissolved in water (200 mL), basified to pH 8 with 10% aqueous sodium bicarbonate, and extracted with ethyl acetate (2×500 mL). The combined organic layers were washed with water (200 mL), then brine (200 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 25% to 35% ethyl acetate in hexanes to give 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (LCMS, approx. 85%) as a brown oil. This material was further purified by reverse-phase chromatography using 50-60% acetonitrile in water to give 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (16.5 g, 72 mmol, 53% yield) as a brown oil. 1 H NMR(400MHz,DMSO-d6):δ 5.86(s,1H),5.65(s,1H),5.48(s,2H),3.56(t,J=5.2Hz,4H),2.06(s,3H),1.96-1.87(m,4H).m / z(ESI):228.2(M+H) + .

[0187] [Table 10]

[0188] Intermediate 6: 6-(3,3,3-trifluoropropoxy)pyridin-2-amine [ka] To a solution of 6-fluoropyridin-2-amine (50 g, 450 mmol, Combi-Blocks) in 1,4-dioxane (500 mL) under a nitrogen atmosphere was added 3,3,3-trifluoropropan-1-ol (102 g, 892 mmol, Apollo), and the reaction was cooled to 0 °C. NaH (60% in mineral oil, 42.8 g, 1780 mmol) was added to the reaction mixture at 0 °C, and the resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was quenched with cold water (500 mL) and extracted with ethyl acetate (2 × 1000 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in hexane to afford the title compound (45 g, 50% yield) as a light brown oil. 1 H NMR(400MHz,DMSO-d6):δ 7.30-7.26(t,J=7.8Hz,1H),6.02-6.00(dd,J=7.8,0.8Hz,1H),5.89-5.86(m,3H),4. 36-4.33(t,J=6.2Hz,2H),2.79-2.67(qt,J=11.5,6.2Hz,2H).m / z(ESI):207.1(M+H) + .

[0189] Intermediate 7: 6-(3,3-difluorocyclobutyl)-4-methylpyridin-2-amine [ka] Step 1: To a solution of 3,3-difluorocyclobutane-1-carboxylic acid (3.0 g, 22 mmol, Combi-Blocks) and DMAP (0.269 g, 2.20 mmol) in dichloromethane (30 mL) at 0 °C was added tert-butanol (4.22 mL, 44.1 mmol) followed by dicyclohexylcarbodiimide (5.00 g, 24.2 mmol). The reaction mixture was stirred at RT for 18 h, and then diethyl ether (20 mL) was added to the reaction mixture at 0 °C. The precipitated solid was filtered off, and the filtrate was washed with 1.5 N HCl (100 mL), water, and brine, dried over Na SO , and concentrated under reduced pressure to give tert-butyl 3,3-difluorocyclobutane-1-carboxylate (2.78 g, 14.5 mmol, 65.6% yield) as a clear oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 2.93(dddd,J=14.8,7.5,3.8,2.1Hz,1H),2.63-2.87(m,4H),1.42(d,J=2.3Hz,9H).

[0190] Step 2: To a solution of 2-bromo-6-fluoro-4-methylpyridine (1.5 g, 7.9 mmol, TCI Chemicals) and tert-butyl 3,3-difluorocyclobutane-1-carboxylate (1.82 g, 9.47 mmol) in toluene (35 mL) at 0 °C, sodium bis(trimethylsilyl)amide in THF (11.84 mL, 11.84 mmol, 1 M, Symeax Laboratories) was added dropwise, and the reaction mixture was stirred at 0 °C for 20 min and at rt for 4 h. The reaction mixture was quenched with a saturated aqueous solution of NH Cl (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash column chromatography eluting with a gradient of 0% to 20% EtOAc in petroleum ether to give tert-butyl 1-(6-bromo-4-methylpyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.6 g, 3.2 mmol, 41% yield) as a clear yellow oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.48(t,J=1.0Hz,1H),7.34(t,J=1.0Hz,1H),3.15-3.31(m,2H),2.63-2.89(m,2H),2.34(s,3H),1.36(s,9H).m / z(ESI):362.0(M+H) + .

[0191] Step 3: To a solution of tert-butyl 1-(6-bromo-4-methylpyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylate (1.4 g, 2.8 mmol) in dichloromethane (24 mL) at RT was added TFA (0.87 mL, 11.3 mmol). The reaction mixture was stirred for 18 h and then concentrated to give 1-(6-bromo-4-methylpyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylic acid (0.90 g, 2.2 mmol, 77% yield) as a brown, viscous liquid. 1H NMR(300MHz,DMSO-d6):δ ppm 7.47(s,1H),7.38(s,1H),3.25(q,J=12.8Hz,2H),2.66-2.85(m,2H),2.33(s,3H).m / z(ESI):306.0(M+H) + .

[0192] Step 4: A solution of 1-(6-bromo-4-methylpyridin-2-yl)-3,3-difluorocyclobutane-1-carboxylic acid (0.60 g, 1.4 mmol) in 2-xylene (7.0 mL) was stirred at 120 °C for 2 h. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (2 × 50 mL), washed with water (50 mL) and brine, dried over Na SO , filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 5% EtOAc in petroleum ether to give 2-bromo-6-(3,3-difluorocyclobutyl)-4-methylpyridine (0.41 g, 1.2 mmol, 85% yield) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.39(s,1H),7.25(s,1H),3.47(qt,J=9.1,4.5Hz,1H),2.73-2.97(m,4H),2.29(s,3H).m / z(ESI):262.0(M+H) + .

[0193] Step 5: A mixture of 2-bromo-6-(3,3-difluorocyclobutyl)-4-methylpyridine (0.400 g, 1.53 mmol), (4-methoxyphenyl)methanamine (0.314 g, 2.29 mmol), CsCO (1.49 g, 4.58 mmol), BINAP (0.095 g, 0.153 mmol), and Pd(OAc) (0.034 g, 0.15 mmol) in 1,4-dioxane (4 mL) was stirred at 100 °C for 16 h. The reaction mixture was filtered and diluted with EtOAc. The solution thus obtained was washed with water and brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 10% ethyl acetate in petroleum ether to give 6-(3,3-difluorocyclobutyl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (0.360 g, 1.131 mmol, 74% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.22-7.31(m,2H),6.85(dt,J=8.5,2.1Hz,2H),6.26(s,1H),6.15(s,1H),4.38(d,J=6.0Hz, 2H),3.71(s,3H),3.14-3.22(m,1H),2.71-2.86(m,4H),2.09(s,3H).m / z(ESI):319.1(M+H) + .

[0194] Step 6: To a mixture of 6-(3,3-difluorocyclobutyl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (0.355 g, 1.12 mmol) and anisole (0.244 mL, 2.23 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1.8 mL, 23 mmol) at 0° C. The reaction mixture was stirred at 55° C. for 16 h, then concentrated and diluted with DCM (20 mL). The organic layer was washed with a saturated aqueous solution of NaHCO (3 mL), water, and brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 10% to 20% EtOAc in petroleum ether to give 6-(3,3-difluorocyclobutyl)-4-methylpyridin-2-amine (0.090 g, 0.45 mmol, 41% yield) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 6.27(s,1H),6.12(s,1H),3.18(td,J=8.8,3.1Hz,1H),2.69-2.85(m,4H),2.10(d,J=2.1Hz,3H).m / z(ESI):199.1(M+H) + .

[0195] Intermediate 8: 5-methyl-6-morpholinopyridin-2-amine [ka] A mixture of 6-chloro-5-methylpyridin-2-amine (0.1 g, 0.70 mmol), morpholine (0.092 g, 1.05 mmol), KCO (0.145 g, 1.052 mmol), copper(I) iodide (0.027 g, 0.140 mmol), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.020 g, 0.140 mmol) in DMF (2 mL) was heated in a microwave at 150 °C for 4 h. The reaction mixture was then filtered through a plug of Celite, and the filtrate was diluted with EtOAc, washed with water, brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 15% ethyl acetate in petroleum ether to give 5-methyl-6-morpholinopyridin-2-amine (10 mg, 0.052 mmol, 7% yield) as a pale yellow solid. m / z (ESI): 194.2 (M+H). + .

[0196] Ring AR 2 Preparation of intermediates: Intermediate 9: 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] To a solution of 2-fluoro-4-iodobenzoic acid (300 g, 1.13 mol, Combi-Blocks, San Diego, CA) in DMSO (2.1 L) was added 6-azaspiro[2.5]octane hydrochloride (216 g, 1.47 mol, Wuxi AppTec) at 20 °C. KCO (468 g, 3.38 mol) was then added, and the reaction solution was stirred at 140 °C for 48 h under N. The reaction solution was slowly poured into ice water (4.20 L) and extracted with hexane (2 L × 3). The aqueous phase was removed, and the pH was adjusted to 6 with HCl (2.00 mol / L, aq). A precipitate was obtained and collected by filtration. The solid was washed with water (700 mL × 3) and filtered. The wet solid was spread on a large watch glass and dried in air at 25 °C. 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (280 g, 777 mmol, 68.9% yield) was obtained as a pale yellow solid. 400 MHz DMSO-d6 δ ppm 8.07 (s, 1H), 7.76-7.66 (m, 2H), 3.10 (t, J = 5.2 Hz, 4H), 1.55 (br s, 4H), 0.41 (s, 4H).

[0197] [Table 11]

[0198] Intermediate 10: 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step-1: To a solution of 2-fluoro-4-(methylsulfonyl)benzoic acid (90.0 g, 412 mmol) in DMF (1 L) was added benzyl bromide (78.1 g, 454 mmol) and sodium carbonate (52.5 g, 495 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 × 1 L). The organic extracts were combined, washed with brine (1 L), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (230–400 mesh) using 0–30% ethyl acetate in hexane to give benzyl 2-fluoro-4-(methylsulfonyl)benzoate (100 g, 79% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ 8.16(dd,J=8.2,6.9Hz,1H),7.98-7.86(m,2H),7.48-7.31(m,5H),5.40(s,2H),3.33(s,3H).

[0199] Step-2: To a solution of benzyl 2-fluoro-4-(methylsulfonyl)benzoate (55 g, 180 mmol) in dimethyl sulfoxide (550 mL) was added DIPEA (57.6 g, 446 mmol) followed by 6-azaspiro[2.5]octane (29.8 g, 268 mmol), and the reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 × 1 L). The organic extracts were combined, washed with brine (1 L), dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400 mesh) using 0-10% ethyl acetate in hexane to give benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (55 g, 77% yield) as a white solid. 1H NMR(400MHz,DMSO-d6):δ 7.76(d,J=8.0Hz,1H),7.52-7.45(m,4H),7.43-7.35(m,3H),5.35(s,2H),3.25(s,3 H),3.05(t,J=5.3Hz,4H),1.36(t,J=5.3Hz,4H),0.30(s,4H).m / z(ESI):400.1(M+H) + .

[0200] Step-3: To a solution of benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (65 g, 160 mmol) in THF (108 mL) and methanol (36 mL) was added sodium hydroxide (1 N, 407 mL), and the reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was concentrated under reduced pressure to remove THF and methanol. The remaining aqueous solution was acidified to pH ∼2 with 1.5 N HCl solution. The precipitate was filtered, washed with water (200 mL) and then hexane (200 mL), and dried under vacuum to give 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (42 g, 83% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 16.13(s,1H),8.04(d,J=8.0Hz,1H),7.99(s,1H),7.75(d,J=8.0Hz,1H),3. 29(s,3H),3.17(bs,4H),1.55(bs,4H),0.41(s,4H).m / z(ESI):308.1(M+H) + .

[0201] Intermediate 11: 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: To a 250 mL sealed tube was added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzyl benzoate (9 g, 22.48 mmol, Intermediate 9-5), 1-methylcyclopropane-1-sulfonamide (3.95 g, 29.2 mmol, Combi-Blocks, San Diego, CA), and K2CO3 (6.21 g, 45.0 mmol) in 1,4-dioxane (90 mL). The reaction was degassed and purged with nitrogen for 5 min. To this reaction mixture was added Xantphos (1.301 g, 2.248 mmol), followed by Pd2(dba)3 (1.029 g, 1.12 mmol), and the tube was closed and stirred at 110 °C for 18 h. The reaction mixture was quenched with water (250 mL) and extracted with ethyl acetate (2 × 150 mL). The organic extracts were combined, washed with water (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluted with a gradient of 0% to 15% EtOAc in hexanes to afford benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (6.1 g, 59% yield) as an orange oil. 1 H NMR(400MHz,DMSO-d6):δ 10.06(s,1H),7.62(d,J=8.5Hz,1H),7.48-7.31(m,5H),6.98(s,1H),6.81(d,J=8.5Hz,1H),5.27(s,2H),2.92(t,J=4.96 Hz,4H),1.40-1.30(m,7H),1.16(dd,J=6.4,4.7Hz,2H),0.81(dd,J=6.4,4.7Hz,2H),0.28(s,4H).m / z(ESI):455.2(M+H) + .

[0202] Step 2: To a solution of benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.1 g, 4.6 mmol) in MeOH (20 mL) and ethyl acetate (10 mL) under a nitrogen atmosphere was added 10% Pd—C (1.05 g, 50% (wt / wt)). The reaction mixture was degassed under hydrogen (1 atm, balloon pressure) and stirred for 4 h. The reaction mixture was filtered through a celite bed and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL) to give 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.2 g, 71% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 13.20(s,1H),10.33(s,1H),7.95(d,J=8.6Hz,1H),7.41(s,1H),7.20(d,J=8.6Hz,1H),2.99(s,4H),1. 56(s,4H),1.39(s,3H),1.18(t,J=4.8Hz,2H),0.83(t,J=4.7Hz,2H),0.42(s,4H).m / z(ESI):363.2(MH) + .

[0203] Intermediate 12: 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: To a solution of 3-methyl-3-oxetanamine hydrochloride (5.50 g, 44.5 mmol) and DIPEA (23.3 mL, 134 mmol) in DCM (200 mL) at 0 °C, methyl 4-(chlorosulfonyl)-2-fluorobenzoate (12.4 g, 49.0 mmol) was added, and the mixture was stirred at 0 °C to room temperature for 1 h. The mixture was diluted with 1.0 N HCl (200 mL) and extracted with dichloromethane (150 mL × 2). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified using a Biotage SNAP 100 g column eluting with 0-30% EtOAc-EtOH (3:1) in heptane to give methyl 2-fluoro-4-(N-(3-methyloxetan-3-yl)sulfamoyl)benzoate (13.6 g, 44.8 mmol, 100% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.67(s,1H),8.11(t,J=7.37Hz,1H),7.76-7.82(m,1H),7.69-7.76(m,1H) ,4.56(d,J=6.23Hz,2H),4.18(d,J=6.75Hz,2H),3.90(s,3H),1.42(s,3H).

[0204] Step 2: A mixture of DIPEA (16 mL, 93 mmol), 6-azaspiro[2.5]octane (6.22 g, 55.9 mmol), and methyl 2-fluoro-4-(N-(3-methyloxetan-3-yl)sulfamoyl)benzoate (14.1 g, 46.6 mmol) in anhydrous dioxane was stirred at 100° C. for 20 h. The mixture was cooled to room temperature, quenched with water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried, and evaporated to dryness under reduced pressure. The crude product was purified using a Biotage SNAP 340 g column eluting with 0-40% EtOAc-EtOH (3:1) in heptane to give methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (14.2 g, 35.9 mmol, 77% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.42(s,1H),7.72(d,J=8.04Hz,1H),7.47(d,J=1.56Hz,1H),7.36(dd,J=1.82,8.04Hz,1H),4.55(d,J=5.97H z,2H),4.14(d,J=6.49Hz,2H),3.85(s,3H),3.02-3.09(m,4H),1.44-1.50(m,4H),1.42(s,3H),0.35(s,4H).

[0205] Step 3: A mixture of methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (14.2 g, 35.9 mmol) and lithium hydroxide monohydrate (22.6 g, 538 mmol) in THF-water-MeOH (1:1:1, 300 mL) was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to partially remove the organic solvent. The solution was acidified with 2 N HCl until a pH of less than 3 was reached. The precipitate was filtered and dried in air to give 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (9.94 g, 26.1 mmol, 73% yield) as a white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.51(s,1H),8.04(d,J=8.04Hz,1H),7.89(d,J=1.30Hz,1H),7.66(dd,J=1.69,8.17Hz,1H),4.55(d,J=6. 23Hz,2H),4.09-4.17(m,2H),3.06-3.19(m,4H),1.56(t,J=5.19Hz,4H),1.40(s,3H),0.36-0.46(s,4H).

[0206] Intermediate 13: 4-(N-(tert-butyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: To a solution of 4-bromo-2-fluorobenzoic acid (40 g, 180 mmol) in DMF (600 mL) at 0 °C, sodium carbonate (23.2 g, 219 mmol) and benzyl bromide (22.8 mL, 192 mmol) were added. The reaction mixture was stirred at room temperature for 16 h, then quenched with water (1.5 L) and extracted with ethyl acetate (3 × 500 mL). The organic extracts were combined, washed with water (1500 mL) and brine (500 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in hexane to afford benzyl 4-bromo-2-fluorobenzoate (50 g, 89% yield) as a pale yellow liquid. 1 H NMR (400 MHz, chloroform-d): δ 7.86 (dd, J = 8.0, 7.4 Hz, 1H), 7.50-7.35 (m, 7H), 5.40 (s, 2H).

[0207] Step 2: To a solution of benzyl 4-bromo-2-fluorobenzoate (30 g, 97 mmol) in DMSO (300 mL) at room temperature was added 6-azaspiro[2.5]octane (15.1 g, 136 mmol) and DIPEA (33.9 mL, 194 mmol). The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The organic extracts were combined, washed with brine (600 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 0%-10% ethyl acetate in hexane to give benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (25 g, 64% yield) as a pale yellow oil. 1H NMR (400MHz, chloroform-d):δ 7.61(d,J=8.4Hz,1H),7.47(d,J=8.0Hz,2H),7.43-7.35(m,3H),7.22(s,1H),7.09(d,J=8.4Hz,1 H),5.36(s,2H),3.09(t,J=5.3Hz,4H),1.49(t,J=5.3Hz,4H),0.34(s,4H).m / z(ESI):400.1(MH) + .

[0208] Step 3: A solution of benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (25 g, 62 mmol), DIPEA (21.8 mL, 125 mmol), xantphos (1.81 g, 3.12 mmol), Pd(dba) (1.14 g, 1.25 mmol), and benzyl mercaptan (10 g, 81 mmol) in 1,4-dioxane (250 mL) was degassed and purged with nitrogen for 15 min. The reaction mixture was heated at 100 °C for 16 h in a sealed pressure vessel. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 5%-10% ethyl acetate in hexane to give benzyl 4-(benzylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (20 g, 72% yield) as a pale yellow liquid. 1 H NMR(400MHz,DMSO-d6):δ 7.57-7.53(m,1H),7.48-7.26(m,10H),6.93-6.87(m,2H),5.27(s,2H),4.32(s, 2H),2.95-2.87(m,4H),1.35(t,J=5.3Hz,4H),0.28(s,4H).m / z(ESI):442.2(MH) + .

