Pyridine derivatives as KIF18A inhibitors

Abstract

and a compound of formula (I) as defined herein, which is capable of regulating KIF18A protein, thereby affecting the process of cell cycle and cell proliferation, and treating cancer and cancer-related diseases. The present invention also includes pharmaceutical compositions containing the compounds and methods for treating pathologies associated with KIF18A activity.

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 uses and methods for controlling cell proliferation and treating cancer. [Background technology]

[0002] Cancer is one of the most prevalent diseases afflicting humanity and is the leading cause of death worldwide. Many groups have expended significant time, effort, and financial resources over the past few decades in attempts to find effective treatments or cures for one or more of the many different types of cancer. However, to date, only a few of the available cancer treatments and therapies have met with significant success.

[0003] Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes that govern cellular pathways that control the progression of proliferation through the cell cycle and centrosome cycle can cause the loss of normal regulation of cell proliferation. These unregulated genes may encode various tumor suppressor or oncogene proteins that participate in a cascade of events, resulting in uncontrolled cell cycle progression and cell proliferation. Various kinase and kinesin proteins have been identified that play important roles in cell cycle and mitotic regulation and the progression of normal dividing cells and cancer cells.

[0004] Kinesins are molecular motors that play an important role in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins play a role in several aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics (reviewed in O. Rath and F. Kozielski, “Nature Review Cancer” 12:527-39, 2012). Human kinesins are classified into 14 subfamilies based on sequence homology within the so-called “motor domain,” whose ATPase activity drives unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are responsible for cargo binding, which can include any one of a wide variety of membranous organelles, signal transduction 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” directional motors.

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is thought to affect the dynamics of the plus ends of kinetochore microtubules, which control correct chromosome positioning and spindle tension. Depletion of human KIF18A results in longer spindles, increased chromosome oscillations during metaphase of mitosis, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology 17, 488-98, 2007). KIF18A appears to be a viable target for cancer therapy. KIF18A is overexpressed in various types of cancer, including, but not limited to, colon cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, head and neck cancer, cervical cancer, and ovarian cancer. Furthermore, genetic deletion, knockdown, or inhibition of KIF18A results in the mitotic spindle apparatus in cancer cell lines. Specifically, it has been found that inhibition of KIF18A induces mitotic cell arrest, known vulnerabilities that can promote cell death during mitosis via apoptosis, mitotic catastrophe, or multipolarity-driven lethality or death after mitotic slippage in interphase. Therefore, there is strong interest in discovering inhibitors of 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, inhibition of the ATPase activity of KIF18A is a promising approach for developing novel anticancer drugs. [Means for solving the problem]

[0008] One aspect of the present invention is a novel class of compounds useful for modulating KIF18A protein, alone or in a bound complex with microtubules, to treat KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliopathologies.

[0009] The compounds provided by the present invention have MT-based KIF18A modulating activity, and in particular KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds and pharmaceutically acceptable salts thereof in the preparation and manufacture of pharmaceutical compositions or medicaments for the therapeutic, preventive, acute, or chronic treatment of KIF18A-mediated diseases and disorders, including but not limited to cancer. Thus, the compounds of the present invention are useful in the manufacture of anti-cancer drugs. The present invention also provides a process for preparing the compound of formula I, and intermediates useful in such a process.