[0209] Steps 4 & 5: To a solution of benzyl 4-(benzylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (20 g, 45 mmol) in DCM (160 mL) and water (40 mL) at 0 °C was added sulfuryl chloride (18.3 mL, 225 mmol). The reaction mixture was stirred for 1 h, then diluted with water (200 mL) and extracted with DCM (200 mL). The organic extract was dried over anhydrous Na2SO4, filtered, and cooled to 0 °C. To the above solution was added tert-butylamine (47.8 mL, 451 mmol). The reaction mixture was stirred at room temperature for 1 h, then quenched with water (200 mL) and extracted with DCM (2 × 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate in hexane to give benzyl 4-(N-(tert-butyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (12 g, 61% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 7.71(d,J=8.0Hz,1H),7.63(s,1H),7.55-7.46(m,3H),7.45-7.33(m,4H),5.33(s ,2H),3.01(bs,4H)1.38(bs,4H),1.10(s,9H),0.31(2,4H).m / z(ESI):457.2(MH) + .

[0210] Step 6: To a solution of benzyl 4-(N-(tert-butyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10 g, 21.9 mmol) in ethanol (50 mL) and ethyl acetate (50 mL) at room temperature under a nitrogen atmosphere was added 10% palladium on carbon (4.66 g, 4.38 mmol). The reaction mixture was degassed and stirred under a hydrogen atmosphere (1 atm) at room temperature for 16 h. The reaction mixture was filtered through a Celite bed, and the filter bed was washed with ethyl acetate (200 mL). The filtrate was concentrated under reduced pressure. The crude residue was triturated with diethyl ether (200 mL) to give the title compound (6.0 g, 75% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.06(d,J=8.2Hz,1H),7.98(s,1H),7.73-7.68(m,2H),3.12(t,J=5.3Hz,4 H),1.57(t,J=5.3Hz,4H),1.10(s,9H),0.43(s,4H).m / z(ESI):367.2(MH) + .

[0211] Intermediate 14: 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: To a solution of methyl 2-fluoro-4-methylbenzoate (10.0 g, 59.5 mmol) in carbon tetrachloride (200 mL) was added NBS (11.6 g, 65.4 mmol) and AIBN (0.976 g, 5.95 mmol) at rt. The reaction mixture was stirred at 70 °C for 3 h, then quenched with water (250 mL) and extracted with dichloromethane (2 × 200 mL). The combined organic extracts were washed with brine (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl 2-fluoro-4-methylbenzoate (14.0 g, crude) as a pale yellow oil. 1H NMR (400 MHz, chloroform-d): δ 8.04-7.88 (m, 1H), 7.27-7.13 (m, 2H), 4.46 (s, 2H), 3.96 (s, 3H).

[0212] Step 2: A mixture of methyl 2-fluoro-4-methylbenzoate (14.0 g, 56.7 mmol) and sodium methanesulfonate (12.15 g, 119 mmol) in DMF (42 mL) was irradiated in a microwave oven (Biotage initiator+) at 120 °C for 30 min. The reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic extracts were washed with saturated brine solution (150 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl 2-fluoro-4-((methylsulfonyl)methyl)benzoate (6 g, crude) as an off-white solid.

[0213] Step 3: A mixture of methyl 2-fluoro-4-((methylsulfonyl)methyl)benzoate (6.0 g, 24 mmol) and 6-azaspiro[2.5]octane (2.71 g, 24.4 mmol) in DMSO (30 mL) was irradiated in a microwave oven at 150 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined, washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (4.0 g, crude) as an off-white solid. The material was carried on directly to the next step without further purification. 1H NMR(400MHz,chloroform-d)δ 7.72(d,J=7.8Hz,1H),7.11(s,1H),6.96(dd,J=7.8,1.6Hz,1H),4.24(s,2H),3.93(s,3H),3 .12(t,J=5.4Hz,4H),2.78(s,3H),1.55(t,J=5.5Hz,4H),0.37(s,4H).m / z(ESI):338.1(MH) + .

[0214] Step 4: To a solution of methyl 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.0 g, 3.0 mmol) in THF (15 mL) was added sodium hydroxide (0.474 g, 11.8 mmol) in water (7 mL) and stirred at room temperature for 12 h. The reaction mixture was acidified with 1.5 N HCl solution to pH 3 and extracted with ethyl acetate (5 × 20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.0 g, 10% yield over three steps) as a white solid. m / z (ESI): 324.1 (MH). + .

[0215] Intermediate 15: 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: A mixture of methyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10.5 g, 32.4 mmol, Intermediate 9-2), DIPEA (8.37 mL, 64.8 mmol), Xantphos (1.87 g, 3.24 mmol), and Pd(dba) (2.97 g, 3.24 mmol) in dioxane was bubbled with a stream of argon, and tert-butyl 3-mercaptoazetidine-1-carboxylate (7.66 mL, 40.5 mmol) was added. The mixture was stirred at 100 °C for 18 h. The mixture was cooled to room temperature, concentrated, and purified using a Biotage SNAP 340 g column eluting with 0-25% EtOAc-EtOH (3:1) in heptane to give tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate (13.8 g, 32.0 mmol, 99% yield) as a pale yellow sticky solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 7.55(d,J=8.04Hz,1H),6.79(s,1H),6.76(d,J=8.14Hz,1H),4.34-4.43(m,2H),4.27-4.34(m,1H),3.79(s ,3H),3.70(dd,J=4.67,8.56Hz,2H),2.97-3.04(m,4H),1.41-1.51(m,4H),1.38(s,9H),0.29-0.37(m,1H).

[0216] Step 2: To a solution of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate (13.85 g, 32.0 mmol) in 1,4-dioxane (300 mL) was added oxone monopersulfate (39.4 g, 64.0 mmol) in 150 mL of water. The reaction mixture was stirred at room temperature for 5 h, then 150 mL of ethyl acetate and 150 mL of water were added. The mixture was stirred for 10 min, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organics were combined, washed with brine, dried, filtered, and concentrated. The crude material was purified using a Biotage SNAP 340 g column eluted with a gradient of 0 to 25% EtOAc-EtOH (3:1) in heptane to give tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (12.8 g, 27.5 mmol, 86% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 7.75(d,J=8.04Hz,1H),7.44-7.50(m,2H),4.48-4.55(m,1H),4.09(br.s.,2H),3.97-4. 02(m,2H),3.86(s,3H),3.04-3.17(m,4H),1.42-1.51(m,4H),1.38(s,9H),0.35(s,4H).

[0217] Step 3: A mixture of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (12.77 g, 27.5 mmol) and lithium hydroxide monohydrate (11.53 g, 275 mmol) in THF-water-MeOH (1:1:1, 230 mL) was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure to remove some of the organic solvent. The solution was acidified with 2 N HCl to a pH of less than 3. The precipitate was filtered and dried to give 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (10.6 g, 23.5 mmol, 86% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ ppm 8.03(d,J=8.30Hz,1H),7.93(d,J=1.82Hz,1H),7.72(dd,J=1.69,8.17Hz,1H),4.48-4.60(m,1H),4 .10(br.s.,2H),3.99-4.06(m,2H),3.14-3.22(m,4H),1.49-1.59(m,4H),1.38(s,9H),0.41(s,4H).

[0218] Intermediate 16: 4-(Cyclopropanesulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid [ka] Step 1: To a mixture of methyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (3.69 g, 11.4 mmol, Intermediate 9-2), DIPEA (2.94 mL, 22.8 mmol), Xantphos (0.659 g, 1.14 mmol), and Pd(dba) (1.04 g, 1.14 mmol) in 1,4-dioxane was added cyclopropanethiol (0.928 mL, 12.5 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated. The mixture was purified using a Biotage SNAP 100 g column eluted with a gradient of 0% to 20% EtOAc-EtOH (3:1) in heptane to give methyl 4-(cyclopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (3.42 g, 10.8 mmol, 95% yield) as a yellow oil. 1 H NMR(500MHz,DMSO-d6)δ 7.57(d,J=8.04Hz,1H),7.00(d,J=1.82Hz,1H),6.93(d,J=8.21Hz,1H),3.79(s,3H),2.95-3.04( m,4H),2.26-2.36(m,1H),1.43-1.49(m,4H),1.07-1.16(m,2H),0.55-0.66(m,2H),0.33(s,4H).

[0219] Step 2: To a mixture of methyl 4-(cyclopropylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (3.35 g, 10.6 mmol) in DCM at 0 °C was added 3-chloroperoxybenzoic acid (2.367 g, 13.72 mmol). The mixture was stirred at 0 °C for 30 min. The reaction was quenched with saturated NaHCO and extracted with ethyl acetate. The organic extract was washed with brine, dried, and concentrated. The mixture was purified using a Biotage SNAP 100 g column eluted with a gradient of 0% to 40% EtOAc-EtOH (3:1) in heptane to give methyl 4-(cyclopropylsulfinyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (3.34 g, 10.0 mmol, 95% yield) as a yellow oil. 1 H NMR(500MHz,DMSO-d6)δ 7.70(d,J=8.04Hz,1H),7.30-7.47(m,1H),7.22(d,J=8.02Hz,1H),3.84(s,3H),3.03-3.11(m, 4H),2.52-2.55(m,1H),1.43-1.51(m,4H),0.88-1.01(m,3H),0.77-0.88(m,1H),0.34(s,4H).

[0220] Step 3: To a solution of methyl 4-(cyclopropylsulfinyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (3.33 g, 9.99 mmol) in methanol was added iodobenzene diacetate (6.43 g, 20.0 mmol) and ammonium carbamate (3.12 g, 39.9 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with water and extracted with ethyl acetate and DCM. The organic extracts were combined, washed with brine, dried, and concentrated. The mixture was purified using a Biotage SNAP 100 g column eluted with a gradient of 0 to 60% EtOAc-EtOH (3:1) in heptane to give methyl 4-(cyclopropanesulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (1.89 g, 5.42 mmol, 54.3% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 7.70(d,J=8.04Hz,1H),7.53(d,J=1.56Hz,1H),7.43(dd,J=1.56,8.04Hz,1H),4.29(s,1H),3.85(s,3H),3 .01-3.13(m,4H),2.67-2.75(m,1H),1.43-1.51(m,4H),1.05-1.14(m,1H),0.87-1.00(m,3H),0.35(s,4H).

[0221] Step 4: A mixture of methyl 4-(cyclopropanesulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (1.89 g, 5.42 mmol) and lithium hydroxide monohydrate (0.683 g, 16.3 mmol) in THF-water-MeOH (2:1:1, 32 mL) was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure to remove some of the organic solvent. The solution was acidified with 2 N HCl to a pH below 3. The mixture was extracted with DCM (2×). The extracts were combined, washed with brine, dried, and concentrated to give 4-(cyclopropanesulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.80 g, 5.38 mmol, 99% yield) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.08(d,J=8.30Hz,1H),8.01(d,J=1.56Hz,1H),7.78(dd,J=1.56,8.04Hz,1H),4.44(br.s.,1H),3.16(t,J= 5.32Hz,4H),2.74-2.81(m,1H),1.58(t,J=5.19Hz,4H),1.11-1.22(m,1H),0.89-1.04(m,3H),0.43(s,4H).

[0222] Ar 1 and Ar 2 Compounds containing Intermediate 17: N-(6-fluoropyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] To a solution of 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.0 g, 2.74 mmol, Intermediate 11) in DCM (20 mL) was added 6-fluoropyridin-2-amine (0.308 g, 2.74 mmol, Combi-Blocks), T3P (50% in ethyl acetate, 1.3 mL, 4.1 mmol), and DIPEA (0.958 mL, 5.49 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with DCM (2 x 25 mL). The organic extracts were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexanes to afford the title compound (0.65 g, 52% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 13.09(s,1H),10.28(s,1H),8.20(dd,J=8.0,2.4Hz,1H),8.12-7.92(m,2H),7.36(d,J=2.2Hz,1H),7.17(dd,J=8.6,2.2Hz,1H),6.89(dd,J=8. 0,2.4Hz,1H),2.97(t,J=5.4Hz,4H),1.79-1.56(m,4H),1.41(s,3H),1.32-1.14(m,2H),0.90-0.79(m,2H),0.41(s,4H).m / z(ESI):459.1(MH) + .

[0223] [Table 12]

[0224] [Table 13]

[0225] Intermediate 38: 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide [ka] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (3.0 g, 8.4 mmol, Intermediate 9) was suspended in DCM (10 mL) under argon. Thionyl chloride (1.463 g, 12.29 mmol, Sigma-Aldrich Corporation) was added and the mixture was stirred at rt for 15 min. The mixture was evaporated to dryness under reduced pressure. The crude residue was azeotroped with toluene (2 × 100 mL) and suspended in dichloromethane (50 mL) under argon. A solution of 6-(3,3,3-trifluoropropoxy)pyridin-2-amine (2.0 g, 9.7 mmol, Intermediate 6) and 2,6-lutidine (3.68 g, 34.3 mmol, Sigma-Aldrich Corporation) in dichloromethane (10 mL) was added in one portion. The yellow mixture was stirred at rt for 20 min and then evaporated to dryness under reduced pressure. The crude solid was triturated in methanol (30 mL) for 20 min and then filtered through a sintered glass frit. The solid was dried under a stream of nitrogen to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (3.8 g, 7.0 mmol, 83% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.36(s,4H)1.58-180(m,4H)2.83(dt,J=10.94,5.42Hz,2H)2.91-3.13(m,4 H)4.49(t,J=5.29Hz,2H)6.58(d,J=7.88Hz,1H)7.60-8.00(m,5H)13.20(br s,1H)

[0226] [Table 14]

[0227] Intermediate 39: 4-Bromo-N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] A mixture of 4-bromo-N-(6-bromo-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (5.0 g, 10 mmol, Intermediate 22), 3,3-difluoroazetidine hydrochloride (2.027 g, 15.65 mmol, Combi-Blocks), and CsF (9.51 g, 62.6 mmol) in DMSO (50 mL) was stirred for 60 h at 145° C. The reaction mixture was diluted with ice water (200 mL) and stirred for 30 min. The precipitate was filtered and purified by flash column chromatography using a gradient of 0% to 5% EtOAc in petroleum ether to give 4-bromo-N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (2.4 g, 4.8 mmol, 46% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 13.05(s,1H),8.03(d,J=8.7Hz,1H),7.67(s,1H),7.53-7.56(m,2H),6.2 1(s,1H),4.32-4.41(m,4H),3.33(t,J=5.1Hz,4H),2.28(s,3H),1.72(br s,4H),0.37(s,4H).m / z(ESI):491.1(M+H) + .

[0228] Intermediate 40: Ethyl 2-sulfamoylpropanoate [ka] Step 1: To a solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (200.0 g, 572.0 mmol) in tetrahydrofuran (4000 mL) was slowly added n-BuLi (1.6 M in hexane, 608.0 mL, 973.0 mmol) at −78° C. and stirred for 30 min. Ethyl chloroformate (92.0 mL, 973.0 mmol) in THF (50 mL) was added to the reaction mixture and stirred at −78° C. for 1 h. The reaction mixture was quenched with HCl (1.5 N, 3000 mL) and extracted with EtOAc (2×3000 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)propanoate (250.0 g, 60% purity) as a yellow oil. 1 H-NMR showed the desired peaks, so it was carried forward to the next step without any purification.

[0229] Step 2: To a solution of ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)propanoate (600.0 g, 1.4 mol) in trifluoroacetic acid (2.50 L, 32.45 mol), anisole (500.0 mL, 4.57 mol) was added and stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, quenched with cold 10% aqueous NaHCO (3 L), and extracted with EtOAc (2 × 3 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to give a pale yellow solid (168 g), which was dissolved in DCM (1 L) and precipitated by adding hexane (3000 mL). The solid was filtered and dried under vacuum to give the title compound (109.0 g, 42% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ ppm 7.14(s,2H),4.15(q,J=7.1Hz,2H),3.98(q,J=7.0Hz,1H),1.45(d,J=7.0Hz,3H),1.21(t,J=7.1Hz,3H).m / z(ESI):180.1(MH) + . [Example]

[0230] General Methods and Representative Examples Method A (Pd-catalyzed Br-S coupling) Example 1: 4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide [ka] A glass vial was charged with the following: 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (348 mg, 0.70 mmol, Intermediate 38-1), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) (101 mg, 0.42 mmol, Sigma-Aldrich). ldrich), diacetoxypalladium (16 mg, 0.07 mmol, Strem), rac-((3R,5R,7R)-adamantan-1-yl)((3S,5S,7S)-adamantan-1-yl)(butyl)phosphane (cataCXium® A) (38 mg, 0.11 mmol, Strem), triethylamine (194 μL, 1.40 mmol), and iPrOH (3 mL). The tube was degassed for 3 min, sealed, and heated in an oil bath at 80° C. for 3 h. The heterogeneous mixture was cooled to RT and treated with 2-aminoethan-1-ol (85 mg, 1.4 mmol, Sigma-Aldrich) followed by sodium hypochlorite solution (10 wt %, 1040 mg, 1.40 mmol, Sigma-Aldrich) and stirred at RT for 18 h. To the heterogeneous mixture were added EtOAc (20 mL) and water (5 mL). The insoluble solid was filtered off. The filter cake was washed with 2 × 2 mL of water, followed by 2 × 4 mL of EtOAc. The combined organic extracts were separated and concentrated. The residue was purified by silica gel chromatography (20% to 80% EtOAc in heptane) to afford 4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (106 mg, 0.19 mmol, 28% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 13.04(s,1H),8.26(d,J=8.09Hz,1H),7.91(d,J=7.67Hz,1H),7.77-7.87(m,3H),7.72(d,J=7.26Hz,1H),6.62(d,J=8.09Hz,1H),4.71( m / z(ESI):(M+H) + 543.2.