[0010] In embodiment 1, the present invention provides a compound of formula (I): [ka] or any pharmaceutically acceptable salt thereof, wherein: X 1 is N or -CR 3 and X 2 is N or -CR 4 and X 3 is N or -CR 1 and where X 1 , X 2 and X 3 Only one of the is N, R 1 is the group -ZR 12 where Z is absent, -C 0~4 alk-NR11 -C 0~4 alk-、-C 0~4 alk-(C=O)-、-C 0~4 alk-(C=O)NR 11 -、-C-((C=O)-OR 11 )2-、-C 0~4 alk-(C=O)-O-, -C 0~4 alk-O-, -C 0~4 alk-NR 11 (C=O)-、-C 0~4 alk-NR 11 SO2-C 0~4 alk-、-C 0~4 alk-S-、-C 0~4 alk-S(=O)-、-C 0~4 alk-SO2-、-NR 11 -C 0~4 alk-O-, -C 0~4 alk-S(=O)(=N + (CH3)2)-, -C=N(OH)-, and -N=S(=O)<であり, R 2 は, base-YR 13 であり、ここで、Yが、does not exist、-C 0~4 alk-SC 0~4 alk-、-C 0~4 alk-S=OC 0~4 alk-、-C 0~4 alk-SO2-C 0~4 alk, -SO2NR 13c -C 0~4 alk-、-SO2N(C 1~4 alk)-、-SO2N(C 1~4 alk-OC 1~4 alk)-、-C 0~4 alk-S(=O)(=NH)-、-C 0~4 alk-(C=O)-、-C 0~4 alk-(C=O)-O-, -C 0~4 alk-(C=O)NR 13c -、-NR 13c -、-OC 0~4 alk-、-N=S(=O)<、also-NR 13c -SO2-C 0~4 alk-であり、 R3 H, halo, C 1~4 alk or C 1~4 Helloalk, R 4 H, halo, C 1~8 alk or C 1~4 Helloalk, R 5 H, halo, C 1~8 alk or C 1~4 Helloalk, R 6 H, halo, CN, C 1~8 alk, -OC 1~8 alk, C 0~4 alk-(C=O)-NH-C 0~4 alk, C 1~4 Haloalk, -C 0~4 alk-SO2NH-C 0~4 alk, -C 0~4 alk-SO2N(CH3)-C 0~4 alk or R 6a and R 7 But, H, halo, CN, C 1~8 alk, C 1~4 Helloalk, -OC 1~8 alk or R 7a and Or, R 2 and R 7 can combine with the carbon atoms to which they are each bonded to form a saturated, partially saturated, or unsaturated 5- or 6-membered monocyclic ring fused to a phenyl ring, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and the 5- or 6-membered monocyclic ring is further free from F, Cl, Br, C 1~6 alk, C 1~4 Helloalk, -OR a , -OC 1~4 Haloalk, CN, -NR a R a or oxo; R 6a and R 7aeach independently contains, in each occurrence, 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, CN, C 1~6 alk, C 1~4 Helloalk, -OC 1~4 Haloalk, -C(=O)R b , -C 0-6 alk-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 , -N(R a )C(=O)R a , -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 1~6 alkNR a R a , -NR a C 1~6 alkOR a , -C 0-6 alkNR a R a , -C 0-6 alkOR a , -C 1~6 alkN(Ra )C(=O)R b , -C 1~6 alkOC(=O)R b , -C 0-6 alkC(=O)OR a and oxo; R 8 H, halo, C 1~4 alk or C 1~4 Helloalk, L is -(C=O)-NR 10 -or-NR 10 -(C=O)-, R 9 H, halo, C 1~8 alk or C 1~4 Helloalk, R 10 is H or C 1~4 alk, R X H, [ka] is selected from R Xa , R Xb , R Xc , R Xd , R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk and R Xl Each of these is H, halo, R Xm , or R Xn and Or, R Xa and R Xb vs. R Xc and R Xd vs. R Xe and R Xf vs. R Xg and R Xh vs. R Xiand R Xj pairs of and R Xk and R Xl can independently combine with the carbon atom bonded to each of them to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepanyl ring, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains zero N, O, and S atoms, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains zero F, Cl, Br, C 1~6 alk, C 1~4 Helloalk, -OR a , -OC 1~4 Haloalk, CN, -NR a R a or oxo; Additionally or alternatively, R Xa and R Xb vs. R Xc and R Xd vs. R Xe and R X of f vs. R Xg and R Xh vs. R Xi and R Xj pairs of and R Xk and R Xl each of the pairs can independently combine to form a double bond, R Xa , R Xb , R Xc , R Xd , R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk and R Xl When all of are H, the group ZR 12 is -NR 11 -R 12 and the group -YR 13 is C 0~4 alk-S(=O)2-R 13 or -SO2NR 13c -C0~4 alk-R 13 and L is -NR 10 -(C=O)-, and X 1 is N, or L is —(C═O)—NR 10 - and X 2 If N, then R X teeth, [ka] or R Xa and R Xb can each combine with the carbon atom to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl ring that is spiro to the piperidinyl ring; R 11 and R 13c each independently represents H or C 1~8 alk, R 12 H, halo, CN, -OH, R 12a , or R 12b and R 13 H, halo, CN, R 13a , or R 13b and R Xm , and R 12a , and R 13a each independently contains, at each occurrence, 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, C 1~6 alk, C 1~4 Helloalk, -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 alkNRa 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 aa saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring substituted with 0, 1, 2, 3, or 4 groups selected from , oxo, or a saturated, partially saturated, or unsaturated 3-, 4-, or 5-membered monocyclic ring; R Xn , R 12b , and R 13b each independently at each occurrence is F, Cl, Br, —CHF, —CHF, —CF, —C(═O)OR a , -C 0-6 alkOR a , -OC 1~4 Halo alk, CN, NH2, NH(CH3), N(CH3)2, -(C=O)NR a , -NR a (C=O)C 0~4 alk, -S(=O)2R a or a saturated, partially saturated or unsaturated 3-, 4- or 5-membered monocyclic ring. 1~6 is selected from the group consisting of alk, R a independently, in each occurrence, H or R b and R b But independently, in each case, C 1~6 alk, phenyl, or benzyl, where C 1~6 Alkyl, halo, -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 phenyl or benzyl is substituted with 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 1~4alk is substituted with 0, 1, 2 or 3 substituents selected from

[0011] In embodiment 2, the present invention provides a compound comprising R X But, H, [ka] is selected from where R Xa , R Xb , R Xc and R Xd Each of these is H, halo, R Xm or R Xn and Or, R Xa and R Xb pairs of and R Xc and R Xd can independently combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the pyrrolidinyl, piperidinyl, or morpholinyl ring, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains zero N, O, and S atoms, and further wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains zero F, Cl, Br, C 1~6 alk, C 1~4 Helloalk, -OR a , -OC 1~4 Haloalk, CN, -NR a R a or oxo; Additionally or alternatively, R Xa and R Xb Pairs of and R Xc and R Xd Each pair of can combine to form a double bond A compound is provided.

[0012] In embodiment 3, the present invention provides a compound comprising R X but [ka] The present invention provides a compound wherein

[0013] In embodiment 4, the present invention provides a compound comprising R X but [ka] The present invention provides a compound wherein

[0014] In embodiment 5, the present invention provides a compound comprising R X but [ka] The present invention provides a compound wherein

[0015] In embodiment 6, the present invention provides a compound comprising R Xa , R Xb , R Xc and R Xd Each of the a) selected from H, F, Cl, methyl, ethyl, propyl, isopropyl, —CHF, —CHF, —CF or cyclopropyl; b) Or, R Xa and R Xb Pairs of and R Xc and R Xd can independently combine with the carbon atom to which each is bonded to form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring, wherein each ring is spiro to the pyrrolidinyl ring, piperidinyl ring, or morpholinyl ring, and each of said rings is selected from the group consisting of F, Cl, Br, C 1~6 alk, C 1~4 substituted by 0, 1, 2 or 3 groups selected from haloalk or methoxy; c) Or, R Xa and R Xb Pairs of and R Xc and R Xd each of the pair can independently combine to form >C=CH or >C=CH-CH; R Xe , R Xf , R Xg , R Xh , R Xi , RXj , R Xk and R Xl each of which is H, F or methyl A compound is provided.

[0016] In embodiment 7, the present invention provides a compound wherein L is —NR 10 The compound is -(C=O)-.