[0231] [Table 15]

[0232] [Table 16]

[0233] [Table 17]

[0234] Method B (sulfone formation) Example 2: (R)-4-(Isopropylsulfonyl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] (R)-4-iodo-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (89 mg, 0.17 mmol, Intermediate 29), triphenylphosphine (6 mg, 0.025 mmol, Aldrich, St. Louis, MO, USA), 1,10-phenanthroline (24 mg, 0.132 mmol, Aldrich, St. Louis, USA), palladium(ii) acetate (5 mg, 0.025 mmol, Strem Chemicals Inc., Newburyport, MA, USA), sodium formate (25 mg, 0.37 mmol, Thermo Fisher Scientific, Grand Rapids, MD, USA) in DMSO (2 mL). A mixture of tetrabutylammonium bromide (59 mg, 0.18 mmol, Aldrich, St. Louis, MO, USA) and tetrabutylammonium bromide (59 mg, 0.18 mmol, Aldrich, St. Louis, MO, USA) was stirred at 70 °C under N for 3 h. The mixture was then cooled to room temperature, and isopropyl iodide (0.025 mL, 0.25 mmol, Aldrich, St. Louis, MO, USA) was added. The mixture was then stirred at room temperature for 18 h. The mixture was then diluted with water (20 mL) and then extracted with EtOAc (2 × 40 mL). The organic extracts were combined, then dried over NaSO and concentrated. Chromatographic purification of the residue (silica gel, 0% to 30% EtOAc / heptane) afforded (R)-4-(isopropylsulfonyl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (46 mg, 0.09 mmol, 36% yield) as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 12.63(s,1H),8.31(d,J=8.22Hz,1H),7.82(d,J=1.37Hz,1H),7.77(dd,J=1.56,8.22Hz,1H),7.57-7.66(m,2H),6.64(d,J=7.83Hz,1H),4.17(br d,J=11.93Hz,1H),4.08(br d,J=12.52Hz,1H),3.93(dd,J=3.33,11.35Hz,1H),3.49-3.67(m,3H),3.37(quin,J=6.65Hz,1H),3.10(br t,J=5.18Hz,4H),2.85(dt,J=3.52,12.32Hz,1H),1.72(br s,4H),1.13-1.28(m,9H),0.39(s,4H).m / z(ESI):513.2(M+H)+.

[0235] [Table 18]

[0236] Method C (SNAr) Example 3: (R)—N-(6-(3-hydroxypiperidin-1-yl)pyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] To a solution of N-(6-fluoropyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.44 mmol, Intermediate 17) in DMSO (2 mL) was added (R)-piperidin-3-ol hydrochloride (0.060 g, 0.44 mmol, Essen Scientific) and potassium phosphate tribasic (0.278 g, 1.31 mmol). The reaction mixture was stirred at 130 °C for 16 h, then cooled, quenched with water (5 mL), and extracted with ethyl acetate (2 × 10 mL). The organic extracts were combined, washed with brine solution (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 30-50% ethyl acetate in hexanes to afford the title compound (0.1 g, 43% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.85(s,1H),10.23(s,1H),8.06(d,J=8.6Hz,1H),7.52(d,J=6.1Hz,2H),7.34(s,1H), 7.14(d,J=8.6Hz,1H),6.65-6.34(m,1H),4.78(d,J=4.6Hz,1H),4.13(d,J=11.7Hz,1H) ,4.05-3.85(m,1H),3.63-3.46(m,1H),3.10-2.74(m,6H),1.99-1.58(m,5H),1.42(d,J =13.8Hz,5H),1.20(s,3H),0.84(d,J=5.6Hz,2H),0.38(s,4H).m / z(ESI):540.2(M+H)+.

[0237] [Table 19]

[0238] [Table 20]

[0239] [Table 21]

[0240] [Table 22]

[0241] Method D (amide coupling) Example 4: (R)—N-(6-(3-hydroxypiperidin-1-yl)pyridin-2-yl)-4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] To a solution of 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 0.618 mmol, Intermediate 14) in DMF (3 mL) was added (R)-1-(6-aminopyridin-2-yl)piperidin-3-ol (0.143 g, 0.742 mmol, Intermediate 4-5), HATU (353 mg, 0.928 mmol), and DIPEA (216 μL, 1.24 mmol) and stirred at room temperature for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic extracts were combined, washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 50% ethyl acetate in hexanes to afford the title compound (0.20 g, 65% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6):δ 13.06(s,1H),8.15-8.13(m,1H),7.58-7.50(m,3H),7.37(d,J=7.8Hz,1H) ,6.55(d,J=8.2Hz,1H),4.80(dd,J=7.0,3.6Hz,1H),4.59(s,2H),4.13(d, J=12.4Hz,1H),3.94(d,J=12.4Hz,1H),3.60-2.80(m,7H),1.73(bs,4H),1 .42(bs,4H),1.42(q,J=6.4Hz,3H),0.39(s,4H).m / z(ESI):499.1(M+H)+.

[0242] [Table 23]

[0243] [Table 24]

[0244] [Table 25]

[0245] Method E (Cu-catalyzed sulfonamide formation) Example 5: 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide [ka] 2-Hydroxyethane-1-sulfonamide (0.741 g, 5.92 mmol, Wuxi AppTec), sarcosine (0.172 g, 1.93 mmol, Ark Pharm, Inc.), copper(I) iodide (0.241 g, 1.26 mmol, Sigma-Aldrich Corporation), potassium carbonate (2.78 g, 20.1 mmol, Thermo Fisher Scientific), and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (2.74 g, 5.02 mmol, Intermediate 38) were combined in dry, degassed N,N-dimethylformamide (5 mL) under argon and heated at 130 °C for 50 min. The reaction was cooled to ambient temperature, water (100 mL) and ethyl acetate (150 mL) were added, and the phases were mixed and separated. The organic layer was washed with saturated NH4Cl:NH4OH:HO (1:1:8, 2 x 75 mL) and evaporated to dryness under reduced pressure. The crude product was suspended in toluene (30 mL) and heated at 90 °C for 15 min. The mixture was cooled to ambient temperature, and the solid was filtered off and dried under a stream of nitrogen. The white solid was suspended in water (100 mL) and heated at 90 °C for 20 min. The mixture was cooled to ambient temperature and the solid was dried under a stream of nitrogen to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (2.41 g, 4.44 mmol, 88% yield). 1H NMR(500MHz,DMSO-d6)δ 13.18(s,1H),10.19(br s,1H),8.08(d,J=8.72Hz,1H),7.91(d,J=7.80Hz,1H),7.76(t,J=7.96Hz,1H),7.2 9(d,J=1.99Hz,1H),7.14(dd,J=2.07,8.64Hz,1H),6.57(d,J=7.96Hz,1H),4.93(br s,1H),4.52(t,J=6.12Hz,2H),3.77(t,J=6.43Hz,2H),3.37(t,J=6.43Hz,2H),3.00(br t,J=4.74Hz,4H),2.80-2.87(m,2H),1.74(br s,4H),0.39(s,4H).m / z(ESI):543.2.2(M+H) + .

[0246] Example 6: N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] A mixture of 4-bromo-N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.0 g, 1.9 mmol, Intermediate 27), methyl 2-sulfamoylacetate (0.361 g, 2.89 mmol, Wuxi AppTec), potassium phosphate (1.23 g, 5.78 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.137 g, 0.963 mmol), and copper(I) iodide (0.183 g, 0.963 mmol) in DMF (20 mL) was heated at 90° C. for 16 h. The reaction mixture was then filtered through a plug of Celite. The filtrate was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography eluting with a gradient of 0 to 40% EtOAc in petroleum ether to give N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.580 g, 1.02 mmol, 53% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.85(s,1H),8.04(d,J=8.6Hz,1H),7.51(s,1H),7.23(d,J=2.2Hz,1H),7.09(dd,J=8.7,2.1Hz,1H),6.56(s,1H),3 .74(dt,J=12.5,6.2Hz,6H),2.97(t,J=5.2Hz,4H),2.26(s,3H),1.99(tt,J=13.6,5.4Hz,3H),1.79(s,4H),1.60(br s,4H),0.38(s,4H).m / z(ESI):564.2(M+H) + .

[0247] [Table 26]

[0248] [Table 27]

[0249] [Table 28]

[0250] [Table 29]

[0251] [Table 30]

[0252] Example 8-1: (R)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide, and Example 8-2: (S)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide [ka] Step 1: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (0.63 g, 1.3 mmol, Intermediate 38-1), ethyl 2-sulfamoylpropanoate (0.275 g, 1.52 mmol, Intermediate 40), potassium phosphate tribasic (0.537 g, 2.53 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.090 g, 0.63 mmol), and copper iodide (0.241 g, 1.26 mmol) in DMF (10 mL) was heated at 90 °C for 16 h. The reaction mixture was then filtered, diluted with EtOAc, washed with water, brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 0% to 50% EtOAc in petroleum ether to give ethyl 2-(N-(3-(6-azaspiro[2.5]octan-6-yl)-4-((6-(3,3,3-trifluoropropoxy)pyridin-2-yl)carbamoyl)phenyl)sulfamoyl)propanoate (0.56 g, 0.94 mmol, 74% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 13.19(s,1H),10.68(s,1H),8.09(d,J=8.7Hz,1H),7.91(d,J=7.9Hz,1H),7.77(t,J=7.9Hz,1H),7 .32(d,J=2.2Hz,1H),7.16(dd,J=8.6,2.2Hz,1H),6.58(d,J=8.0Hz,1H),4.51(t,J=6.1Hz,2H),4. 32(q,J=6.9Hz,1H),4.07(qd,J=7.1,5.2Hz,2H),3.00(d,J=5.0Hz,4H),2.84(qt,J=11.5,6.0Hz,2 H),1.74(s,4H),1.49(d,J=6.9Hz,3H),1.14(t,J=7.1Hz,3H),0.39(s,4H).m / z(ESI):598.8(M+H) + .

[0253] Step-2: To a solution of ethyl 2-(N-(3-(6-azaspiro[2.5]octan-6-yl)-4-((6-(3,3,3-trifluoropropoxy)pyridin-2-yl)carbamoyl)phenyl)sulfamoyl)propanoate (0.56 g, 0.94 mmol) in THF (12 mL) was added LiBH (1.871 mL, 3.74 mmol) at −78° C. The reaction mixture was then gradually warmed to room temperature over 2 h, then quenched with a saturated solution of NH Cl (20 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 0% to 50% EtOAc in petroleum ether to give 4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide (0.45 g, 0.81 mmol, 86% yield) as a white solid. m / z (ESI): 557.2 (M+H). + The racemic mixture was subjected to chiral separation by SFC (column used: Lux A1 (250 × 21.2 mm, 5 μm), mobile phase: 80:20 (A:B), A = liquefied CO 2 , B = methanol, flow rate: 80 mL / min).

[0254] Example 8-1: (R)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide. First eluting peak. 1H NMR(400MHz,DMSO-d6)δ ppm 13.18(s,1H),10.22(s,1H),8.07(d,J=8.6Hz,1H),7.90(d,J=7.8Hz,1H),7.76(t,J= 8.0Hz,1H),7.31(d,J=2.2Hz,1H),7.16(dd,J=8.6,2.1Hz,1H),6.57(dd,J=8.1,0.8Hz ,1H),5.03(s,1H),4.51(t,J=6.1Hz,2H),3.85(dd,J=11.1,4.4Hz,1H),3.49(dd,J=11 .1,7.6Hz,1H),3.30(m,1H),2.87-3.24(m,4H),2.83(tt,J=11.5,6.0Hz,2H),1.74(br s,4H),1.30(d,J=6.9Hz,3H),0.39(s,4H).m / z(ESI):557.1(M+H) + .

[0255] Example 8-2: (S)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide. Second eluting peak. 1 H NMR(400MHz,DMSO-d6)δ ppm 13.18(s,1H),10.22(s,1H),8.07(d,J=8.6Hz,1H),7.78-8.03(m,1H),7.75(d,J=7.9 Hz,1H),7.31(d,J=2.2Hz,1H),7.16(dd,J=8.7,2.2Hz,1H),6.57(d,J=8.0Hz,1H),5.0 3(s,1H),4.51(t,J=6.0Hz,2H),3.85(dd,J=11.1,4.4Hz,1H),3.48-3.57(m,2H),3.3 0(td,J=6.9,4.3Hz,1H),2.99(t,J=5.3Hz,4H),2.82(tt,J=11.4,5.9Hz,2H),1.74(br s,4H),1.29(d,J=6.9Hz,3H),0.39(s,4H).m / z(ESI):557.1(M+H) + .

[0256] The stereochemistry was arbitrarily assigned.

[0257] [Table 31]

[0258] [Table 32]

[0259] [Table 33]

[0260] Example 10: N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((1-(hydroxymethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of bis(4-methoxybenzyl)amine (8.95 g, 34.8 mmol) in DCM (50 mL) was added DIPEA (6.06 mL, 43.5 mmol) and methyl 2-(chlorosulfonyl)acetate (5.0 g, 29 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, then quenched with ice water and extracted with DCM. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 15% ethyl acetate in petroleum ether to give methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)acetate (5.5 g, 14 mmol, 48% yield) as a pale yellow gum. 1H NMR(400MHz,DMSO-d6):δ ppm 7.14(d,J=8.4Hz,4H),6.86(d,J=8.4Hz,4H),4.31(s,2H),4.25(s,4H),3.73(s,6H),3.70(s,3H).m / z(ESI):392.1(MH) - .

[0261] Step 2: A mixture of methyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)acetate (1.0 g, 2.5 mmol), K2CO3 (1.054 g, 7.62 mmol), and 1,2-dibromoethane (0.716 g, 3.81 mmol) in DMF (5 mL) was stirred at 65 °C for 16 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 5% ethyl acetate in petroleum ether to afford methyl 1-(N,N-bis(4-methoxybenzyl)sulfamoyl)cyclopropane-1-carboxylate (750 mg, 1.79 mmol, 70% yield) as a pale yellow gum. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.04-7.21(m,4H),6.83-6.94(m,4H),4.32(s,4H),3.72(s,6H),3.69(s,3H),1.67(q,J=4.8,3.6Hz,2H),1.56(q,J=5.7,4.8Hz,2H).

[0262] Step 3: A mixture of methyl 1-(N,N-bis(4-methoxybenzyl)sulfamoyl)cyclopropane-1-carboxylate (2.33 g, 5.55 mmol), TFA (23 mL), and anisole (3.03 mL, 27.8 mmol) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the concentrate was treated with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 50% ethyl acetate in petroleum ether to give methyl 1-sulfamoylcyclopropane-1-carboxylate (0.59 g, 3.3 mmol, 59% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.08(br s,2H),3.70(s,3H),1.48-1.52(m,4H).m / z(ESI):180.0(M+H) + .

[0263] Step 4: A mixture of 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.38 mmol, Intermediate 27), methyl 1-sulfamoylcyclopropane-1-carboxylate (0.103 g, 0.578 mmol), copper(I) iodide (0.073 g, 0.38 mmol), potassium phosphate tribasic (0.163 g, 0.770 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.027 g, 0.19 mmol) in DMF (3 mL) was heated at 90 °C for 16 h. The reaction was then filtered through a plug of Celite, and the filtrate was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 28% to 35% EtOAc in petroleum ether to afford methyl 1-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)cyclopropane-1-carboxylate (0.15 g, 0.24 mmol, 63.1% yield) as a white solid. m / z (ESI): 618.2 (M+H). + .

[0264] Step 5: To a solution of methyl 1-(N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)cyclopropane-1-carboxylate (0.150 g, 0.243 mmol) in THF (8 mL) at −78° C. was added lithium borohydride (0.486 mL, 0.971 mmol). The reaction mixture was gradually warmed to room temperature over 2 h, then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 40% to 45% EtOAc in petroleum ether to give N-(6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)-4-((1-(hydroxymethyl)cyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.090 g, 0.15 mmol, 63% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ ppm 12.89(s,1H),10.13(s,1H),8.04(d,J=8.6Hz,1H),7.51(s,1H),7.32(d,J=2.2 Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),6.57(s,1H),4.98(t,J=6.2Hz,1H),3.55-3 .86(m,6H),2.96(s,4H),2.26(s,3H),1.98(q,J=8.7,7.5Hz,4H),1.65-1.75(m ,4H),1.06-1.19(m,2H),0.93-1.06(m,2H),0.39(s,4H).m / z(ESI):590.2(M+H) + .

[0265] [Table 34]

[0266] Method E (Cu-catalyzed sulfonamide formation followed by reduction) Example 11: N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 4-bromo-N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.17 g, 0.35 mmol, Intermediate 39), methyl 2-sulfamoylacetate (0.079 g, 0.52 mmol), copper(I) iodide (0.066 g, 0.35 mmol), potassium phosphate tribasic (0.147 g, 0.692 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.025 g, 0.17 mmol) in DMF (4 mL) was heated at 90 °C for 16 h. The reaction mixture was then filtered through a plug of Celite. The filtrate was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 30% EtOAc in petroleum ether to give methyl 2-(N-(4-((6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.16 g, 0.28 mmol, 82% yield) as a semisolid. 1H NMR(400MHz,DMSO-d6):δ ppm 13.12(br s,1H),10.65(s,1H),8.07(dd,J=8.6,1.8Hz,1H),7.57(s,1H),7.28(t,J=2.0Hz,1H),7.15(dt,J=8.6 ,2.0Hz,1H),6.19(s,1H),4.32-4.46(m,6H),3.64(s,3H),2.98(t,J=5.0Hz,4H),2.28(s,3H),1.76(br s,4H),0.39(s,4H).m / z(ESI):564.2(M+H) + .

[0267] Step 2: To a solution of methyl 2-(N-(4-((6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.16 g, 0.28 mmol) in THF (3.2 mL) was added dropwise a 2 M solution of lithium borohydride in THF (0.284 mL, 0.568 mmol) at 0 °C. The reaction mixture was gradually warmed to room temperature over 1 h, then quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by reverse-phase column chromatography using a gradient of 0 to 60% acetonitrile in water to give N-(6-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.095 g, 0.18 mmol, 62% yield) as a white solid. 1H NMR(400MHz,DMSO-d6):δ ppm 13.08(s,1H),10.20(s,1H),8.05(d,J=8.6Hz,1H),7.56(s,1H),7.26(d,J=2.2Hz,1H),7.12(dd,J=8.6,2.2Hz,1H),6.18(s,1H),4.93(br s,1H),4.36(t,J=12.4Hz,4H),3.75(q,J=6.0Hz,2H),3.35(t,J=6.5Hz,2H),2.96(t,J=5.3Hz,4H),2.27(s,3H),1.74(br s,4H),0.38(s,4H).m / z(ESI):564.2(M+H) + .

[0268] Examples 12-1 and 12-2: 2-(6-azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)benzamide and 2-(6-azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)benzamide [ka] Step 1: To a solution of (R)-4-bromo-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.0 g, 2.1 mmol, Intermediate 30) in THF (20 mL) was added dropwise dibutylmagnesium (1.0 M solution in THF, 1.24 mL, 1.24 mmol) at 0 °C and stirred for 10 min. The reaction mixture was cooled to -78 °C, and n-butyllithium (2.5 M solution in hexane, 0.989 mL, 2.47 mmol) was added and stirred for 10 min. 1,2-Dicyclopropyldisulfane (0.301 g, 2.06 mmol, Wuxi AppTec) was added dropwise and stirred at room temperature for 2 h. The reaction mixture was quenched with 2 N HCl (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic extracts were combined, washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluted with a gradient of 30% ethyl acetate in hexanes to afford (R)-4-(cyclopropylthio)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.90 g, 91% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 12.91(s,1H),8.06(d,J=8.4Hz,1H),7.70-7.59(m,2H),7.40-7.26(m,2H),6.61-6.58(m ,1H),4.11(dd,J=25.9,12.9Hz,2H),3.93(dd,J=11.5,3.2Hz,1H),3.62-3.55(m,2H),3.0 3(t,J=5.5Hz,4H),2.83(td,J=12.2,3.4Hz,1H),2.38(dq,J=7.3,3.8,3.2Hz,1H),1.72(s ,4H),1.20-1.16(m,6H),0.66-0.62(m,2H),0.38(d,J=1.6Hz,4H).m / z(ESI):479.2(M+H) + .

[0269] Step 2: To a solution of (R)-4-(cyclopropylthio)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.90 g, 1.9 mmol) in dichloromethane (10 mL) was added m-CPBA (43.3 mg, 0.188 mmol) at 0° C. and stirred at the same temperature for 3 h. The reaction mixture was quenched with 10% aqueous sodium bicarbonate solution (15 mL) and extracted with DCM (2×20 mL). The organic extracts were combined, washed with brine solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 1% to 50% ethyl acetate in hexane to give 4-(cyclopropylsulfinyl)-N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (650 mg, 70% yield) as a pale yellow solid. 1 H NMR (400MHz, chloroform-d):δ 12.89(s,1H),8.23(d,J=8.3Hz,1H),7.81(dd,J=7.9,4.6Hz,1H),7.57(td,J=8.0,3.3Hz,1H),7.30(dd,J=8.3, 1.8Hz,1H),7.25(d,J=1.8Hz,1H),6.42(dd,J=8.2,3.7Hz,1H),4.18-3.95(m,3H),3.81-3.65(m,2H),3.09(q,J =6.3,5.6Hz,4H),2.97(tt,J=12.8,11.7,2.7Hz,1H),2.63(ddd,J=12.7,10.4,1.9Hz,1H),2.23(tt,J=7.3,4.4 Hz,1H),1.31-1.27(m,4H),1.19-1.15(m,5H),0.77-0.73(m,2H),0.40(d,J=1.7Hz,4H).m / z(ESI):495.2(M+H) + .

[0270] Step 3: To a solution of 4-(cyclopropylsulfinyl)-N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.65 g, 1.30 mmol) in MeOH (20 mL) was added iodobenzene diacetate (1.27 g, 3.94 mmol) and ammonium carbamate (410 mg, 5.26 mmol) at 0 °C for 10 min, then warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic extracts were combined, washed with brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 40% ethyl acetate in hexane to give 4-(cyclopropanesulfonimidoyl)-N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, racemic) as a pale yellow solid. 1 H NMR (400 MHz, chloroform-d): δ 12.67 (s, 1H), 8.45 (dd, J = 8.3, 1.2 Hz, 1H), 7.93 (t, J = 1.5 Hz, 1H), 7.84 (dt, J = 8.3, 1.5 Hz, 1H), 7.82-7.72 (m, 1H), 7.66-7.56 (m, 1H), 6.46 (d, J = 8.2 Hz, 1H), 4.22-3.92 (m, 3H), 3.92-3.62 (m, 2H), 3.33-3.11 (m, 4H), 2.99 (td, J = 12. 2,3.5Hz,1H),2.77-2.55(m,2H),2.01-1.69(m,4H),1.47(ddt,J=9.9,7.0,5.0Hz,1H),1.30(dd,J=6.2,1.0Hz,3H ),1.28-1.20(m,2H),1.18-1.08(m,1H),1.00(qd,J=8.0,6.0Hz,1H),0.43(d,J=1.1Hz,4H).m / z(ESI):510.2(M+H) + . The racemic mixture was separated by chiral separation using SFC ((S,S) Whelk-01 (250 × 30 mm, 5 μm) column, mobile phase: 70:30 (A:B), A = liquefied CO2, B = methanol, flow rate: 70 mL / min).

[0271] Example 12-1: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)benzamide. 1 H NMR(400MHz,chloroform-d)δ 12.64(s,1H),8.44(d,J=8.1Hz,1H),7.93(d,J=1.7Hz,1H),7.83(dd,J=8.3,1.8Hz,1H),7.77(d,J=7.8H z,1H),7.60(t,J=8.0Hz,1H),6.46(d,J=8.1Hz,1H),4.13-4.01(m,3H),3.80-3.64(m,2H),3.19-3.13(m, 4H),2.98(td,J=12.2,3.6Hz,1H),2.67-2.60(m,2H),2.01-1.50(m,3H),1.47(ddt,J=9.7,6.8,4.8Hz,1H ),1.32-1.26(m,6H),1.15(qd,J=7.9,4.9Hz,1H),1.05-0.95(m,1H),0.42(s,4H).m / z(ESI):510.2(M+H) + .

[0272] Example 12-2: 2-(6-azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)benzamide. 1H NMR (400MHz, chloroform-d):δ 12.65(s,1H),8.44(d,J=8.2Hz,1H),7.93(d,J=1.7Hz,1H),7.83(dd,J=8.2,1.8Hz,1H),7.77(d,J=7.8Hz,1H),7.59(t,J=8. 1Hz,1H),6.45(d,J=8.3Hz,1H),4.13-3.95(m,3H),3.73(dddd,J=17.1,9.9,8.1,5.2Hz,2H),3.19-3.13(m,4H),2.98(td,J=1 2.3,3.6Hz,1H),2.63(dq,J=10.8,3.9Hz,2H),2.01-1.50(m,3H),1.47(dtd,J=10.2,4.8,2.4Hz,1H),1.32-1.29(m,2H),1.2 9(d,J=6.2Hz,4H),1.14(ddd,J=10.1,7.9,3.8Hz,1H),0.99(dtd,J=9.0,7.4,4.9Hz,1H),0.42(s,4H).m / z(ESI):510.2(M+H) + .

[0273] The stereochemistry was arbitrarily assigned.

[0274] [Table 35]

[0275] Example 14: N-(6-(cyclopropylmethoxy)pyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A solution of 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (5.0 g, 14 mmol, Intermediate 11) in DCM (50 mL) was treated with DIPEA (7.19 mL, 41.2 mmol), 6-fluoropyridin-2-amine (1.84 g, 16.5 mmol), followed by T3P (17.46 g, 27.4 mmol, 50% in EtOAc, Spectrochem) at rt. The reaction mixture was then stirred for 16 h before being quenched with water and extracted with DCM. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 15% to 20% EtOAc in petroleum ether to give N-(6-fluoropyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.0 g, 6.5 mmol, 48% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.09(s,1H),10.28(s,1H),8.20(d,J=7.7Hz,1H),8.03(t,J=9.0Hz,2H),7.36(s,1H),7.17(d,J=8.5Hz,1H),6.89(d,J=8.0 Hz,1H),2.97(t,J=5.3Hz,4H),1.67(s,4H),1.41(s,3H),1.21(s,2H),0.81-0.89(m,2H),0.41(s,4H).m / z(ESI):459.1(M+H) + .

[0276] Step 2: A solution of cyclopropylmethanol (23.59 mg, 0.327 mmol) in DMF (1.5 mL) was treated with sodium hydride (13.08 mg, 0.327 mmol, 60% in mineral oil) at 0 °C under a N atmosphere and stirred for 10 min. To the reaction mixture was then added a solution of N-(6-fluoropyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.218 mmol) in DMF (0.5 mL). The resulting solution was stirred at rt for 2 h, then quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by reverse-phase HPLC to give N-(6-(cyclopropylmethoxy)pyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.20(s,1H),10.22(br s,1H),8.08(d,J=8.6Hz,1H),7.85(d,J=7.8Hz,1H),7.72(t,J=7.9Hz,1H),7.36(d,J=2.2Hz,1H),7.1 7(dd,J=8.7,2.2Hz,1H),6.56(d,J=8.0Hz,1H),4.12(d,J=7.2Hz,2H),2.98(d,J=5.3Hz,4H),1.71(br s,4H),1.41(s,3H),1.24-1.35(m,1H),1.17-1.27(m,2H),0.80-0.88(m,2H ),0.55-0.64(m,2H),0.39(s,4H),0.28-0.36(m,2H).m / z(ESI):511.2(M+H) + .

[0277] Example 15: N-(6-(cyclopropylmethoxy)pyridin-2-yl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of 6-hydroxypicolinic acid (5.0 g, 36 mmol) in MeOH (83 mL) was added H2SO4 (4.79 mL, 90 mmol) dropwise at rt. The reaction mixture was then heated at reflux for 18 h, after which the volatiles were evaporated, and the concentrate was gradually neutralized with NaHCO3 (100 mL) solution to maintain a pH of 7-8. The reaction mixture was then extracted with CHCl2. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was triturated with petroleum ether to give methyl 6-hydroxypicolinate (4.2 g, 27 mmol, 76% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.54(s,1H),7.64(dd,J=8.9,7.0Hz,1H),7.16(dd,J=7.0,1.0Hz,1H),6.73(dd,J=8.9,1.0Hz,1H),3.84(s,3H).m / z(ESI):154.1(M+H) + .

[0278] Step 2: A solution of methyl 6-hydroxypicolinate (1.0 g, 6.4 mmol) and sodium 2-chloro-2,2-difluoroacetate (1.971 g, 12.93 mmol, TCI India) in acetonitrile (25 mL) was heated at 85° C. for 72 h. The reaction mixture was then cooled to rt and evaporated to dryness to give methyl 6-(difluoromethoxy)picolinate (2.1 g, 6.3 mmol, 98% yield) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.12(ddd,J=11.3,6.7,2.7Hz,1H),7.92-7.97(m,1H),7.50-7.91(m,1H),7.34-7.42(m,1H),3.89(s,3H).m / z(ESI):204.1(M+H) +.

[0279] Step 3: To a solution of methyl 6-(difluoromethoxy)picolinate (2.0 g, 5.9 mmol) in THF (90 mL) was added LiOH (11.81 mL, 23.63 mmol, 2 M solution in HO). The reaction mixture was stirred at rt for 16 h, then quenched with 1 N HCl (pH = 2-3) and extracted with CHCl. ​​The organic layer was washed with brine, dried over NaSO, filtered, and concentrated to give 6-(difluoromethoxy)picolinic acid as a pale yellow solid, which was used in the next step without purification. 1 H NMR(300MHz,DMSO-d6)δ ppm 13.34(s,1H),8.02-8.19(m,1H),7.91(d,J=7.4Hz,1H),7.79(t,J=72.6Hz,1H),7.34(d,J=8.2Hz,1H).m / z(ESI):190.0(M+H) + .

[0280] Step 4: To a solution of 6-(difluoromethoxy)picolinic acid (0.80 g, 4.1 mmol) in a mixture of tert-butanol (2.5 mL) and toluene (28 mL) at rt under a N atmosphere was added EtN (2.30 mL, 16.51 mmol), followed by diphenylphosphorazidate (1.31 mL, 6.19 mmol). The reaction mixture was heated at 100 °C for 16 h, then neutralized with aqueous NaHCO (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 2% to 5% EtOAc in petroleum ether to afford tert-butyl (6-(difluoromethoxy)pyridin-2-yl)carbamate (0.51 g, 1.9 mmol, 47% yield) as a pale yellow oil. 1H NMR(400MHz,DMSO-d6)δ ppm 9.85(s,1H),7.83(t,J=8Hz,1H),7.73-7.36(m,2H),6.66(d,J=12Hz,1H),1.47(s,9H).m / z(ESI):204.1(M- t Bu) + ,161.1(M-Boc) + .

[0281] Step 5: To a solution of tert-butyl (6-(difluoromethoxy)pyridin-2-yl)carbamate (0.50 g, 1.9 mmol) in 1,4-dioxane (3.0 mL) was added 4.0 M HCl in dioxane (9.98 mL, 39.9 mmol) over 5 min at rt. The reaction mixture was stirred for 6 h, then quenched with saturated aqueous NaHCO solution (100 mL) and extracted with CHCl. ​​The organic extract was washed with brine, dried over NaSO, filtered, and concentrated to give 6-(difluoromethoxy)pyridin-2-amine (0.31 g, 1.8 mmol, 95% yield) as an orange oil, which was used in the next step without purification. 1 H NMR(300MHz,DMSO-d6)δ ppm 7.21-7.79(m,2H),6.23(d,J=7.7Hz,3H),6.05(d,J=7.7Hz,1H).m / z(ESI):161.1(M+H) + .

[0282] Step 6: To a solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.40 g, 1.3 mmol, Intermediate 9-1) in DCM (5.0 mL) was added DIPEA (0.676 mL, 3.87 mmol) followed by T3P (2.28 mL, 3.87 mmol, 50% in ethyl acetate) at rt and stirred for 15 min. A solution of 6-(difluoromethoxy)pyridin-2-amine (0.327 g, 1.93 mmol) in dichloromethane (2.0 mL) was then added. The resulting mixture was stirred at rt for 16 h, then quenched with water (50 mL) and extracted with CHCl. ​​The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 17% EtOAc in petroleum ether to give 4-bromo-N-(6-(difluoromethoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.30 g, 0.62 mmol, 48% yield) as a pale yellow gummy liquid. 1 H NMR(300MHz,DMSO-d6)δ ppm 13.45(s,1H),7.92-8.17(m,3H),7.70-7.80(m,1H),7.57(d,J=6.7Hz,2H),6.84(d,J=7. 9Hz,1H),3.05(t,J=5.3Hz,4H),1.69(s,4H),0.38(s,4H).m / z(ESI):452.0,454.0(M+H) + .

[0283] Step 7: A mixture of 4-bromo-N-(6-(difluoromethoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.30 g, 0.66 mmol), 2-hydroxyethane-1-sulfonamide (0.125 g, 0.995 mmol), potassium phosphate (0.422 g, 1.99 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.094 g, 0.66 mmol), and copper(I) iodide (0.126 g, 0.663 mmol) in DMF (3.0 mL) was heated at 90 °C for 16 h. The reaction mixture was filtered through a plug of Celite, and the filtrate was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 5% to 44% EtOAc in petroleum ether to give N-(6-(difluoromethoxy)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.18 g, 0.36 mmol, 54% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 13.50(s,1H),10.26(s,1H),8.11(t,J=8.0Hz,2H),7.96(t,J=8.0Hz,1H),7.30(d,J= 2.2Hz,1H),7.16(dd,J=8.7,2.2Hz,1H),6.81(d,J=8.0Hz,1H),4.96(t,J=5.6Hz, 1H),3.77(q,J=6.0Hz,2H),3.38(d,J=6.4Hz,2H),2.99(t,J=5.5Hz,4H),1.72(br s,4H),0.40(s,4H).m / z(ESI):497.1(M+H) + .

[0284] Example 16: N-(6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of ethyl 2-hydroxyacetate (5.0 g, 48 mmol, Combi-Blocks) in THF (100 mL) was added methylchloromagnesium (48.0 mL, 3.0 M in THF, 144 mmol), and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na SO , filtered, and concentrated to give 2-methylpropane-1,2-diol (2.3 g, 26 mmol, 53% yield) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6)δ ppm 4.49(t,J=5.8Hz,1H),4.10(br s,1H),3.12-3.16(m,2H),1.03(s,6H).

[0285] Step 2: To a solution of 6-fluoropyridin-2-amine (0.700 g, 6.24 mmol) and 2-methylpropane-1,2-diol (0.844 g, 9.37 mmol) in dioxane (7 mL) at rt was added NaH (60% in mineral oil, 0.749 g, 18.7 mmol). The reaction mixture was stirred at 80 °C for 4 h, cooled to rt, quenched with saturated aqueous NH Cl, and extracted with EtOAc. The organic extract was washed with brine, dried over Na SO , filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 80% ethyl acetate in petroleum ether to give 1-((6-aminopyridin-2-yl)oxy)-2-methylpropan-2-ol (0.60 g, 3.3 mmol, 53% yield) as an orange oil. 1H NMR(400MHz,DMSO-d6)δ ppm 7.25-7.29(m,1H),5.97(d,J=7.8Hz,1H),5.87(d,J=7.8Hz,1H),5.82(s,2H),4.56(s,1H),3.88(s,2H),1.15(s,6H).m / z(ESI):183.2(M+H) + .

[0286] Step 3: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.30 g, 0.97 mmol, Intermediate 9-1), DIPEA (0.203 mL, 1.16 mmol), T3P (50% in ethyl acetate, 0.691 mL, 1.16 mmol), and 1-((6-aminopyridin-2-yl)oxy)-2-methylpropan-2-ol (0.211 g, 1.16 mmol) in DCM (3 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 5% to 30% ethyl acetate in petroleum ether to give 4-bromo-N-(6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.42 mmol, 44% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 13.08(s,1H),8.05(d,J=8.4Hz,1H),7.85(d,J=7.8Hz,1H),7.69-7.76(m,2H),7.55-7.5 9(m,1H),6.59(d,J=8.0Hz,1H),4.60(s,1H),4.06(s,2H),3.06(t,J=5.3Hz,4H),1.73(br s,4H),1.22(s,6H),0.39(s,4H).m / z(ESI):476.1(M+H) + .

[0287] Step 4: A mixture of 4-bromo-N-(6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.27 g, 0.57 mmol), methyl 2-sulfamoylacetate (0.131 g, 0.854 mmol), potassium phosphate (0.302 g, 1.42 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.040 g, 0.28 mmol), and copper(I) iodide (0.108 g, 0.569 mmol) in DMF (4 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 80% ethyl acetate in petroleum ether to give methyl 2-(N-(4-((6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.25 g, 0.46 mmol, 80% yield) as a pale yellow oil. m / z (ESI): 547.2 (M+H). + .

[0288] To a solution of methyl 2-(N-(4-((6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.24 g, 0.44 mmol) in THF (3.75 mL) at −30° C. was added LiBH (0.439 mL, 0.878 mmol), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NHCl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 30% to 90% ethyl acetate in petroleum ether to give N-(6-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.091 g, 0.18 mmol, 40% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.10(br s,1H),8.07(d,J=8.7Hz,1H),7.84(d,J=7.6Hz,1H),7.72(t,J=7.9Hz,1H),7.28(d,J=2.2Hz,1H),7.12(dd,J=8.6,2.1Hz,1H) ,6.55(d,J=8.0Hz,1H),4.58(s,1H),4.05(s,2H),3.76(t,J=6.5Hz,2H),3.35(t,J=6.5Hz,2H),2.99(t,J=5.2Hz,4H),1.75(br s,4H),1.21(s,6H),0.39(s,4H).m / z(ESI):519.2(M+H) + .

[0289] [Table 36]

[0290] [Table 37]

[0291] Example 17: 4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of 3,3,3-trifluoropropan-1-ol (0.550 g, 4.83 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (0.386 g, 9.64 mmol, 60% in oil) at 10° C. and stirred at room temperature for 30 min. To the reaction mixture was added a solution of 2-bromo-6-fluoro-4-methylpyridine (0.61 g, 3.2 mmol, Combi-Blocks) in dioxane (4 mL). The resulting solution was stirred at room temperature for 2 h, then quenched with ice-cold water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 4% ethyl acetate in petroleum ether to give 2-bromo-4-methyl-6-(3,3,3-trifluoropropoxy)pyridine (0.76 g, 85% yield) as a clear oil. 1 H NMR (400 MHz, chloroform-d): δ ppm 6.96 (s, 1H), 6.53 (s, 1H), 4.51-4.56 (m, 2H), 2.56-2.66 (m, 2H), 2.29 (s, 3H). m / z (ESI): 284.0 (M+H) + .