[0017] In embodiment 8, the present invention provides a compound wherein L is —(C═O)—NR 10 -

[0018] In embodiment 9, the present invention provides a compound wherein L is —NR 10 -(C=O) and X 1 Ga-CR 4 and X 2 is N and X 3 Ga-CR 1 and formula (Ia): [ka] The present invention provides a compound having the formula:

[0019] In subembodiment 9a, the present invention provides a compound of formula (Ia-1): [ka] The present invention provides a compound having the formula:

[0020] In embodiment 10, the present invention provides a compound wherein L is —(C═O)—NR 10 - and X 1 Ga-CR 4 and X 2 is N and X 3 Ga-CR 1 and formula (Ib): [ka] The present invention provides a compound having the formula:

[0021] In subembodiment 10a, the present invention provides a compound of formula (Ib-1): [ka] The present invention provides a compound having the formula:

[0022] In embodiment 11, the present invention provides a compound wherein L is —NR 10 -(C=O) and X 1 is -N and X 2 Ga-CR 3 and X 3 Ga-CR 1 and formula (Ic): [ka] The present invention provides a compound having the formula:

[0023] In subembodiment 11a, the present invention provides a compound of formula (Ic-1): [ka] The present invention provides a compound having the formula:

[0024] In embodiment 12, the present invention provides a compound wherein L is —(C═O)—NR 10 - and X 1 is -N and X 2 Ga-CR 3 and X 3 Ga-CR 1 and formula (Id): [ka] The present invention provides a compound having the formula:

[0025] In subembodiment 12a, the present invention provides a compound of formula (Id-1): [ka] The present invention provides a compound having the formula:

[0026] In embodiment 13, the present invention provides a compound wherein L is —NR 10 -(C=O) and X 1 Ga-CR4 and X 2 Ga-CR 3 and X 3 is N, and the compound of formula (Ie): [ka] The present invention provides a compound having the formula:

[0027] In embodiment 14, the present invention provides a compound wherein L is —(C═O)—NR 10 - and X 1 Ga-CR 4 and X 2 Ga-CR 3 and X 3 is N and the formula (If): [ka] The present invention provides a compound having the formula:

[0028] In embodiment 15, the present invention provides a compound comprising R 10 is H or methyl.

[0029] In embodiment 16, the present invention provides a compound comprising R X But, H, [ka] The present invention provides a compound selected from:

[0030] In embodiment 17, the present invention provides a compound comprising R X but, [ka] The present invention provides a compound wherein

[0031] In subembodiment 17a, the present invention provides a compound comprising R X but, [ka] The present invention provides a compound wherein

[0032] In embodiment 18, the present invention provides compounds where Z is absent, —NH—, —(C═O)—, —CH(CH)—(C═O)NH—, —C—((C═O)—O—(CH)), —C—((C═O)—O—(CH)), —CH(CH)—(C═O)—O—, —C(CH)—(C═O)—O—, —(C═O)—O—, —N(CH)—, —O—, —NH(C═O)—, —(C═O)NH, —CH—(C═O)—O—, —CHNCH—, —NCH—, —CH—(C═O)—NH—, —NHSO—, —CHSO—, —NHCH—, or —NHCHCH—O—.

[0033] In subembodiment 18a, the invention provides compounds wherein Z is absent.

[0034] In embodiment 19, the present invention provides a compound comprising R 12 but, a) H, F, Cl, Br, OH, or CN, b) C substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, -CF3, -CH2OH, -OH, -OCH3, -C(=O)OH, -C(=O)OCH3, -C(=O)NH, -C(=O)NCH3, -NHC(=O)H, -NHC(=O)CH3, -NCH3C(=O)CH3, -NH2, -NH(CH3), or -N(CH3)2. 1~6 alk, or c) a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 6-, 7-, 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, and substituted with 0, 1, 2, 3, or 4 groups selected from F, Cl, Br, CN, methyl, ethyl, -CF3, -CH2OH, -CH2CH2OH, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -C(=O)NH2, -C(=O)OH, -C(=O)OCH3, -SO2CH3-, or oxo. The present invention provides a compound selected from:

[0035] In embodiment 20, the present invention provides a compound comprising R 12 cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxolanyl, morpholinyl, phenyl, [ka] where each R 12 is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, methyl, ethyl, CN, —CF, —CHOH, —CHCHOH, —OH, —OCH, —COOH, —CONH, COOCH, —CONH(CH), —NH, —SOCH, or oxo.

[0036] In embodiment 21, the present invention provides a compound comprising R 1 Base-ZR 12 where Z is absent, —NH—, —O—, —NHSO—, or —CHSO—; R 12 is H, pyrrolidinyl, oxetanyl, cyclopropyl, or cyclobutyl, or R 12 is substituted with 0, 1, 2 or 3 OH, CF3, or -CH2OH groups 1~6 A compound that is an alk is provided.

[0037] In embodiment 22, the present invention provides compounds wherein Y is absent, —S—, —SO—, —SOCH—, —SOCH(CH)—, —SONH—, —SONNHCH—, —SON(CHCH)—, —SON(CHC≡CH)—, SON(CHCHOCH)—, —S(═O)(═NH)—, —C═O—, —CH—(C═O)—, —(C═O)—O—, —CH(C═O)—O—, —(C═O)NH—, —(C═O)—N(CH)—, —CH—(C═O)—NH—, —NH—, —O—, —N═S(═O)<, or —NHSO—.

[0038] In subembodiment 22a, the invention provides compounds wherein Y is absent.

[0039] In embodiment 23, the present invention provides a compound comprising R 13 but, a) H, halo, or CN; b) R selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 6-, 7-, 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, and substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, ethyl, isopropyl, CHF, CF, CHOH, —OH, —OCH, —NH, —NH(CH), oxo, cyclopropyl, or cyclobutyl. 13a , or c) C substituted with 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, —OH, —CF3, cyclopropyl, or cyclobutyl. 1~6 R selected from alk 13b The present invention provides a compound selected from:

[0040] In embodiment 24, the present invention provides a compound comprising R 13a each independently substituted with 0, 1, 2 or 3 groups selected from F, Cl, methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3, -OCH3, -CH2CH2OCH3, or oxo; [ka] The present invention provides a compound selected from:

[0041] In embodiment 25, the present invention provides a compound comprising R13b is selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, or neopentyl, each independently substituted with 0, 1, 2, or 3 groups selected from F, CF, OH, or cyclopropyl.

[0042] In embodiment 26, the present invention provides a compound comprising R 2 But the group -YR 13 where Y is absent, -SO2-, or -SO2NH-; R 13 is tert-butyl, or R is selected from cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl 13a where R 13a is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, methyl, or CF3.

[0043] In embodiment 27, the present invention provides a compound comprising R 2 But the group -YR 13 where Y is -SO2- and R 13 is cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl, each substituted with 0, 1, 2, or 3 methyl groups.

[0044] In embodiment 28, the present invention provides a compound comprising R 3 is H, F or methyl.

[0045] In embodiment 29, the present invention provides a compound comprising R 4 is H, F, Cl, cyclopropyl, —(C═O)CH 3 or CF 3 .

[0046] In embodiment 30, the present invention provides a compound comprising R 4 is H.

[0047] In embodiment 31, the present invention provides a compound comprising R 5 is H.

[0048] In embodiment 32, the present invention provides a compound comprising R 6 is H, F, Br, methyl, CN, methoxy, cyclopropyl, —(C═O)NH 2 , —CF 3 , furanyl, pyridinyl, morpholinyl, or —SO 2 NHC(CH 3 ) 3 .

[0049] In embodiment 33, the present invention provides a compound comprising R 6 is H or F.

[0050] In embodiment 34, the present invention provides a compound comprising R 7 is H, F, Br, Cl, CN, methyl, methoxy, cyclopropyl, or R 2 and R 7 in combination with the carbon atoms to which they are attached to form the group: [ka] Provided is a compound capable of forming:

[0051] In embodiment 35, the present invention provides a compound comprising R 7 is H, F, or methyl.

[0052] In embodiment 36, the present invention provides a compound comprising R 8 is H, F, or methyl.

[0053] In embodiment 37, the present invention provides a compound comprising R 8 is H.

[0054] In embodiment 38, the present invention provides a compound comprising R 9 is H.

[0055] In embodiment 39, the present invention provides a compound comprising R 10 is H.

[0056] In embodiment 40, the present invention provides a compound selected from the following, or any pharmaceutically acceptable salt thereof:

[0057] [Table 1]

[0058] [Table 2]

[0059] [Table 3]

[0060] [Table 4]

[0061] [Table 5]

[0062] [Table 6]

[0063] [Table 7]

[0064] [Table 8]

[0065] In embodiment 41, the present invention provides a compound selected from the following, or any pharmaceutically acceptable salt thereof:

[0066] [Table 9]

[0067] [Table 10]

[0068] [Table 11]

[0069] [Table 12]

[0070] [Table 13]

[0071] or any pharmaceutically acceptable salt thereof.

[0072] Another aspect of the present invention is a composition comprising a novel class of compounds, or pharmaceutically acceptable salts thereof, useful for modulating KIF18A protein, either alone or in a binding complex with microtubules.

[0073] In embodiment 42, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0074] Yet another aspect of the present invention is a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a novel class of compounds useful for regulating KIF18A protein, alone or in a binding complex with microtubules, or a pharmaceutically acceptable salt thereof.

[0075] In embodiment 43, the present invention provides a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering a therapeutically effective amount of a compound described in embodiments 1 to 41, or a composition described in embodiment 42, to a patient in need thereof.

[0076] In embodiment 44, the invention provides the method of embodiment 43, wherein the condition is (a) a solid tumor or a blood-borne tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Bart's lymphoma; (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) cancers selected from the group consisting of melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0077] In subembodiment 44a, the invention provides the method of embodiment 43, wherein the condition is a cancer selected from the group consisting of melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia. See Zhang C. et.al., "Kif18A is involved in human breast carcinogenesis", Carcinogenesis, 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.

[0078] In embodiment 45, the present invention provides a method for reducing the size of a solid tumor in a subject, the method comprising administering a therapeutically effective amount of a compound described in embodiments 1-41, or a composition described in embodiment 42, to a subject in need thereof.

[0079] In embodiment 46, the present invention provides a method for treating a cell proliferation disorder in a subject, the method comprising administering a therapeutically effective amount of a compound described in embodiments 1-41, or a composition described in embodiment 42, to a subject in need thereof.

[0080] In embodiment 47, the present invention provides a method for inhibiting KIF18A in a cell, comprising contacting the cell with a compound described in embodiments 1 to 41, or a pharmaceutically acceptable salt thereof, or a composition described in embodiment 42.

[0081] Yet another aspect of the present invention is a method for preparing a novel class of compounds, or pharmaceutically acceptable salts thereof, useful for modulating KIF18A protein, alone or in a binding complex with microtubules.

[0082] In embodiment 48, the present invention provides methods of preparing compounds of formula (I) described herein.

[0083] In embodiment 49, the present invention provides intermediate compounds used in the methods of preparing compounds of formula (I) described herein. DETAILED DESCRIPTION OF THE INVENTION

[0084] Detailed Description of the Invention 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.

[0085] Examples of isotopes suitable for inclusion in compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C 、13 C and 14 Carbon, such as C 38 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P and 35 and isotopes of sulfur such as, but not limited to, S.

[0086] Certain isotopically labeled compounds of the present invention, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready means of detection.

[0087] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances because it may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0088] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0089] Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0090] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0091] Specific embodiments of the present invention include the compounds exemplified in the Examples below, as well as pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof.

[0092] Unless otherwise stated, the following definitions apply to terms found in the specification and claims.

[0093] "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 also contain one or two double or triple bonds. The notation COalk refers to a direct bond. 1~6 Examples of alkyl include, but are not limited to: [ka]

[0094] The term "benzo group", alone or in combination, means the divalent radical CH=, one representation of which is -CH=CH-CH=CH-, which when attached adjacent to another ring forms a benzene-like ring, e.g., tetrahydronaphthylene, indole, etc.