[0292] Step 2: A mixture of 2-bromo-4-methyl-6-(3,3,3-trifluoropropoxy)pyridine (0.71 g, 2.5 mmol), (4-methoxyphenyl)methanamine (0.514 g, 3.75 mmol), cesium carbonate (2.443 g, 7.50 mmol), xantphos (0.289 g, 0.500 mmol), and Pd(dba) (0.023 g, 0.025 mmol) in 1,4-dioxane (14 mL) was stirred at 100 °C for 16 h. The reaction mixture was filtered through a Celite bed, and the filtrate was washed with water, brine, dried over NaSO, and concentrated. The concentrate was purified by flash column chromatography using 6% ethyl acetate in petroleum ether to give N-(4-methoxybenzyl)-4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.65 g, 1.91 mmol, 76% yield) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.23(d,J=8.7Hz,2H),6.94(t,J=5.9Hz,1H),6.82-6.90(m,2H),5.89(s,1H),5.71(s,1H), 4.33(t,J=6.1Hz,4H),3.71(s,3H),2.56-2.66(m,2H),2.07(s,3H).m / z(ESI):341.1(M+H) + .

[0293] Step 3: A solution of N-(4-methoxybenzyl)-4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.30 g, 0.88 mmol), anisole (0.193 mL, 1.76 mmol), TFA (1.5 mL, 19 mmol) in dichloromethane (3 mL) was stirred for 1.5 h at 55° C. The reaction mixture was then concentrated, and the residue was dissolved in water, basified to pH 8 with 10% sodium bicarbonate, and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 20% ethyl acetate in petroleum ether to give 4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.16 g, 0.73 mmol, 82% yield) as a yellow oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 5.88(s,1H),5.74(s,1H),4.30(t,J=6.1Hz,2H),2.60-2.68(m,2H),2.05(s,3H).m / z(ESI):221.1(M+H) + .

[0294] Step 4: A mixture of 4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.16 g, 0.73 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.270 g, 0.872 mmol, Intermediate 9-1), EtN (0.304 mL, 2.18 mmol), and T3P (50% solution in ethyl acetate, 1.386 g, 2.180 mmol) in 1,2-dimethoxyethane (4 mL) was heated at 80 °C for 16 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 8% ethyl acetate in petroleum ether to give 4-bromo-N-(4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.39 mmol, 54% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 13.04(s,1H),8.02(d,J=8.5Hz,1H),7.77(s,1H),7.68(d,J=2.0Hz,1H),7.56(dd,J=8.4,1.9Hz,1H),6.45(s,1H),4.49(t,J=6.1 Hz,2H),3.05(t,J=5.3Hz,4H),2.82(dt,J=11.5,5.8Hz,2H),2.31(s,3H),1.66-1.78(m,4H),0.37(s,4H).m / z(ESI):512.1(M+H) + .

[0295] Step 5: A mixture of 4-bromo-N-(4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.39 mmol), 2-hydroxyethane-1-sulfonamide (0.073 g, 0.59 mmol), potassium phosphate tribasic (0.166 g, 0.781 mmol), copper(I) iodide (0.074 g, 0.39 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (0.028 g, 0.20 mmol) in DMF (3 mL) was stirred at 95° C. for 16 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by reverse-phase column chromatography using a gradient of 65% acetonitrile in water to give 4-((2-hydroxyethyl)sulfonamido)-N-(4-methyl-6-(3,3,3-trifluoropropoxy)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.166 g, 0.298 mmol, 76% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.09(s,1H),10.21(br s,1H),8.06(d,J=8.6Hz,1H),7.78(s,1H),7.27(d,J=2.1Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),6.42(s,1H),4.96(br s,1H),4.49(t,J=6.1Hz,2H),3.76(t,J=6.4Hz,2H),3.38-3.40(m,2H),2.96-3.20(m,4H ),2.76-2.88(m,2H),2.31(s,3H),1.60-1.80(m,4H),0.38(s,4H).m / z(ESI):557.2(M+H) + .

[0296] [Table 38]

[0297] Example 18: 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (1.0 g, 2.5 mmol, Intermediate 9-4), ethyl 2-sulfamoylacetate (0.626 g, 3.75 mmol), potassium phosphate (1.06 g, 5.00 mmol), copper(I) iodide (0.476 g, 2.50 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.178 g, 1.25 mmol) in DMF (15 mL) was heated at 90 °C for 16 h. The reaction mixture was then filtered through a plug of Celite, and the filtrate was diluted with EtOAc, washed with water, brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 0% to 25% EtOAc in petroleum ether to give benzyl 4-((2-ethoxy-2-oxoethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.75 g, 1.5 mmol, 53% yield) as an orange oil. 1 H NMR(400MHz,DMSO-d6):δ ppm 10.45(s,1H),7.64(d,J=8.5Hz,1H),7.29-7.48(m,5H),6.93(d,J=2.1Hz,1H),6.79(dd,J=8.5,2.0Hz,1H),5.28(s,2H),4.31(s,2H),4.0 5(dq,J=19.5,7.1Hz,2H),2.94(t,J=5.3Hz,4H),1.37(t,J=5.3Hz,4H),1.16(dt,J=11.2,7.1Hz,3H),0.28(s,4H).m / z(ESI):487.2(M+H) + .

[0298] Step 2: To a solution of benzyl 4-((2-ethoxy-2-oxoethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.55 g, 1.1 mmol) in ethyl acetate (3 mL) and methanol (6 mL) was added palladium on carbon (10%, 0.28 g, 0.26 mmol), and stirring under a hydrogen atmosphere (1 atm) was continued for 2 h. The reaction mixture was then filtered through a Celite bed and washed with methanol (150 mL). The filtrate was concentrated and triturated with EtO to give 4-((2-ethoxy-2-oxoethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.55 g, 1.4 mmol, 90% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 10.69(s,1H),7.93(d,J=8.6Hz,1H),7.31(d,J=2.1Hz,1H),7.12(dd,J=8.7,2.1Hz,1H),4.31(s,2H),4.07(q ,J=7.1Hz,2H),3.00(t,J=5.4Hz,4H),1.57(s,4H),1.14(t,J=7.1Hz,3H),0.42(s,4H).m / z(ESI):397.1(M+H) + .

[0299] Step 3: To a solution of 5-methyl-6-morpholinopyridin-2-amine (45.0 mg, 0.232 mmol, Intermediate 8) in DMF (3 mL) at room temperature was added 4-((2-ethoxy-2-oxoethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (92 mg, 0.23 mmol), DIPEA (48.8 μL, 0.279 mmol), and HATU (106 mg, 0.279 mmol). The reaction mixture was then stirred for 12 h, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 15% ethyl acetate in petroleum ether to give ethyl 2-(N-(4-((5-methyl-6-morpholinopyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (50 mg, 0.087 mmol, 38% yield) as a pale yellow solid. m / z (ESI): 572.2 (M+H). + .

[0300] Step 4: To a solution of ethyl 2-(N-(4-((5-methyl-6-morpholinopyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (50 mg, 0.087 mmol) in THF (10 mL) at 0° C. was added lithium borohydride (65.6 μL, 0.131 mmol, 2 M in THF). The reaction mixture was then stirred at rt for 3 h before being quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 30% ethyl acetate in petroleum ether to afford 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30 mg, 0.057 mmol, 64.8% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.10(d,J=5.4Hz,1H),10.21(s,1H),8.08(dd,J=9.6,3.7Hz,1H),7.83(t,J=6.8Hz,1H),7.55(dd,J=9.2,4.2Hz,1H),7.26(d,J=5.4Hz,1H),7 .13(dd,J=8.7,2.3Hz,1H),4.95(s,1H),3.75(m,6H),3.11(q,J=4.4Hz,4H),2.97(d,J=6.6Hz,4H),2.69(d,J=2.9Hz,2H),2.22(s,3H),1.77(br s,4H),0.38(d,J=5.7Hz,4H).m / z(ESI):530.2(M+H) + .

[0301] Example 19: (R)—N-(4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 2,6-dichloro-4-iodopyridine (1.8 g, 6.6 mmol, Combi-Blocks), cyclopropylboronic acid (0.565 g, 6.57 mmol, Combi-Blocks), potassium carbonate (0.908 g, 6.57 mmol), and Xphos-Pd-G3 (0.278 g, 0.329 mmol, Strem Chemicals) in 1,4-dioxane (10 mL) was stirred at 100 °C for 3 h. The reaction mixture was filtered through a bed of Celite. The filtrate was concentrated, and the residue was triturated with diethyl ether to give 2,6-dichloro-4-cyclopropylpyridine (0.95 g, 5.0 mmol, 77% yield) as a brown semi-solid.

[0302] Step 2: A mixture of 2,6-dichloro-4-cyclopropylpyridine (0.90 g, 4.8 mmol), (R)-2-methylmorpholine hydrochloride (0.988 g, 7.18 mmol, Suzhou Chemicals), and CsF (2.91 g, 19.1 mmol) in DMSO (9 mL) was stirred at 145 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 5% to 50% ethyl acetate in petroleum ether to give (R)-4-(6-chloro-4-cyclopropylpyridin-2-yl)-2-methylmorpholine (1.1 g, 4.4 mmol, 91% yield) as an orange oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 6.50(s,1H),6.39(s,1H),3.84-4.11(m,4H),3.50(dt,J=11.7,2.6Hz,2H),2.78(td,J=12.3,3.5Hz,1H),1.87(td ,J=8.5,4.3Hz,1H),1.15(d,J=6.2Hz,3H),0.98(dt,J=8.4,3.3Hz,2H),0.78-0.85(m,2H).m / z(ESI):253.1(M+H)+ .

[0303] Step 3: A mixture of (R)-4-(6-chloro-4-cyclopropylpyridin-2-yl)-2-methylmorpholine (1.0 g, 4.0 mmol), (4-methoxyphenyl)methanamine (0.775 mL, 5.93 mmol), CsCO (2.58 g, 7.91 mmol), BINAP (0.246 g, 0.396 mmol), and palladium(II) acetate (0.089 g, 0.40 mmol) in dioxane (15 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 5% to 40% ethyl acetate in petroleum ether to give (R)-4-cyclopropyl-N-(4-methoxybenzyl)-6-(2-methylmorpholino)pyridin-2-amine (1.2 g, 3.4 mmol, 86% yield) as an orange oil. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.15-7.28(m,2H),6.74-6.92(m,2H),6.48(t,J=6.0Hz,1H),5.61(s,1H) ,5.54(s,1H),4.29(d,J=6.0Hz,2H),3.79-4.06(m,4H),3.71(s,3H),3.4 0-3.52(m,2H),2.26-2.36(m,1H),1.63(td,J=8.0,4.0Hz,1H),1.11(d,J =6.2Hz,3H),0.80-0.89(m,2H),0.58-0.66(m,2H).m / z(ESI):354.2(M+H) + .

[0304] Step 4: A mixture of (R)-4-cyclopropyl-N-(4-methoxybenzyl)-6-(2-methylmorpholino)pyridin-2-amine (1.0 g, 2.8 mmol) and HSO (1.51 mL, 28.3 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 h. The reaction mixture was made basic (pH = 9) with 1 N NaOH and extracted with EtOAc. The organic extract was washed with brine, dried over NaSO, filtered, and concentrated to give (R)-4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-amine as a brown, viscous liquid. 1 H NMR(400MHz,DMSO-d6):δ ppm 5.64-5.78(m,1H),5.52(d,J=2.4Hz,1H),5.39(br s,2H),4.00(d,J=12.6Hz,1H),3.81-3.94(m,2H),3.46-3.52(m,2H),2.62(td,J=12.3,3.3Hz,1H),2.29(td,J=12.7 ,2.2Hz,1H),1.61-1.69(m,1H),1.13(d,J=6.2Hz,3H),0.84-0.88(m,2H),0.62-0.66(m,2H).m / z(ESI):234.2(M+H) + .

[0305] Step 5: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.50 g, 1.6 mmol, Intermediate 9-1), DIPEA (0.845 mL, 4.84 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in ethyl acetate, 1.452 mL, 4.84 mmol), and (R)-4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-amine (0.40 g, 1.7 mmol) in dichloromethane (15 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 80% ethyl acetate in petroleum ether to give (R)-4-bromo-N-(4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.50 g, 0.94 mmol, 58% yield) as a white sticky solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 12.67(s,1H),8.00(d,J=8.5Hz,1H),7.63(s,1H),7.53(d,J=8.5Hz,1H),7.34(s,1H),6.35(s,1H),4.01-4.18(m,3H),3.90(dd, J=11.1,3.1Hz,1H),3.51-3.63(m,2H),3.01(t,J=5.5Hz,4H),2.78(td,J=12.3,3.5Hz,1H),1.87(td,J=8.5,4.3Hz,1H),1.69(br s,4H),1.16(d,J=6.3Hz,3H),0.98-1.04(m,2H),0.72-0.80(m,2H),0.35(s,4H).m / z(ESI):525.1(M+H) + .

[0306] Step 6: A mixture of (R)-4-bromo-N-(4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.30 g, 0.57 mmol), 2-hydroxyethane-1-sulfonamide (0.107 g, 0.856 mmol), potassium phosphate tripotassium (0.303 g, 1.43 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.041 g, 0.28 mmol), and copper(I) iodide (0.109 g, 0.571 mmol) in N,N-dimethylformamide (9 mL) was stirred at 90° C. for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 20% to 80% ethyl acetate in petroleum ether to give (R)-N-(4-cyclopropyl-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.155 g, 0.272 mmol, 48% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 12.73(s,1H),8.04(dd,J=8.7,2.9Hz,1H),7.37(d,J=2.8Hz,1H),7.23(t,J=2.6Hz,1H) ,7.10(dt,J=8.7,2.6Hz,1H),6.34(d,J=2.7Hz,1H),4.14(d,J=12.9Hz,1H),4.10(d,J=1 2.9Hz,1H),3.91(d,J=11.3Hz,1H),3.76(t,J=6.5Hz,2H),3.53-3.61(m,2H),3.01(t,J =5.5Hz,4H),2.79(td,J=9.2,4.6Hz,1H),2.42-2.48(m,2H),1.82-1.92(m,2H),1.68(br s,4H),1.18(d,J=6.2Hz,3H),1.00(d,J=8.2Hz,2H),0.77(d,J=5.2Hz,2H),0.37(s,4H).m / z(ESI):570.2(M+H)+ .

[0307] Example 20: (R)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 2,6-dichloro-4-(trifluoromethyl)pyridine (6.0 g, 28 mmol, Combi-Blocks), (R)-2-methylmorpholine hydrochloride (4.59 g, 33.3 mmol), and DIPEA (9.70 mL, 55.6 mmol) in ethanol (30 mL) was heated in a microwave at 100° C. for 1 h. The reaction mixture was concentrated and purified by flash column chromatography, eluting with a gradient of 0% to 20% ethyl acetate in petroleum ether, to give (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-methylmorpholine (6.0 g, 21 mmol, 77% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.11(s,1H),6.97(s,1H),4.02-4.25(m,2H),3.76-3.97(m,1H),3.39-3.63(m,2H),2.92(td,J =3.5,12.5Hz,1H),2.60(dd,J=10.4,13.0Hz,1H),1.15(d,J=6.2Hz,3H).m / z(ESI):281.1(M+H) + .

[0308] Step 2: A mixture of (R)-4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-2-methylmorpholine (2.0 g, 7.1 mmol), (4-methoxyphenyl)methanamine (1.173 g, 8.55 mmol), and DIPEA (2.489 mL, 14.25 mmol) in NMP (10 mL) was stirred in a microwave at 180° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 25% ethyl acetate in petroleum ether to give (R)-N-(4-methoxybenzyl)-6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-amine (1.5 g, 2.8 mmol, 39% yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.25(dd,J=4.7,7.1Hz,2H),6.76-6.98(m,2H),6.05(d,J=6.4Hz,2H),4.37(d,J=5.8Hz,2H),3.89-4.15(m,2H),3. 75-3.95(m,1H),3.73(s,3H),3.38-3.60(m,2H),2.63-2.89(m,1H),2.41(dd,J=10.3,12.7Hz,1H),1.22(d,J=6.2Hz 3H).m / z(ESI):382.1(M+H) + .

[0309] Step 3: A mixture of (R)-N-(4-methoxybenzyl)-6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-amine (1.5 g, 3.9 mmol) and HSO (2.096 mL, 39.3 mmol) in dichloromethane (50 mL) was stirred at room temperature for 5 h. The reaction mixture was concentrated, and the residue was dissolved in ice-cold water, made basic (pH 10) with 10% NaOH, and extracted with EtOAc. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by reverse-phase column chromatography eluting with a gradient of 0% to 80% acetonitrile in water to give (R)-6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-amine (0.30 g, 1.1 mmol, 29% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 6.13(br s,2H),6.08(s,1H),5.98(d,J=1.1Hz,1H),4.05-4.16(m,1H),3.94-4.05(m,1H),3.87(ddd,J=1.4,3.6,11.5Hz,1H),3.41-3 .59(m,2H),2.74(ddd,J=3.5,11.8,12.8Hz,1H),2.42(dd,J=10.4,12.8Hz,1H),1.13(d,J=6.2Hz,3H).m / z(ESI):262.1(M+H) + .

[0310] Step 4: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.20 g, 0.64 mmol, Intermediate 9-1), (R)-6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-amine (0.253 g, 0.967 mmol), DIPEA (0.338 mL, 1.93 mmol), and T3P (50% in EtOAc, 1.231 g, 1.934 mmol) in dichloromethane (5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 30% ethyl acetate in petroleum ether to give (R)-4-bromo-N-(6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.30 g, 0.54 mmol, 84% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d): δ ppm 13.20(s,1H),8.04(d,J=8.4Hz,1H),7.82(s,1H),7.71(d,J=2.0Hz,1H),7.57( dd,J=1.9,8.5Hz,1H),6.92(s,1H),4.24(dd,J=12.9,21.6Hz,2H),3.94(d,J=11 .4Hz,1H),3.33-3.72(m,2H),3.06(s,4H),2.52(m,1H),2.93(t,J=11.6Hz,1H) ,1.70(s,4H),1.38(d,J=5.1Hz,3H),0.38(s,4H).m / z(ESI):553.1,555.1(M+H) + .

[0311] Step 5: A mixture of (R)-4-bromo-N-(6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.30 g, 0.54 mmol), methyl 2-sulfamoylacetate (0.125 g, 0.813 mmol), potassium phosphate (0.230 g, 1.08 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (0.039 g, 0.27 mmol), and copper(I) iodide (0.103 g, 0.542 mmol) in N,N-dimethylformamide (5 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 40% ethyl acetate in petroleum ether to give (R)-2-(N-(4-((6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)methyl acetate (0.25 g, 0.40 mmol, 74% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.21(s,1H),10.69(s,1H),8.04(d,J=8.6Hz,1H),7.77(s,1H),7.25(d,J=2.2Hz,1H ),7.12(dd,J=2.1,8.7Hz,1H),6.82(s,1H),4.45(s,2H),4.02-4.27(m,2H),3.90(dd ,J=3.4,11.5Hz,1H),3.51-3.65(m,4H),2.91-3.02(m,4H),2.55-2.64(m,1H),1.96( s,2H),1.66(s,4H),1.15(dd,J=4.3,6.7Hz,3H),0.34(s,4H).m / z(ESI):626.1(M+H) + .