[0095] The terms "oxo" and "thioxo" refer to the groups =O (as in carbonyl) and =S (as in thiocarbonyl), respectively.

[0096] "Halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0097] "C α~β "Haloalk" refers to the above alk group 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.

[0098] Group N(R a )R a As such, two R a Included are substituents where the groups together form a ring which optionally contains an N, O, or S atom, such as: [ka] Examples of such groups include:

[0099] Group N(C α~β alk)C α~β As alk (wherein α and β are as defined above), two C α~β Included are substituents where the alk groups together form a ring optionally containing an N, O, or S atom, such as: [ka] Examples of such groups include:

[0100] "Bicyclic ring" refers to a group characterized by two joined rings. Bicyclic rings can be carbocyclic (all ring atoms are carbon) or heterocyclic (ring atoms consist of, in addition to carbon atoms, e.g., one, two, or three heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., decalin and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom, a spiroatom, which is usually a quaternary carbon. Examples of spirocyclic compounds include: [ka] (b) Fused bicyclic compounds include, but are not limited to, compounds in which two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic compounds include: [ka] and (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, include, but are not limited to: For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings, each sharing three of its five carbon atoms. Examples of bridged bicyclic compounds include: [ka] These include, but are not limited to:

[0101] "Carbocycle" or "carbocyclic", by itself or in combination with other terms, means "C α~β Examples of carbocycles include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene, and the like.

[0102] "Heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may be found in the claims include: [ka] These may include, but are not limited to:

[0103] "Pharmaceutically acceptable salts" refers to salts prepared by conventional means and are well known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. When the compounds of the present invention contain an acidic functional group, such as a carboxy group, suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkali, alkaline earth, ammonium, and quaternary ammonium cations. For additional examples of "pharmacologically acceptable salts," see below and Berge et al., J. Pharm. Sci. 66:1 (1977).

[0104] "Saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogens, substituents that are not saturated with hydrogens at all, and substituents that are partially saturated with hydrogens.

[0105] A "leaving group" generally refers to a group readily displaceable by a nucleophile, such as an amine, thiol, or alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferred leaving groups are indicated herein where appropriate.

[0106] The term "protecting group" generally refers to a group known 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 identified herein as appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyls include, but are not limited to, benzyl, orthomethylbenzyl, trityl, and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl, and the like, as well as salts thereof, 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 radicals, preferably having 6 to 10 carbon atoms, include, but are not limited to, cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl, and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, and the like. Mixtures of protecting groups can be used to protect the same amino group, such as a primary amino group being protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups, together with the nitrogen to which they are attached, can also form heterocyclic rings, such as 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, and maleimidyl, and these heterocyclic groups can further contain adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups can be mono-, di-, or trisubstituted, such as nitrophthalimidyl. Amino groups can also be protected against undesired reactions, such as oxidation, by forming an addition salt with hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, and the like.Many of the amino acid protecting groups are also suitable for protecting carboxy, hydroxy, and mercapto groups, for example, aralkyl groups. Alkyl groups such as tert-butyl are also suitable for protecting hydroxy and mercapto groups.

[0107] 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 can yield a mono- or disilylamino group. Silylation of an amino alcohol compound can yield an N,N,O-trisilyl derivative. Removal of the silyl function from a silyl ether function is easily achieved by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a separate reaction step or in situ during the reaction with an alcohol group. Suitable silylating agents include, for example, trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. In addition, methods for preparing these amine derivatives from the corresponding amino acids, amino acid amides, or amino acid esters are well known to those skilled in the art of organic chemistry, including amino acid / amino acid ester or amino alcohol chemistry.

[0108] Protecting groups are removed under conditions that do not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like. A preferred method involves the removal of a protecting group, such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, or the like, or a mixture thereof. A t-butoxycarbonyl protecting group can be removed using an inorganic or organic acid, such as HCl or trifluoroacetic acid, in an appropriate solvent system such as dioxane or methylene chloride. The resulting amino salt 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.

[0109] Compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted heteroaryl groups (Y' = O, S, NR), as illustrated in the following examples: [ka] It should be noted that although one form may be named, described, represented, and / or claimed herein, all tautomeric forms are intended to be inherently included in such naming, description, representation, and / or claim.

[0110] 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 through in vivo physiological action, such as hydrolysis or metabolism, to become a compound of the present invention after the prodrug is administered to a patient. The suitability and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art. For general reviews of prodrugs involving 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 that are cleaved in vivo by esterases to release the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Drugs containing acidic NH groups, such as imidazoles, imides, and indoles, have also been masked with 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, 4 / 11 / 81) discloses Mannich-base hydroxamic acid prodrugs, their preparation, and use.

[0111] The present specification and claims include lists of chemical species (sometimes referred to as Markush groups) using the phrases "selected from and" and "or is." When this term is used in this application, unless otherwise specified, it is intended to include the group as a whole, or any single member thereof, or any subgroup thereof. The use of this phrase is merely for shorthand purposes and does not in any way limit the exclusion of individual elements or subgroups, where appropriate.

[0112] Pharmaceutical Compositions, Dosages, and Routes of Administration Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein together with a pharmaceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. Administration of the compounds is described in more detail below.

[0113] Suitable pharmaceutical formulations can be determined by those skilled in the art depending on the route of administration and the desired dosage. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co., Easton, Pennsylvania, 1990). Formulations can affect the physical state, stability, in vivo release rate, and in vivo excretion rate of the administered drug. Depending on the route of administration, suitable doses can be calculated according to body weight, body surface area, or organ size. Further refinement of calculations required to determine an appropriate therapeutic dose can be routinely performed by those skilled in the art without undue experimentation, particularly in light of the dosage information and assays disclosed herein and pharmacokinetic data obtained from animal or human clinical trials.

[0114] The phrases "pharmaceutically 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 and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such excipients for pharmaceutically active substances is known 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 comprises corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride. May contain: 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, copper 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.

[0115] 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.

[0116] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali metals 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 iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0117] Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids. Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate. Other suitable pharmaceutically acceptable salts are well 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 acid, sulfonic acid, sulfoacid, or phosphoacid, or N-substituted sulfamic acid, 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, and with amino acids such as 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-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamate) or with other acid organic compounds such as ascorbic acid.

[0118] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation depends upon the route of administration chosen.

[0119] For oral administration, suitable compositions can be easily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known 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, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds disclosed herein with solid excipients, optionally grinding the resulting mixture, and processing the granular mixture, after adding suitable auxiliary agents as needed, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can be added as needed. Pharmaceutically acceptable ingredients are well known for various types of formulations and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavoring agents, coating agents, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various formulation types.

[0120] When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is typically in the form of a solid (e.g., a tablet, capsule, pill, powder, or lozenge) or a liquid preparation (e.g., an aqueous suspension, solution, elixir, or syrup).

[0121] When administered in tablet form, the composition may further comprise a functional solid and / or functional solid carrier such as gelatin or an adjuvant. The tablet, capsule, and powder may contain about 1 to about 95% of the compound, preferably about 15 to about 90% of the compound.

[0122] When administered in the form of a solution or suspension, a functional liquid and / or functional liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. Liquid formulations of the composition can further comprise saline solution, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in the form of a solution or suspension, the composition can comprise 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. When administered in liquid form, the composition can be supplied as a rapidly dissolving solid formulation that is dissolved or suspended immediately prior to administration.

[0123] 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. Preparation of such parenterally acceptable solutions, taking into due consideration pH, isotonicity, stability, and the like, is within the skill of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compounds disclosed herein. Such compositions may be prepared for administration as a solution of the free base or pharmacologically acceptable salt in water, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations may optionally contain a preservative to prevent the growth of microorganisms.

[0124] Injectable compositions can include sterile aqueous solutions, suspensions, or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, the form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi, optionally by the inclusion of a preservative. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one contemplated embodiment, the carrier is non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size of the compound in dispersion embodiments, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it is preferable to include an isotonic agent, for example, sugar 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.

[0125] Sterile injectable preparations are prepared by incorporating the active compound in the required amount in a suitable solvent with various other necessary ingredients as listed above, followed by filtration sterilization.Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other desired ingredients from the ingredients listed above.In the embodiment of sterile powder for preparing sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains a powder of active ingredients plus any other desired ingredients from the solution that has been previously sterile-filtered.

[0126] Slow-release or sustained-release formulations can also be prepared to control the release of active compounds in contact with body fluids in the gastrointestinal tract and provide a substantially constant and effective level of the active compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. Furthermore, the slow-release approach can enhance absorption via saturable or restricted pathways in the gastrointestinal tract. For example, for this purpose, the compound can be embedded in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, optionally with a suitable surfactant. In this context, embedding can refer to the incorporation of microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0127] For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray dispensed from a pressurized pack or nebulizer using a suitable propellant. In pressurized aerosol embodiments, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0128] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., bolus injection or continuous infusion).The injection preparation can be provided in a unit dosage form (e.g., ampoules or multi-dose containers) with added preservatives.The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0129] Pharmaceutical preparations for parenteral administration include aqueous solutions of the compound in water-soluble form. Furthermore, suspensions of the compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention can be in powder form, which can be reconstituted with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0130] The compounds disclosed herein can also be formulated in rectal compositions such as suppositories or retention enemas (e.g., containing conventional suppository bases). In addition to the formulations described above, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by injection (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 can be formulated as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0131] In particular, 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 capsules or ovules alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavorings or coloring agents. Such liquid preparations can be prepared using pharmaceutically acceptable additives 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 can contain other substances, such as salts or sugar alcohols such as mannitol or glucose, to make the solution isotonic with blood.

[0132] For veterinary use, the compounds disclosed herein are administered in an appropriately acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0133] In some embodiments, the compounds disclosed herein may be used in the treatment of KIF18A-associated disorders, either alone or in combination with another drug or intervention conventionally used to treat such disorders. All components necessary for such treatment can be packaged into a kit. Specifically, the present invention provides kits for use in the treatment of disorders, including a compound disclosed herein and a packaged set of pharmaceutical agents, including buffers and other ingredients for preparing a deliverable form of the agent, and / or equipment for delivering such pharmaceutical agents, and / or any pharmaceutical agents used in combination therapy with the compounds disclosed herein, and / or instructions for treating the disorder packaged with the pharmaceutical agents. The instructions can be fixed on any tangible medium, such as printed paper or a computer-readable magnetic or optical medium, or can refer to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0134] A "therapeutically effective amount" refers to an amount effective to treat, prevent progression of, or alleviate existing symptoms of the subject being treated. Determining an 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 a compound that produces a desired effect. For example, in a 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.

[0135] The amount of compound administered will depend on the subject being treated, the subject's age, health, sex, and weight, type of concurrent treatment (if any), 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 pressure. Individual needs vary, but determining the optimal range of effective amounts of the compound is within the skill of the art. Such doses can be administered in a single dose or divided into multiple doses.

[0136] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal 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, and head and neck cancer, ovarian cancer, and endometrial cancer. While the term "cancer" as used herein is not limited to any specific form of disease, the method of the present invention is believed to be particularly effective for cancers that are known to involve unregulated levels of KIF18A or to depend on KIF18A for proper chromosome segregation and survival in mammals.

[0137] As used herein, the terms "treat," "treating," and "treatment" refer to therapies including, but not limited to, curative, prophylactic, and preventative therapies. Prophylactic treatment generally constitutes either preventing the onset of a disorder altogether or delaying the onset of a pre-clinical stage of a disorder in an individual.

[0138] As used herein, the term "patient," "subject," or "mammal" refers to any "patient," "subject," or "mammal," including humans, cows, horses, dogs, and cats. In one embodiment of the present invention, the mammal is a human.

[0139] The term "comprising" is meant to be open-ended, including the indicated components, but not excluding other elements.

[0140] The term "Formula I" includes any sub-formulas.