[0312] Step 6: To a solution of (R)-2-(N-(4-((6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)methyl acetate (0.25 g, 0.40 mmol) in THF (5 mL) at −78 °C, LiBH (2.0 M in THF, 0.599 mL, 1.20 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was quenched with a saturated aqueous solution of NH Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by reverse-phase column chromatography eluting with a gradient of 0% to 60% acetonitrile in water to give (R)-4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)-4-(trifluoromethyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.10 g, 0.17 mmol, 42% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.22(s,1H),10.23(s,1H),8.07(d,J=8.6Hz,1H),7.83(s,1H),7.27(d,J=2.2Hz,1H),7. 13(dd,J=2.1,8.7Hz,1H),6.88(s,1H),4.94(s,1H),4.14-4.34(m,2H),3.93(d,J=10.7Hz ,1H),3.76(t,J=6.5Hz,2H),3.57(t,J=11.4Hz,2H),3.36(t,J=6.4Hz,2H),2.86-3.06(m, 5H),2.60(m,1H),1.71(s,4H),1.18(d,J=6.2Hz,3H),0.38(s,4H).m / z(ESI):598.2(M+H) + .

[0313] Example 21: N-(5-cyano-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 6-fluoropyridin-2-amine (5.0 g, 45 mmol, Combi-Blocks) and N-iodosuccinimide (10.5 g, 46.8 mmol) in acetonitrile (50 mL) was stirred at 10 °C for 30 min and then at room temperature for 1 h. The reaction mixture was concentrated, and the residue was diluted with water. The precipitate was filtered and purified by flash column chromatography eluting with 0% to 30% EtOAc in petroleum ether to give 6-fluoro-5-iodopyridin-2-amine (8.9 g, 37 mmol, 84% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.74(t,J=8.8Hz,1H),6.53(s,2H),6.19(dd,J=8.3,2.3Hz,1H).m / z(ESI):238.9(M+H) + .

[0314] Step 2: A mixture of 6-fluoro-5-iodopyridin-2-amine (1.0 g, 4.2 mmol), Zn(CN) (0.296 g, 2.52 mmol), Pd(dba) (0.192 g, 0.210 mmol), and dppf (0.233 g, 0.420 mmol) in dioxane (9 mL) and water (1 mL) was stirred at 100 °C for 16 h. The reaction mixture was filtered through a Celite bed, and the filtrate was washed with water, brine, dried over anhydrous NaSO, and concentrated. The concentrate was purified by flash column chromatography using 0% to 50% ethyl acetate in petroleum ether to give 6-amino-2-fluoronicotinonitrile (0.51 g, 3.7 mmol, 89% yield) as a brown solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.81(t,J=9.1Hz,1H),7.64(s,1H),7.51(s,2H).m / z(ESI):138.1(M+H) + .

[0315] Step 3: A mixture of 6-amino-2-fluoronicotinonitrile (0.50 g, 3.6 mmol), 4,4-difluoropiperidine hydrochloride (1.322 g, 8.39 mmol), and DIPEA (5.10 mL, 29.2 mmol) in DMSO (5 mL) was stirred for 16 h at 145° C. The reaction mixture was concentrated and purified by flash column chromatography eluting with 15% to 25% EtOAc in petroleum ether to afford 6-amino-2-(4,4-difluoropiperidin-1-yl)nicotinonitrile (0.60 g, 2.5 mmol, 69.1% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.52(d,J=8.4Hz,1H),6.82(s,2H),5.99(d,J=8.5Hz,1H),3.60-3.68(m,4H),2.00-2.10(m,4H).m / z(ESI):239.1(M+H) + .

[0316] Step 4: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.3 g, 0.967 mmol, Intermediate 9-1), oxalyl chloride (0.127 mL, 1.451 mmol), and DMF (1 drop) in dichloromethane (5 mL) was stirred at 0 °C for 2 h. The reaction mixture was concentrated, and the residue was dissolved in dioxane (10 mL). To the above solution was added a solution of 6-amino-2-(4,4-difluoropiperidin-1-yl)nicotinonitrile (0.230 g, 0.967 mmol) and triethylamine (0.404 mL, 2.90 mmol) in 1,4-dioxane (3 mL), and the resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 5% to 15% ethyl acetate in petroleum ether to give 4-bromo-N-(5-cyano-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.19 g, 0.36 mmol, 37% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.40(s,1H),8.14(d,J=8.4Hz,1H),8.03(d,J=8.5Hz,1H),7.84(d,J=8.5Hz,1H),7.73(d,J=2.0Hz,1 H),7.58(dd,J=8.5,1.9Hz,1H),3.76-3.83(m,4H),3.06(t,J=5.3Hz,4H),2.08-2.20(m,4H),1.68(br s,4H),0.39(s,4H).m / z(ESI):532.1(M+H) + .

[0317] Step 5: A mixture of 4-bromo-N-(5-cyano-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.19 g, 0.36 mmol), 2-hydroxyethane-1-sulfonamide (0.067 g, 0.54 mmol), tribasic potassium phosphate (0.152 g, 0.716 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.025 g, 0.18 mmol), and copper(I) iodide (0.068 g, 0.36 mmol) in N,N-dimethylformamide (3 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC using acetonitrile and 0.1% TFA in water to give N-(5-cyano-6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2,2,2-trifluoroacetate (0.040 g, 0.058 mmol, 16% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.45(s,1H),10.28(s,1H),8.09(dd,J=12.7,8.5Hz,2H),7.84(d,J=8.4Hz,1H),7.28(d,J=2.2Hz,1H),7.14(dd,J=8.7,2.1Hz,1H),4.95(br s,1H),3.72-3.82(m,6H),3.37(t,J=6.4Hz,2H),2.92-3.00(m,4H),2.08-2.18(m,4H),1.70(br s,4H),0.39(s,4H).m / z(ESI):575.2(M+H) + .

[0318] Example 22: N-(6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 6-bromo-5-methylpyridin-2-amine (650 mg, 3.48 mmol, Sibian Chemicals), 4,4-difluoropiperidine hydrochloride (1643 mg, 10.43 mmol, Combi-Blocks), and DIPEA (3035 μL, 17.38 mmol) in NMP (6.5 mL) was heated at 180 °C for 8 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 30% ethyl acetate in petroleum ether to give 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-amine (350 mg, 1.54 mmol, 44.3% yield) as a pale yellow gum. 1 H NMR(300MHz,DMSO-d6):δ ppm 7.12(dd,J=7.9,2.3Hz,1H),6.05(dd,J=8.0,2.2Hz,1H),5.47(s,2H),3.08(q,J=3.9,2.5Hz,4H),1.26-2.48(m,7H).m / z(ESI):228.1(M+H) + .

[0319] Step 2: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (573 mg, 1.85 mmol, Intermediate 9-1), triethylamine (644 μL, 4.62 mmol), T3P (50% in ethyl acetate, 1.47 g, 2.31 mmol), and 6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-amine (350 mg, 1.54 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 15% ethyl acetate in petroleum ether to give 4-bromo-N-(6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 0.96 mmol, 62.5% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.01(s,1H),8.04(d,J=8.6Hz,1H),7.85(d,J=8.0Hz,1H),7.67(d,J=2.0Hz,1H),7.15-7.66(m,2H),3.09-3.32(m ,4H),3.04(t,J=5.3Hz,4H),2.24(s,3H),1.91-2.23(m,4H),1.21-1.99(m,4H),0.38(s,4H).m / z(ESI):519.1(M+H) + .

[0320] Step 3: A mixture of 4-bromo-N-(6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.385 mmol), 2-hydroxyethane-1-sulfonamide (72.3 mg, 0.578 mmol), potassium phosphate tribasic (163 mg, 0.770 mmol), (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (27.4 mg, 0.193 mmol), and copper(I) iodide (73.3 mg, 0.385 mmol) in N,N-dimethylformamide (2 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 30% ethyl acetate in petroleum ether to give N-(6-(4,4-difluoropiperidin-1-yl)-5-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.177 mmol, 46.1% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.03(s,1H),10.21(br s,1H),8.07(d,J=8.6Hz,1H),7.86(d,J=8.0Hz,1H),7.57(d,J=8.1Hz,1H),7.26(d,J=2.2Hz,1H),7.12(dd,J=8.7,2.1Hz,1H),4.95(br s,1H),3.74-4.80(m,2H),3.36-3.40(m,2H),3.20-3.28(m,4H),2.92-3.02(m,4H),2 .24(s,3H),2.09-2.16(m,4H),1.70-1.90(m,4H),0.38(s,4H).m / z(ESI):564.2(M+H) + .

[0321] Example 23: N-(6-(4,4-difluorocyclohexyl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of 4,4-difluorocyclohexan-1-one (1.0 g, 7.5 mmol, Combi-Blocks) in THF (10 mL) was added LiHMDS (1.0 M in THF, 8.95 mL, 8.95 mmol) at −78° C. The reaction mixture was stirred for 1 h, and then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.93 g, 8.20 mmol) was added at −78° C. The resulting solution was gradually warmed to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, filtered, and concentrated. To a solution of the residue in 1,4-dioxane (20 mL) was added potassium acetate (1.46 g, 14.91 mmol), bispinacolatodiboron (2.272 g, 8.95 mmol), and PdCl(dppf) (0.546 g, 0.746 mmol). The reaction mixture was stirred at 100 °C for 16 h, then diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 20% ethyl acetate in petroleum ether to give 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 3.69 mmol, 49.5% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d): δ ppm 6.41 (t, J = 3.7 Hz, 1H), 2.53-2.68 (m, 2H), 2.43 (t, J = 6.7 Hz, 2H), 1.91-2.06 (m, 2H), 1.29 (s, 12H).

[0322] Step 2: A mixture of 6-bromo-4-methylpyridin-2-amine (800 mg, 4.28 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.148 g, 4.70 mmol), tribasic potassium phosphate (1907 mg, 8.98 mmol), and PdCl(dppf)-CHCl adduct (349 mg, 0.428 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 20% to 30% ethyl acetate in petroleum ether to give 6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-amine (800 mg, 3.57 mmol, 83% yield) as a brown gummy solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 6.49(d,J=2.4Hz,1H),6.41(dt,J=5.0,3.0Hz,1H),6.18(s,1H),5.73(s,2H) ),2.59-2.77(m,4H),2.12(s,3H),2.0-2.10(m,2H).m / z(ESI):225.1(M+H) + .

[0323] Step 3: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 0.645 mmol, Intermediate 9-1), DIPEA (338 μL, 1.93 mmol), HATU (368 mg, 0.967 mmol), and 6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-amine (217 mg, 0.967 mmol) in DMF (5 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 10% to 20% ethyl acetate in petroleum ether to give 4-bromo-N-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.290 mmol, 45.0% yield) as a gray solid. 1 H NMR (300MHz, chloroform-d): δ ppm 13.21(s,1H),8.09-8.26(m,2H),7.37-7.55(m,2H),7.04(t,J=1.0Hz,1H),6.52-6.60(m,1H),3.10(t,J=5.4Hz, 4H),2.74-2.90(Wm,4H),2.40(s,3H),2.14-2.28(m,2H),1.70-1.90(m,4H),0.43(s,4H).m / z(ESI):516.1(M+H) + .

[0324] Step 4: A mixture of 4-bromo-N-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.290 mmol), 2-hydroxyethane-1-sulfonamide (54 mg, 0.436 mmol), tribasic potassium phosphate (154 mg, 0.726 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (21 mg, 0.145 mmol), and copper(I) iodide (55.3 mg, 0.290 mmol) in DMF (5 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 30% to 40% ethyl acetate in petroleum ether to give N-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.268 mmol, 92% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.35(s,1H),8.02-8.12(m,2H),7.96(s,1H),7.27(s,1H),7.22(s,1H) ,7.13(d,J=8.9Hz,1H),6.63(m,1H),3.76(d,J=6.6Hz,2H),2.99(s,2H) ,2.90(s,4H),2.81(s,1H),2.74(s,1H),2.47(d,J=2.4Hz,2H),2.37(s, 2H),2.19(s,3H),1.70-1.90(m,4H),0.40(s,4H).m / z(ESI):561.2(M+H) + .

[0325] Step 5: A mixture of N-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.178 mmol) and 10% Pd / C (50 mg, 0.047 mmol) in ethanol (5 mL) was stirred under a hydrogen atmosphere (14 psi) at room temperature for 6 h. The reaction mixture was filtered through a Celite bed. The filtrate was concentrated, and the residue was triturated with diethyl ether and hexanes to give N-(6-(4,4-difluorocyclohexyl)-4-methylpyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (10.6 mg, 0.019 mmol, 1011% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.28(s,1H),7.98(t,J=6.0Hz,2H),7.15(d,J=2.2Hz,1H),6.98-7.05(m,1H),6.86(s,1H),3.73(t,J=6.6Hz,2H),3.24(t,J=6.6Hz, 2H),2.95(d,J=5.5Hz,4H),2.72-2.80(m,1H),2.31(s,3H),1.90-2.12(m,8H),1.70-1.84(m,4H),0.36(s,4H).m / z(ESI):563.2(M+H) + .

[0326] Example 24: (R)—N-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 6-bromo-5-fluoropicolinic acid (3.0 g, 14 mmol, Combi-Blocks), (R)-2-methylmorpholine hydrochloride (2.25 g, 16.36 mmol, Combi-Blocks), potassium acetate (2.94 g, 30.0 mmol), and copper powder (0.867 g, 13.6 mmol) in 1,4-dioxane (15 mL) was stirred at 90° C. for 16 h. The reaction mixture was filtered through a bed of Celite, diluted with water, and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 40% to 75% ethyl acetate in petroleum ether to give (R)-5-fluoro-6-(2-methylmorpholino)picolinic acid (1.3 g, 5.4 mmol, 40% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.91(bs,1H),7.65(dd,J=13.1,8.1Hz,1H),7.54(dd,J=8.0,3.0Hz,1H),3.94(t,J=2.2Hz,1H),3.80-3.92(m,2H),3.64(tdd,J=11. 9,5.7,2.6Hz,2H),2.96(ddd,J=12.9,11.7,3.4Hz,1H),2.65(dd,J=12.8,10.2Hz,1H),1.15(d,J=6.2Hz,3H).m / z(ESI):241.1(M+H) + .

[0327] Step 2: A mixture of (R)-5-fluoro-6-(2-methylmorpholino)picolinic acid (1.3 g, 5.4 mmol), triethylamine (1.095 g, 10.82 mmol), and diphenylphosphorazidate (1.787 g, 6.49 mmol) in tert-butanol (13 mL) was stirred at 90° C. for 16 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a gradient of 0% to 30% ethyl acetate in petroleum ether to give tert-butyl (R)-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)carbamate (1.2 g, 3.8 mmol, 71% yield) as a pale yellow solid. 1 H NMR(300MHz,DMSO-d6)δ ppm 9.91(s,1H),7.40-7.58(m,1H),7.20(d,J=19.6Hz,1H),3.82-3.94(m,1H),3.67-3.80(m,2H),3.58-3.69(m,2H),2. 83-3.09(m,1H),2.63(dt,J=12.2,9.5Hz,1H),1.20(d,J=18.9Hz,9H),1.12(d,J=6.2Hz,3H).m / z(ESI):312.1(M+H) + .

[0328] Step 3: To a solution of tert-butyl (R)-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)carbamate (1.2 g, 3.8 mmol) in dichloromethane (12 mL) was added hydrochloric acid in 1,4-dioxane (10 mL, 20 mmol) at 0 °C and stirred at room temperature for 4 h. The reaction mixture was concentrated, and the residue was diluted with ice water (50 mL), basified (pH 9) with 10% aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 40% to 60% ethyl acetate in petroleum ether to give (R)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine (0.63 g, 3.0 mmol, 77% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.28-7.43(m,1H),7.18(t,J=7.7Hz,1H),6.07(dd,J=8.5,2.1Hz,2H),3.85(dd,J=11.5,3.1Hz,1H),3.60-3.83(m,2 H),3.58(dd,J=11.7,2.7Hz,2H),2.92(td,J=12.2,3.3Hz,1H),2.61(dd,J=12.7,10.2Hz,1H),1.11(d,J=6.1Hz,3H). m / z(ESI):212.1(M+H) + .

[0329] Step 4: To a solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (1.057 g, 3.41 mmol, Intermediate 9-1) in CHCl (10 mL), DIPEA (1.101 g, 8.52 mmol), T3P (2.71 g, 4.26 mmol, 50% in EtOAc), and (R)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine (0.60 g, 2.8 mmol) were added at room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted with CHCl. ​​The organic extract was washed with brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 60% to 80% ethyl acetate in petroleum ether to give (R)-4-bromo-N-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.38 g, 0.76 mmol, 27% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.01(s,1H),8.04(d,J=8.4Hz,1H),7.75(dd,J=8.5,2.5Hz,1H),7.69(d,J=1. 9Hz,1H),7.44-7.66(m,2H),3.89(d,J=13.1Hz,1H),3.83(d,J=11.7Hz,2H),3. 67(t,J=10.9Hz,2H),3.05(d,J=6.1Hz,4H),2.95(t,J=10.8Hz,1H),2.60-2.68 (m,1H),1.70(s,4H),1.16(d,J=6.2Hz,3H),0.39(s,4H).m / z(ESI):504.1(M+H) + .

[0330] Step 5: A mixture of (R)-4-bromo-N-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (380 mg, 0.755 mmol), methyl 2-sulfamoylacetate (139 mg, 0.906 mmol), potassium phosphate (320 mg, 1.51 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (129 mg, 0.906 mmol), and copper(I) iodide (28.8 mg, 0.151 mmol) in N,N-dimethylformamide (3.8 mL) was stirred at 90° C. for 6 h. The reaction mixture was filtered through a Celite bed, diluted with water, and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 40% to 70% ethyl acetate in petroleum ether to give methyl (R)-2-(N-(4-((5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ate (200 mg, 0.347 mmol, 46.0% yield) as a pale yellow gummy liquid. 1 H NMR(400MHz,DMSO-d6)δ ppm 13.03(d,J=4.4Hz,1H),10.66(s,1H),8.09(d,J=8.6Hz,1H),7.71-7.95(m,1H),7.58(dd,J =12.8,8.6Hz,1H),7.28(dd,J=11.2,2.2Hz,1H),7.14(ddd,J=7.3,5.5,1.9Hz,1H),4.41(s, 1H),4.03(q,J=7.1Hz,2H),3.80-3.97(m,3H),3.65-3.67(m,2H),3.60(s,3H),2.93-2.99( m,3H),1.99(s,2H),1.73(s,4H),1.16(d,J=5.8Hz,3H),0.40(s,4H).m / z(ESI):576.2(M+H) + .

[0331] Step 6: To a solution of methyl (R)-2-(N-(4-((5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)ate (200 mg, 0.347 mmol) in THF (4 mL) at 0° C. was added lithium borohydride (2.0 M in THF, 0.521 mL, 1.04 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 40% to 80% ethyl acetate in petroleum ether to give (R)-N-(5-fluoro-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (70 mg, 0.13 mmol, 37% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.76-13.48(m,1H),10.22(s,1H),7.88-8.42(m,1H),7.76(dt,J=9.3,4.6Hz,1H),7.57(ddt,J=12.9,9.1,3.9Hz,1H),7.27(d,J=6.1Hz,1 H),7.13(q,J=7.8,5.2Hz,1H),4.95(s,1H),3.91(s,1H),3.79-3.81(m,4H),3.68(s,4H),2.91-2.97(m,5H),2.64(d,J=9.0Hz,1H),1.86(br s,4H),0.95-1.31(m,3H),0.38(br s,4H).m / z(ESI):548.2(M+H) + .

[0332] Example 25: (R)—N-(4-cyano-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: A mixture of 2,6-dichloroisonicotinonitrile (3.0 g, 17 mmol, Combi-Blocks), (4-methoxyphenyl)methanamine (2.379 g, 17.34 mmol), and DIPEA (3.03 mL, 17.34 mmol) in dimethyl sulfoxide (30 mL) was stirred at 110 °C for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 20% ethyl acetate in petroleum ether to give 2-chloro-6-((4-methoxybenzyl)amino)isonicotinonitrile (3.8 g, 14 mmol, 80% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.96-8.02(m,1H),7.22-7.30(m,2H),6.94,(s,1H),6.86-6.92(m,2H), 6.84(s,1H),4.36(d,J=5.8Hz,2H),3.72(s,3H).m / z(ESI):274.1(M+H) + .

[0333] Step 2: A mixture of 2-chloro-6-((4-methoxybenzyl)amino)isonicotinonitrile (1.85 g, 6.76 mmol), (R)-2-methylmorpholine hydrochloride (2.139 g, 15.55 mmol, Combi-Blocks), and DIPEA (9.44 mL, 54.1 mmol) in ethanol (20 mL) was stirred at 150 °C for 76 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a gradient of 0% to 10% ethyl acetate in petroleum ether to give (R)-2-((4-methoxybenzyl)amino)-6-(2-methylmorpholino)isonicotinonitrile (0.59 g, 1.7 mmol, 26% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6):δ ppm 7.28(br s,1H),7.22-7.24(m,2H),6.83-6.91(m,2H),6.21(s,1H),6.06(s,1H),4.35(d,J=5.9Hz,2H),3.97-4.10(m,2H),3.80-3.88(m,1H),3. 72(s,3H),3.39-3.52(m,2H),2.75(td,J=12.3,3.5Hz,1H),2.42(dd,J=12.8,10.4Hz,1H),1.12(d,J=6.2Hz,3H).m / z(ESI):339.2(M+H) + .

[0334] Step 3: A mixture of (R)-2-((4-methoxybenzyl)amino)-6-(2-methylmorpholino)isonicotinonitrile (0.59 g, 1.7 mmol) and TFA (2.821 mL, 36.61 mmol) in dichloromethane (6 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated, neutralized (pH 7) with 10% NaHCO solution, and extracted with dichloromethane. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 20% ethyl acetate in petroleum ether to give (R)-2-amino-6-(2-methylmorpholino)isonicotinonitrile (0.325 g, 1.49 mmol, 85% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 6.23(s,1H),6.15(s,2H),5.97(s,1H),4.07(dt,J=12.7,2.1Hz,1H),3.92-4.02(m,2H),3.38-3.53( m,2H),2.72(td,J=12.2,3.6Hz,1H),2.34-2.42(m,1H),1.10(d,J=6.2Hz,3H).m / z(ESI):219.1(M+H) + .

[0335] Step 4: A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.25 g, 0.81 mmol, Intermediate 9-1), DIPEA (0.422 mL, 2.42 mmol), T3P (50% in ethyl acetate, 1.539 g, 2.418 mmol), and (R)-2-amino-6-(2-methylmorpholino)isonicotinonitrile (0.211 g, 0.967 mmol) in dichloromethane (4 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 20% ethyl acetate in petroleum ether to give (R)-4-bromo-N-(4-cyano-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.263 g, 0.515 mmol, 63.9% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.21(s,1H),8.00-8.10(m,1H),7.76(s,1H),7.71(d,J=1.9Hz,1H),7.57(dd,J=8.5,1.9Hz,1H),7.13(s,1H),4.23(d,J=12.8Hz,1H) ),4.17(d,J=12.9Hz,1H),3.93(d,J=9.9Hz,1H),3.50-3.61(m,2H),3.0-3.08(m,4H),2.89-2.99(m,1H),2.58-2.64(m,1H),1.68(br s,4H),1.17(d,J=6.2Hz,3H),0.37(s,4H).m / z(ESI):512.2(M+H) + .

[0336] Step 5: A mixture of (R)-4-bromo-N-(4-cyano-6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (260 mg, 0.509 mmol), methyl 2-sulfamoylacetate (156 mg, 1.02 mmol), potassium phosphate tribasic (216 mg, 1.02 mmol), copper(I) iodide (194 mg, 1.02 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (72.4 mg, 0.509 mmol) in DMF (2 mL) was stirred at 90° C. for 16 h. The reaction mixture was filtered through a Celite pad. The filtrate was washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by flash column chromatography using a 40% gradient of EtOAc in petroleum ether to afford (R)-2-(N-(4-((4-cyano-6-(2-methylmorpholino)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)methyl acetate (250 mg, 0.429 mmol, 84% yield) as a pale yellow gum. m / z (ESI): 583.2 (M+H). + .

[0337] Step 6: To a solution of (R)-2-(N-(4-((4-cyano-6-(2-methylmorpholino)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)methyl acetate (250 mg, 0.429 mmol) in THF (2 mL) at −30° C. was added LiBH (2.0 M in THF, 429 μL, 0.858 mmol). The mixture was then stirred at 0° C. for 30 min. The reaction mixture was quenched with a saturated aqueous solution of NH Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 20% to 50% ethyl acetate in petroleum ether to give (R)-N-(4-cyano-6-(2-methylmorpholino)pyridin-2-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 0.216 mmol, 50.4% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.25(s,1H),10.23(br s,1H),8.07(dd,J=8.7,2.9Hz,1H),7.78(d,J=2.8Hz,1H),7.28(d,J=3.1Hz,1H),7.07-7.17(m,2H),4.96(br s,1H),4.13-4.26(m,2H),3.93(d,J=11.4Hz,1H),3.76(td,J=6.6,2.5Hz,2H),3.57(d,J =11.7Hz,2H),3.37(dd,J=6.7,2.7Hz,2H),2.88-3.02(m,5H),2.54-2.62(m,1H),1.71(br s,4H),1.17(d,J=6.3Hz,3H),0.39(s,4H).m / z(ESI):555.2(M+H) + .

[0338] Example 26: 4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide [ka] Step 1: To a solution of 6-fluoropyridin-2-amine (5.0 g, 45 mmol, Apollo Scientific) in dichloromethane (100 mL) was added EtN (15.54 mL, 112 mmol) and acetyl chloride (4.76 mL, 66.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, then diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0% to 20% ethyl acetate in petroleum ether to give N-(6-fluoropyridin-2-yl)acetamide (4.0 g, 26 mmol, 58% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 10.65(s,1H),7.93-8.01(m,2H),6.29(d,J=2.6Hz,1H),2.09(s,3H).m / z(ESI):155.1(M+H) + .

[0339] Step 2: A mixture of N-(6-fluoropyridin-2-yl)acetamide (4.0 g, 26 mmol), cesium carbonate (16.91 g, 51.9 mmol), and 2-methylpropane-2-thiol (3.51 g, 38.9 mmol) in DMF (60 mL) was stirred at 80° C. for 24 h. The reaction mixture was quenched with ice-cold water, and the precipitated solid was filtered and dried to give N-(6-(tert-butylthio)pyridin-2-yl)acetamide (4.0 g, 18 mmol, 69% yield) as an off-white solid. 1H NMR(400MHz,DMSO-d6):δ ppm 10.34(s,1H),7.86(d,J=8.5Hz,1H),7.61(t,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),2.11(s,3H),1.48(s,9H).m / z(ESI):225.1(M+H) + .

[0340] Step 3: To a solution of N-(6-(tert-butylthio)pyridin-2-yl)acetamide (3.5 g, 16 mmol) in dichloromethane (75 mL) at 0 °C was added m-CPBA (75%, 3.59 g, 15.6 mmol) and stirred at room temperature for 16 h. The reaction mixture was quenched with 10% sodium bicarbonate and extracted with dichloromethane. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and triturated with diethyl ether to give N-(6-(tert-butylsulfinyl)pyridin-2-yl)acetamide (3.3 g, 13 mmol, 88% yield) as a white solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 10.68(s,1H),8.18(d,J=8.3Hz,1H),8.03(t,J=8.0Hz,1H),7.52(d,J=7.5Hz,1H),2.12(s,3H),1.15(s,9H).m / z(ESI):241.1(M+H) + .

[0341] Step 4: A mixture of N-(6-(tert-butylsulfinyl)pyridin-2-yl)acetamide (3.3 g, 13 mmol), iodobenzene diacetate (17.69 g, 54.9 mmol), and ammonium carbonate (5.36 g, 68.7 mmol) in methanol (75 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was treated with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and triturated with diethyl ether to give N-(6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)acetamide (2.1 g, 8.2 mmol, 60% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 10.82(s,1H),8.29(d,J=8.4Hz,1H),8.03(t,J=8.0Hz,1H),7.75(dd,J=7.6,0.9Hz,1H),4.11(s,1H),2.14(s,3H),1.29(s,9H).

[0342] Step 5: A solution of N-(6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)acetamide (2.24 g, 8.77 mmol), imidazole (1.194 g, 17.55 mmol), DMAP (0.536 g, 4.39 mmol), and TBS-Cl (1.587 g, 10.53 mmol) in CHCl (50 mL) was stirred at room temperature for 2.5 h. The reaction mixture was quenched with cold water and extracted with CHCl. ​​The organic extract was washed with water, brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography using a 15% gradient of EtOAc in petroleum ether to afford N-(6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)acetamide (2.7 g, 7.3 mmol, 83% yield) as a white solid. 1H NMR(400MHz,DMSO-d6):δ ppm 10.70(s,1H),8.27(d,J=8.4Hz,1H),8.01-8.07(m,1H),7.68(d,J=7.6Hz,1H),2.1 5(s,3H),1.28(s,9H),0.86(s,9H),-0.07(d,3H),-0.11(d,3H).m / z(ESI):256(M-2 t Bu) + .

[0343] Step 6: A mixture of N-(6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)acetamide (1.5 g, 4.1 mmol) and aqueous sodium hydroxide (2.5 M, 32.5 mL, 81 mmol) in methanol (30 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated and the residue was treated with water. The precipitated solid was filtered and dried to give (6-aminopyridin-2-yl)(tert-butyl)((tert-butyldimethylsilyl)imino)-λ 6 -sulfanone (1.2 g, 3.7 mmol, 90% yield) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.58(t,J=7.8Hz,1H),7.09(d,J=7.3Hz,1H),6.60(d,J=8.3Hz,1H),6.35(s,2H ),1.26(s,9H),0.85(s,9H),-0.07(s,3H),-0.13(s,3H).m / z(ESI):214.1(M-2 t Bu) + .

[0344] Step 7: 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.50 g, 1.6 mmol, Intermediate 9-1), DIPEA (0.845 mL, 4.84 mmol), T3P (50% solution in ethyl acetate, 3.08 g, 4.84 mmol), and (6-aminopyridin-2-yl)(tert-butyl)((tert-butyldimethylsilyl)imino)-λ in dichloromethane (10 mL).6 A mixture of 4-bromo-N-(6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.32 mmol, 20% yield) was stirred at room temperature for 48 h. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography eluting with a gradient of 0 to 15% ethyl acetate in petroleum ether to give 4-bromo-N-(6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.32 mmol, 20% yield) as a pale yellow gum. 1 H NMR(400MHz,DMSO-d6):δ ppm 12.86(s,1H),8.51(d,J=8.4Hz,1H),8.13(t,J=8.0Hz,1H),8.00(d,J=8.4Hz,1H),7.77(d,J =7.6Hz,1H),7.68(d,J=1.8Hz,1H),7.55(dd,J=8.5,1.8Hz,1H),2.97-3.10(m,4H),1.60(br s,4H),1.33(s,9H),0.82(s,9H),0.33(s,4H),-0.12(s,3H).-0.14(s,3H).m / z(ESI):507.0(M-2 t Bu) + .

[0345] Step 8: A mixture of 4-bromo-N-(6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.20 g, 0.32 mmol), methyl 2-sulfamoylacetate (0.074 g, 0.48 mmol), potassium phosphate tribasic (0.137 g, 0.645 mmol), copper(I) iodide (0.061 g, 0.32 mmol), and (1R,2R)-N,N′-dimethyl-1,2-cyclohexanediamine (0.023 g, 0.16 mmol) in DMF (4 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl 2-(N-(4-((6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.18 g, 0.26 mmol, 81% yield) as a pale yellow gum. m / z (ESI): 692.2 (M+H). + .

[0346] Step 9: A mixture of methyl 2-(N-(4-((6-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.18 g, 0.260 mmol) and tetrabutylammonium fluoride (1 M solution in THF, 0.390 mL, 0.390 mmol) in THF (4 mL) was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to give methyl 2-(N-(4-((6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.10 g, 0.17 mmol, 66% yield) as a pale yellow gum. m / z (ESI): 578.1 (M+H). + .

[0347] Step 10: To a solution of methyl 2-(N-(4-((6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.10 g, 0.17 mmol) in THF (3 mL) at 0 °C was added LiBH (2.0 M solution in THF, 0.173 mL, 0.346 mmol) and stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC to give 4-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylpropan-2-ylsulfonimidoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.016 g, 0.029 mmol, 16% yield) as a white solid. 1H NMR(400MHz,DMSO-d6):δ ppm 13.16(s,1H),10.26(s,1H),8.53(d,J=8.4Hz,1H),8.17-8.05(m,2H),7.82(dd ,J=7.5,0.9Hz,1H),7.29(d,J=2.2Hz,1H),7.14(dd,J=8.6,2.1Hz,1H),4.95(br s,1H),4.04(s,1H),3.76-3.80(m,2H),3.37(t,J=6.5Hz,2H),2.99(t,J=5.4 Hz,4H),1.60-1.70(m,3H),1.35(s,9H),0.36(s,4H).m / z(ESI):550.2(M+H) + .

[0348] Examples 27-1 and 27-2: 2-(6-azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(6-(3,3,3-trifluoropropoxy)-2-pyridinyl)benzamide and 2-(6-azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(6-(3,3,3-trifluoropropoxy)-2-pyridinyl)benzamide [ka] A mixture of 4-(cyclopropanesulfonimidoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.200 g, 0.598 mmol, Intermediate 16), 6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.160 g, 0.78 mmol, Intermediate 6), TATU (0.250 g, 0.776 mmol, Combi-Blocks), DMF (6 mL), and DIPEA (0.309 g, 0.426 mL, 2.39 mmol, Aldrich) was stirred at room temperature for 18 h. The mixture was diluted with saturated Na2CO3 and EtOAc. The organic phase was washed with Na2CO3, water, and brine, dried over Na2SO4, and concentrated in vacuo. The crude reaction was purified by silica gel chromatography (0 to 100% EtOAc in heptane). The reaction product was obtained as an off-white solid. m / z (ESI): 523.1 (M+H) + The racemic mixture was purified by chiral SFC (Regis (S,S) Whelk-01 (250 × 21 mm, 5 mm), mobile phase: 65% liquid CO 2 and 35% MeOH, flow rate: 80 mL / min).

[0349] Example 27-1: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfonimidoyl)-N-(6-(3,3,3-trifluoropropoxy)-2-pyridinyl)benzamide. First eluting peak (68 mg, ee>99%). 1H NMR(400MHz,chloroform-d)δ 12.92(s,1H),8.45(d,J=8.29Hz,1H),8.00(d,J=7.67Hz,1H),7.95(d,J=1.66Hz,1H),7.85(dd,J= 1.76,8.19Hz,1H),7.66(t,J=7.88Hz,1H),6.55(d,J=8.09Hz,1H),4.54(t,J=6.63Hz,2H),3.15(t ,J=5.29Hz,4H),2.55-2.72(m,3H),1.66-1.98(m,5H),1.46(tdd,J=5.05,6.87,10.18Hz,1H),1.2 4(tdd,J=4.90,6.95,10.21Hz,1H),1.13(dq,J=5.18,7.95Hz,1H),0.94-1.04(m,1H),0.42(s,4H). 19 F NMR (377 MHz, chloroform-d) δ −64.71 (s, 3F).

[0350] Example 27-2: 2-(6-Azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfonimidoyl)-N-(6-(3,3,3-trifluoropropoxy)-2-pyridinyl) second eluting peak (67 mg, ee, 99.3%). 1 H NMR(400MHz,chloroform-d)δ 12.92(s,1H),8.45(d,J=8.29Hz,1H),8.00(d,J=7.88Hz,1H),7.95(d,J=1.66Hz,1H),7 .85(dd,J=1.66,8.29Hz,1H),7.66(t,J=7.98Hz,1H),6.55(d,J=8.09Hz,1H),4.54(t,J= 6.74Hz,2H),3.15(t,J=5.29Hz,4H),2.54-2.73(m,3H),1.69-1.80(m,4H),1.41-1.49(m ,1H),1.19-1.29(m,2H),1.08-1.17(m,1H),0.98(dq,J=5.29,7.98Hz,1H),0.42(s,4H). 19 F NMR (376 MHz, chloroform-d) δ −64.70 (s, 3F).

[0351] The stereochemistry was arbitrarily assigned.

[0352] [Table 39]

[0353] Example 31: 4-(Azetidin-3-ylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(3,3,3-trifluoropropoxy)pyridin-2-yl)benzamide trifluoroacetate [ka] Step-1: A mixture of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.200 g, 0.444 mmol, Intermediate 15), 6-(3,3,3-trifluoropropoxy)pyridin-2-amine (0.119 g, 0.577 mmol, Intermediate 6), DMF (4 mL), Hunig's base (0.229 g, 0.316 mL, 1.78 mmol, Aldrich), and TATU (0.250 g, 0.776 mmol, Combi-Blocks) was stirred at room temperature overnight. The mixture was diluted with saturated Na2CO3 and EtOAc. The organic phase was removed, washed with Na2CO3, water, and brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (0-100% EtOAc-heptane) afforded tert-butyl 3-((3-(6-azaspiro[2.5]octan-6-yl)-4-((6-(3,3,3-trifluoropropoxy)pyridin-2-yl)carbamoyl)phenyl)sulfonyl)azetidine-1-carboxylate as an off-white solid. m / z (ESI): 639.2 (M+H). + .