[0141] How to use KIF18A inhibitors The present disclosure provides compounds having MT-based KIF18A regulatory activity, specifically 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 dosage of a compound of Formula I. Therefore, the compounds of the present invention can be used to treat cell proliferation disorders, including uncontrolled cell growth, 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. The compounds are also useful for cilia-related disorders and for ablating haploid germ cell populations, which can be used as male contraceptives.

[0142] In addition, the compounds of the present invention are useful for preventing or treating cancer and other KIF18A-mediated diseases or disorders, but are not limited thereto. For example, the compounds of the present invention are useful for preventing or treating various solid tumors and hematologically derived tumors, such as carcinomas, including, but not limited to, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including squamous cell carcinoma and small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma). tumors); hematopoietic tumors of the lymphatic system (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma).

[0143] The compounds of the present invention are also useful in the treatment of cancer-related indications such as solid tumors, sarcomas (particularly Ewing's sarcoma and osteosarcoma), hematopoietic malignancies including retinoblastoma, rhabdomyosarcoma, neuroblastoma, leukemia and lymphoma, tumor-induced pleural or pericardial effusion, and malignant ascites.

[0144] Based on the ability to regulate kinesin, which affects angiogenesis, the compounds of the present invention are also useful for the treatment and therapy of proliferative diseases.Specifically, these compounds can be used to treat inflammatory diseases such as various inflammatory rheumatoid diseases, especially symptoms in the locomotor system, especially chronic polyarthritis, including rheumatoid arthritis, juvenile arthritis, or arthritic psoriasis; paraneoplastic syndromes or tumor-induced inflammatory diseases, cloudy effusions, collagen diseases, such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma, or mixed collagen diseases; post-infectious arthritis (no pathogens found living in or within the affected body part), seronegative spondyloarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis, or arthropathy; or any further combination thereof.

[0145] The compounds of the present invention can also be used as active agents for conditions such as arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary arteries and cerebral collateral arteries, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter-associated disease, bone fractures, cat-scratch fever, rubeosis, neovascular glaucoma, and retinopathies such as 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, hematopoietic cancers, and hyperproliferative disorders such as thyroid hyperplasia (particularly Graves' disease), and cysts (e.g., hypervascularization of the ovarian stroma, a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)), since these diseases require the proliferation of vascular cells for growth and / or metastasis.

[0146] In addition to being useful for human treatment, these compounds are useful for 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.

[0147] Use in combination The compounds of the invention can be taken or administered as the sole active pharmaceutical agent, but they can also be used in combination with one or more compounds of the invention or in combination with other drugs. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.

[0148] The term "co-therapy" (or "combination-therapy") in defining the use of a compound of the invention and another pharmaceutical agent includes the administration of each agent sequentially in a dosing regimen that provides the beneficial effect of the drug combination, and also includes the administration of the drugs together substantially simultaneously, such as in a single capsule having a fixed ratio of the active agents or in separate capsules for each agent.

[0149] In particular, administration of the compounds of the present invention may be combined with additional therapies known to those skilled in the art of cancer prevention or treatment, such as radiation therapy, small molecule targeted agents (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies (e.g., naked and drug conjugated), immunotherapeutic antibodies (checkpoint inhibitors, bispecific T cell engagers), and anti-neoplastic or cytotoxic agents.

[0150] When formulated as a fixed dose, such combination products utilize the compounds of the present invention within the acceptable dosage range. When a combination formulation is inappropriate, the compounds of Formula I may also be administered sequentially with known anticancer or cytotoxic agents. The present invention is not limited in the order of administration; compounds of the present invention may be administered prior to, concurrently with, or after the administration of the known anticancer or cytotoxic agent.

[0151] There are many anti-cancer drugs available in commercial use, in clinical evaluation, and in preclinical development that are selected for the treatment of neoplasia by combination drug chemotherapy. These drugs fall into several major categories, including antibiotic-type agents, alkylating and alkylating-like agents, antimitotic agents, targeted small molecule agents, antimetabolites, hormonal agents, immunological agents, anti-angiogenic agents, interferon-type agents, and other classes of agents.

[0152] The present disclosure also provides methods of 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 aspect, such treatments include, but are not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, targeted small molecule agents, and radiation therapy to provide a synergistic or additive therapeutic effect.

[0153] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure, hi some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules (e.g., 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™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; benzodopa, carboquone, metholedone, and the like. aziridines such as melamine, methylameramine, methylmelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, actinomycin, ausramycin, 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, puromycin Antibiotics such as keramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and eno Pyrimidine analogs such as citabine and floxuridine; androgens such as calcitriol, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydrochloride Ciurea; 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.

[0154] Also included as suitable chemotherapy cell conditioners are antihormonal agents that act to modulate or inhibit hormone action on tumors, such as antiestrogens, including, for example, tamoxifen, (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, 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; mitomycin C; mitoxantrone; vinblastine; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; topotecan; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO).

[0155] Optionally, the compound or pharmaceutical composition of the disclosure may be any of Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Abraxane, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfalazine, alvocidib, 3-aminopyridine-2-carboxylates, benzodiazepines, benzocaine ... Carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, antitumor herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agent, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exateca cefotaxime, exisulind, ferruginol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lutecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, talazoparib, niraparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-3 8. It can be used in combination with commonly prescribed anticancer drugs such as salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar, and CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, Kisqali; abemaciclib, Verzenio).

[0156] The present disclosure further relates to methods of combining the compounds or pharmaceutical compositions provided herein with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in mammals. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0157] Radiation therapy can be administered by one of several methods, or a combination of these methods, including, but not limited to, external beam therapy, internal radiation therapy, interstitial irradiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially restricted radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. This 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 can be a radionuclide such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclide that emits photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can be a fluid made from any solution of the radionuclide, such as a solution of I-125 or I-131, or a radioactive fluid can be produced using a slurry of a suitable fluid containing microparticles of a solid radionuclide, such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied as a gel or radioactive microspheres.

[0158] 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, an anti-glycolytic agent, or an autophagy inhibitor.