[0354] Step-2: tert-Butyl 3-((3-(6-azaspiro[2.5]octan-6-yl)-4-((6-(3,3,3-trifluoropropoxy)pyridin-2-yl)carbamoyl)phenyl)sulfonyl)azetidine-1-carboxylate (0.118 g, 0.184 mmol) was dissolved in DCM (8 mL) and TFA (4 mL). The reaction mixture was stirred at RT for 30 min and concentrated in vacuo. EtOAc was added to the TFA salt and evaporated. The product was obtained as an off-white solid. 1 H NMR(400MHz, methanol-d4)δ 8.38(d,J=8.09Hz,1H),7.90-7.96(m,2H),7.85(dd,J=1.66,8.29Hz,1H),7.74(t,J=7.98Hz,1H),6.60(d,J =8.09Hz,1H),4.57(t,J=6.32Hz,2H),4.42(d,J=7.46Hz,4H),3.14-3.23(m,4H),2.66-2.80(m,2H),1.81(br s,4H),0.44(s,4H). 19 F NMR (376 MHz, methanol-d4) δ -66.16 (s, 3F), -76.96 (s, 3F). m / z (ESI): 539.2 (M+H) + .

[0355] Biological Experiment Examples The following assays were used to test representative example compounds of the present invention. Data for those examples tested according to the procedures described below are set forth in Table A below.

[0356] KIF18A enzyme assay: Microtubule-induced ATPase activity assays were used to measure KIF18A enzyme activity after compound treatment. Compounds were serially diluted 2-fold in DMSO (Sigma Inc.) over a 22-point concentration range. Recombinant human KIF18A (1-467His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography (Amgen Inc.). The concentrations of KIF18A protein, microtubules (MTs), and ATP in the reaction were optimized for a standardized homogeneous enzyme assay using the ADP-Glo™ Kinase / ATPase Assay Kit (Promega Inc.). The assay measures ADP formed from the ATPase reaction. A 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 μM Taxol (Cytoskeleton Inc), and 30 μg / mL pigeonhole microtubules (Cytoskeleton Inc)) was prepared. Compounds and KIF18A protein (30 nM) were added to the prepared reaction buffer and incubated at room temperature for 15 min. ATP (Km, 75 μM) was then added to the reaction mixture and incubated at room temperature for an additional 15 min. 5 μL of ADP-Glo™ reagent was mixed with 2.5 μL of the reaction mixture and incubated at room temperature for 40 min. 10 μL of ADP-Glo™ detection reagent was added and incubated at room temperature for 40 min. An EnVJision microreader (Perkin Elmer) equipped with an ultra-luminescence module was used. Luminescence is read using a chromatograph (Inc). Concentration-response curve fitting and IC 50 Quantification of was performed using Genedata Screener Software (Standard 15.0.1, Genedata Inc) using a four-parameter logistic regression fitting model.

[0357] In Table A, data for compounds exemplified in this application and its priority documents are provided as representative compounds of the invention, as compound names and biological data, as follows (IC 50 The unit is uM (if available). Example # refers to the example number.

[0358] [Table 40]

[0359] [Table 41]

[0360] [Table 42]

[0361] [Table 43]

[0362] [Table 44]

[0363] [Table 45]

[0364] [Table 46]

[0365] [Table 47]

[0366] [Table 48]

[0367] [Table 49]

[0368] [Table 50]

[0369] [Table 51]

[0370] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. Those skilled in the art will understand that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the foregoing description is illustrative and not limiting. The scope of the invention should, therefore, be determined not with reference to the foregoing description, but instead with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

[0371] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication was individually indicated to be so incorporated.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, X １ is N or -CR ６ and R １ is the group -Z-R １２ where Z is -C ０～４ alk-, -NR １１ -, -NR １１ SO ２ -C ０～４ alk-, -SO ２ NR １１ -C ０～４ alk-, -NR １１ SO ２ NR １１ -, -NR １１ SO ２ NR １１ -C (=O) -O-, -C ０～４ alk-S(=O)(=NH)-,C ０～４ alk-NR １１ -S (=O) (=NH), -C ０～４ alk-S-, -C ０～４ alk-S(=O)-,-C ０～４ alk-SO ２ -, C ０～４ alk-O-, -P-, -P(=O), -P(=O) ２ , -(C=O)-, -(C=O)NR １１ -, -C=N(OH)-, or -NR １１ (C=O); Or, The group -Z-R １２ -N=S(=O)-(R １２ ) ２ where two R １２ may alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R ２ is a halo or group -Y-R １３ where Y is -C ０～４ alk-, -N(C ０～１ alk)-C ０～４ alk-, -C(=O)NR ａ R ａ (C １～４ alk)-, -OC ０～４ alk-, -S-, -S=O, -S(=O) ２ -, -SO ２ N (C ０～１ alk)-C ０～４ alk-, -N(C ０～１ alk)-SO ２ -C ０～４ alk-, -C ０～４ alk-S(=O)(=NH)-, -(C=O)-, -C ０～４ alk-(C═O)—O—; or The group -Y-R １３ -N=S(=O)-(R １３ ) ２ where two R １３ may alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R ３ is H, methyl, or ethyl; R ４ H, halo, CN, C １～４ alk, or C １～４ haloalk; R ５ is H, halo, C １～８ alk, or C １～４ haloalk; R ６ H, halo, CN, C １～８ alk, C １～４ haloalk, -O-C ０～６ alk- or R ６ａ and R ７ is H, halo, C １～８ alk, or C １～４ haloalk; R ８ is H, halo, C １～８ alk, or C １～４ haloalk; R ９ is H, halo, C １～８ alk, or C １～４ haloalk; R ｘ is selected from the group consisting of: 【Chemistry 2】 R １０ａ , R １０ｂ , R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｇ , R １０ｈ , R １０ｉ , and R １０ｊ Each of these is H, halo, and R １０ｋ , or R １０ｌ Is it; Or, alternatively, R １０ａ and R １０ｂ Pair with R １０ｃ and R １０ｄ Pair with R １０ｅ and R １０ｆ Pair with R １０ｇ and R １０ｈ Pair with or R １０ｉ and R １０ｊ and each pair of independently bonded to the carbon atom to which it is bonded, R ｘ and wherein said 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further wherein said 3-, 4-, 5-, or 6-membered monocyclic ring is selected from F, Cl, Br, C １～６ alk, C １～４ haloalk, -OR ａ , -OC １～４ haloalk, CN, -NR ａ R ａ or oxo; R １１ is H or C １～８ alk; R １２ is H, R １２ａ , or R １２ｂ and R １３ is R １３ａ or R １３ｂ and R ６ａ , R １０ｋ , R １２ａ , and R １３ａ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings, which in each instance contain 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and which are substituted by 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C １～６ alk, C １～４ haloalk, -OR ａ , -OC １～４ haloalk, CN, -C(=O)R ｂ , -C(=O)OR ａ , —C(═O)NR ａ R ａ , -C(=NR ａ ) NR ａ R ａ , —OC(═O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２～６ alkNR ａ R ａ , -OC ２～６ alkOR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR ａ R ａ , -NR ａ R ａ , -N(R ａ ) C(=O)R ｂ , -N(R ａ ) C(=O) OR ｂ , -N(R ａ )C(=O)NR ａ R ａ , -N(R ａ ) C(=NR ａ ) NR ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ 、 -N(R ａ )S(=O) ２ NR ａ R ａ 、 -NR ａ C ２～６ alkNR ａ R ａ 、 -NR ａ C ２～６ alkOR ａ 、 -C １～６ alkNR ａ R ａ 、 -C １～６ alkOR ａ 、 -C １～６ alkN(R ａ )C(=O)R ｂ 、 -C １～６ alkOC(=O)R ｂ 、 -C １～６ alkC(=O)NR ａ R ａ 、 -C １～６ alkC(=O)OR ａ 、 R １４ 、 and oxo; R １０ｌ , R １２ｂ , and R １３ｂ is independently, at each occurrence, F, Cl, Br, —C(═O)OR ａ , -OR ａ , -C １～２ haloalk, -OC １～４ haloalk, CN, NH ２ , NH(CH ３ ), or N(CH ３ ) ２ C substituted by 0, 1, 2, 3, 4, or 5 groups selected from １～６ alk is selected from the group consisting of; R １４ is independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings, which in each instance contain 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and which are substituted by 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C １～６ alk, C １～４ haloalk, -OR ａ , -OC １～４ haloalk, CN, -C(=O)R ｂ , -C(=O)OR ａ , —C(═O)NR ａ R ａ , -C(=NR ａ ) NR ａ R ａ , —OC(═O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２～６ alkNR ａ R ａ , -OC ２～６ alkOR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ NR ａ R ａ , -NR ａ R ａ , -N(R ａ ) C(=O)R ｂ , -N(R ａ ) C(=O) OR ｂ , -N(R ａ )C(=O)NR ａ R ａ , -N(R ａ ) C(=NR ａ ) NR ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ , -N(R ａ ) S(=O) ２ NR ａ R ａ 、 -NR ａ C ２～６ alkNR ａ R ａ 、 -NR ａ C ２～６ alkOR ａ 、 -C １～６ alkNR ａ R ａ 、 -C １～６ alkOR ａ 、 -C １～６ alkN(R ａ )C(=O)R ｂ 、 -C １～６ alkOC(=O)R ｂ 、 -C １～６ alkC(=O)NR ａ R ａ 、 -C １～６ alkC(=O)OR ａ 、 and oxo; R ａ is independently, at each occurrence, H or R ｂ and R ｂ is independently, in each occurrence, C １～６ alk, phenyl, or benzyl, wherein １～６ alk is halo, —OH, —OC １～４ alk, -NH ２ , -NHC １～４ alk, -OC(=O)C １～４ alk, or -N(C １～４ alk) C １～４ alk, wherein said phenyl or benzyl is substituted by 0, 1, 2, or 3 substituents selected from halo, C １～４ alk, C １～３ haloalk, -OH, -OC １～４ alk, -NH ２ , -NHC １～４ alk, -OC(=O)C １～４ alk, or -N(C １～４ alk) C １～４ alk is substituted by 0, 1, 2, or 3 substituents selected from

2. R ｘ 2. The compound of claim 1, wherein: 【Transformation 3】

3. X １ Ga-CR ６ The compound of any one of claims 1 to 2, having formula (Ia): 【Chemistry 4】

4. X １ The compound of any one of claims 1 to 3 having formula (Ib), wherein is N. 【Transformation 5】

5. R ３ The compound of any one of claims 1 to 4, wherein is H or methyl.

6. R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｇ , R １０ｈ , R １０ｉ , and R １０ｊ Each of these is H, halo, and C. １～６ alk, or C １～４ haloalk, R １０ａ and R １０ｂ and each pair of R ｘ 6. The compound of claim 1, wherein the ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, forming a saturated 3-, 4-, or 5-membered monocyclic ring spiro to the ring of

7. R １０ｃ , R １０ｄ , R １０ｅ , R １０ｆ , R １０ｇ , R １０ｈ , R １０ｉ , and R １０ｊ is H, methyl, or ethyl; １０ａ and R １０ｂ and each of the pairs of R ｘ 7. The compound of claim 1, wherein the ring is a cyclopropyl, cyclobutyl, or cyclopentyl ring that is spiro to the ring of

8. R ｘ The compound according to any one of claims 1 to 7, wherein is selected from the following: 【Transformation 6】

9. R ｘ The compound according to any one of claims 1 to 8, wherein: 【Transformation 7】

10. Z is absent, NH-, -NHSO ２ - (CH ２ ) ０～４ -, -N(CH ３ )-SO ２ - (CH ２ ) ０～４ -, -NCH ３ SO ２ NH, -NHSO ２ NH-C(=O)-O-, -SO ２ NH-(CH ２ ) ０～４ -, -(CH ２ ) ０～２ -S(=O)(=NH)-,-(CH ２ ) ０～２ -S-, -(CH ２ ) ０～２ -S(=O)-, (CH ３ CH)-S(=O)-,-(CH ２ ) ０～２ -SO ２ The compound according to any one of claims 1 to 9, which is -, -O-, -P(=O), -(C=O)-, or -NH(C=O).

11. The group -Z-R １２ -N=S(=O)-(R １２ ) ２ wherein the two R １２ can alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, selected from: 【Transformation 8】

12. R １ But, -Z-R １２ where Z is absent, NH—, —NHSO ２ - (CH ２ ) ０～４ -, -N(CH ３ )-SO ２ - (CH ２ ) ０～４ -, -NCH ３ SO ２ NH, -NHSO ２ NH-C(=O)-O-, -SO ２ NH-(CH ２ ) ０～４ -, -(CH ２ ) ０～２ -S(=O)(=NH)-,-(CH ２ ) ０～２ -S-, -(CH ２ ) ０～２ -S(=O)-, (CH ３ CH)-S(=O)-,-(CH ２ ) ０～２ -SO ２ -, -O-, -P(=O), -(C=O)-, or -NH(C=O), and R １２ but, (c) H; (d) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, 【Chemistry 9】 wherein each of said rings is selected from the group consisting of OH, F, methyl, —CH ２ OH, -C(=O)OCH ３ , -C(=O)OC(CH ３ ) ３ , N.H. ２ substituted by 0, 1, 2, or 3 groups selected from , CN, and oxo; or (e) 0, 1, 2, or 3 of OH, F, or —C(═O)OCH ３ , -NH ２ , -NH(CH ３ ), or -N(CH ３ ) ２ C, substituted by １～６ alk, The compound according to any one of claims 1 to 11, selected from:

13. R １ The group -Z-R １２ where Z is —NHSO ２ -or-SO ２ NH- and R １２ is oxetanyl, cyclopropyl, or R １２ is substituted by 0, 1, 2, or 3 OH groups １～６ The compound according to any one of claims 1 to 12, wherein the compound is alk.

14. R １ Group -Z-R １２ where Z is -NHSO ２ - and R １２ Ga-CH ２ -CH ２ The compound according to any one of claims 1 to 13, wherein the group is -OH.

15. R ２ is halo or a group -Y-R １３ where Y is absent and -SO ２ NH-(CH ２ ) ０～４ -, NH-, -NH-SO ２ -(CH) ２ ) ０～４ -, -O-(CH ２ ) ０～４ , -O-(CH(CH ３ ))-, -(CH ２ ) ０～４ -S(=O)(=NH)-, -(C=O)-, -(CH ２ ) ０～４ -(C=O)-O-, or -(CH ２ ) １～４ and R １３ F, Cl, Br, C １～６ alk, C １～４ haloalk, -OH, -OC １～４ haloalk, CN, R １４ a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or an 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, substituted by 0, 1, 2, or 3 groups selected from , and oxo; or R １３ F, Cl, Br, -OH, -OC １～４ C substituted by 0, 1, 2, 3, 4, or 5 groups selected from haloalk, or CN １～６ alk, The compound according to any one of claims 1 to 14.

16. R ２ is a saturated 5- or 6-membered monocyclic ring, each of said rings containing 0, 1, or 2 N atoms and 0 or 1 O atoms, and each of said rings is selected from the group consisting of F, Cl, Br, C １～６ alk, C １～４ haloalk, -OH, -OCH ３ , -OC １～４ haloalk, CN, R １４ 16. The compound of any one of claims 1 to 15, substituted with 0, 1, 2, or 3 groups selected from:

17. R ２ but, (a) F, Br; (b) Group -YR １３ [where Y is absent and R １３ morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, 3,6-dihydro-2H-pyranyl, 【Chemistry 10】 wherein each of the rings is F, Cl, Br, methyl, CF ３ , C.H. ２ OH, CH(CH ３ )OH, C(CH ３ ) ２ OH, -OH, -OCHF ２ , CN, oxo, or cyclopropyl; or (c) Group -YR １３ wherein Y is absent and -SO ２ NH-, NH, -O-, S(=O)(=NH)-, -O-(CH ２ ), -O-(CH(CH ３ ))-, C(=O)-, C(=O)-O-, -CH ２ C(=O)-O-, or -CH ２ -, where R １３ is either: 【Chemistry 11】 (wherein each ring is F, Cl, Br, methyl, CF ３ , —OH, or CN), or R １３ is H, or F, Cl, Br, methyl, CF ３ , —OH, or C substituted by 0, 1, 2, 3, 4, or 5 groups selected from １～６ alk], The compound according to any one of claims 1 to 16,

18. R ２ (a) halo; (b) a group -Y-R １３ wherein Y is absent and R １３ morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, 【Chemistry 12】 wherein each of the rings is selected from F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ , CN, and oxo); or (c) a group -Y-R １３ (wherein Y is NH, —O—, —O—(CH ２ ) -, -O-(CH ２ )-(CH ２ ) -, or -O-(CH ２ )-(CH ２ )-(CH ２ )-, where R １３ but, 【Chemistry 13】 or R １３ is F, Cl, Br, methyl, CF ３ , —OH, or C substituted by 0, 1, 2, 3, 4, or 5 groups selected from １～６ 18. The compound according to any one of claims 1 to 17, wherein:

19. R ２ The compound according to any one of claims 1 to 18, wherein 【Chemistry 14】

20. R ２ is F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ 20. The compound of any one of claims 1 to 19, which is morpholinyl or piperidinyl substituted by 0, 1, 2, or 3 groups selected from , CN, or oxo.

21. R ２ The compound of any one of claims 1 to 20, wherein is morpholinyl substituted by 1, 2 or 3 methyl groups.

22. R ４ The compound of any one of claims 1 to 21, wherein is selected from H, F, methyl, CN, or Br.

23. R ４ The compound of any one of claims 1 to 22, wherein is H.

24. R ５ The compound of any one of claims 1 to 23, wherein is H.

25. R ６ H, methyl, cyclopropyl, CN, CF ３ or azetidinyl.

26. R ７ The compound of any one of claims 1 to 25, wherein is H.

27. R ８ The compound according to any one of claims 1 to 26, wherein is H or F.

28. R ９ The compound according to any one of claims 1 to 27, wherein is H or F.

29. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: Table 1 Table 2 Table 3 Table 4 Table 5

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

31. 31. A method of treating a condition treatable by a KIF18a inhibitor, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a composition according to claim 30.

32. The condition is (a) a tumor of solid or hematological origin selected from cancer of the bladder, endometrium, squamous cell lung, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gallbladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; (b) a hematopoietic tumor of the lymphoid system selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; (c) an acute or chronic lymphocytic tumor of the lymphoid system selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma; 32. The method of claim 31, wherein the cancer is selected from the group consisting of: (a) a myeloid hematopoietic tumor selected from diffuse myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (b) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (c) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (d) a tumor of the central and peripheral nervous system selected from malignant melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

33. 31. A method for reducing the size of a solid tumor in a subject, said method comprising administering to said subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 29 or a composition of claim 30.

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

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