[0159] Anti-angiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, can be used with the disclosed compounds and pharmaceutical compositions described herein. Anti-angiogenic 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 include those described in 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, EP 931788, and the like. and EP 0 780 386, all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferably, they selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (i.e., MMP-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.

[0160] The compounds of the present invention include 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, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, 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, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, Rudarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon Lon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, natural 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, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC631570, octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel ru, pamidronate, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasbriembodiment, rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonel amine, 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, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, barbican, verteporfin, vinorelbine rhamnosin, virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diazicon, 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, CA125MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), idiotype 105AD7MAb (CRC Technology), idiotype 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, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering) It may also be used in combination therapy with other antineoplastic agents such as melanoma oncolysate vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital) or valspodar.

[0161] The compounds of the present invention may further be used in combination with VEGFR inhibitors. Other compounds described in the following patents and patent applications may be used in combination therapy: U.S. Patent No. 6,258,812, U.S. Patent Application Publication No. 2003 / 0105091, WO 01 / 37820, U.S. Patent No. 6,235,764, WO 01 / 32651, U.S. Patent No. 6,630,500, U.S. Patent No. 6,515,004, U.S. Patent No. 6,713,485, U.S. Patent No. 5,521,184, U.S. Patent No. 5,770,599, U.S. Patent No. 5,747,498, WO 02 / 68406. FRET, 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.

[0162] In some embodiments, the therapeutic combination comprises 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 chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. Agents may be agonists, antagonists, allosteric modulators, toxins, or more generally, may act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or arresting cell growth.

[0163] Exemplary 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 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 invention can also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of a growth factor, such as antagonists and antibodies or antigen-binding regions of hepatocyte growth factor (HGF, also known as scatter factor) that specifically bind to the receptor "c-met."

[0164] 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 the binding of integrins to their ligands (Fanslow et al., U.S. Patent Application Publication No. 2002 / 0042368), specifically binding anti-eph receptor and / or anti-eph receptor 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 the binding of integrins to their ligands (Fanslow et al., U.S. Patent Application Publication No. 2002 / 0042368), anti-eph receptor and / or anti-eph receptor antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-eph receptor antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 016271 ... or anti-ephrin antibodies or antigen-binding regions (U.S. Pat. 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), and 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).

[0165] Additional anti-angiogenic / anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 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); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC: anti-angiogenic agent (ConjuChem, Canada); angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 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 (Abbott, 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 Publication No. 02233610); Platelet Factor 4 (RepliGen, USA, EP 407122); Vascular Endothelial Growth Factor Antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis Inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, α5β3 Integrin, 2nd Generation (Applied Molecular Evolution, USA and MediImmune, USA); Gene Therapy, Retinopathy (Oxford BioMedica, UK); Enzastaurin Hydrochloride (USAN), (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitors (Alchemia, Australia); VEGF antagonists (Regeneron, USA); rBPI21 and BPI-derived antiangiogenic agents (XOMA, USA); PI88 (Progen, Australia); cilengitide (pINN) (Merck KGaA; Munich Technical University, Scripps Clinic and Research Foundation, USA); cetuximab (INN) (Aventis, France); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); endostatin (Boston Children's Hospital, USA); ATN161 (Attenuon, USA); angiostatin (Boston Children's Hospital, USA); 2-methoxyestradiol (Boston Children's Hospital, USA); ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (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); xanthorrhizol (Yonsei University, South Korea); gene-based vaccine, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California, San Diego, USA); PX478 (ProlX, USA); metastatin (EntreMed, USA); troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, USA) University, Canada; CDP791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); vaccine, angiogenesis (EntreMed, USA); urokinase plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1 alpha inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea) Korea); GW2286 (GlaxoSmithKline, UK); EHT0101 (ExonHit, France); CP868596 (Pfizer, USA);CP564959 (OSI, USA); CP547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN633 (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol (EntreMed, USA); Anginex (Maastricht University, Netherlands and University of Minnesota, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-α inhibitor (National Institute on Aging, USA); SU11248 (Pfizer, USA and SUGEN, USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB116 (University of South Florida, USA and Yale University, USA); CS706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG13925 (Agouron, USA); tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South MAb, vascular endothelial growth factor (Xenova, UK); Irsogladine (INN) (Nippon Shinyaku, Japan);RG13577 (Aventis, France); WX360 (Wilex, Germany); squalamine (pINN) (Genaera, USA); RPI4610 (Sirna, USA); cancer therapy (Marinova, Australia); heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (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); TZ93 (Tsumura, Japan); tumstatin (Beth Israel Hospital, USA); cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0166] 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, cAMP analogs, and drugs 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 (involved in autophagy), can also be used.

[0167] 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; pegfilblastim; palifermin; filgrastim; denosumab; ancestim; AMG102; AMG386; AMG479; AMG655; AMG745; AMG951; and AMG706, or pharmaceutically acceptable salts thereof.

[0168] 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), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin A), etc.), and / or other chemotherapeutic agents such as steroids, steroids, steroid hormones, steroid hormone receptor antagonists (e.g., steroid hormone receptor antagonists), ... D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and eliminates cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, nitrogen mustards (e.g., antiproliferative / antimitotic alkylating agents such as 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, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan, nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozocin), trazene-dacarbazine (DTIC), folic acid analogs (e.g., antiproliferative / antimitotic antimetabolites such as 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 hydroamic 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), multikinase inhibitors (e.g., TG02 and sorafenib), hormone (e.g., estrogen) and hormonal agonists such as leutinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN163L), 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., 17AAG 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., Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or analogs or derived variants of any of the above.

[0169] 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.

[0170] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, and flurandole. In certain embodiments, the compounds of the present invention may include, but are not limited to, benzodiazepine, 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 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 to treat nausea. Examples of drugs that can be used to treat nausea include the following: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0171] 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 EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and anti-immunotherapies (including PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents), GITR agonists, CAR-T cells, and BiTEs.

[0172] 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, e.g., 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.

[0173] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European Patent Application Publication No. 520722, published December 30, 1992; European Patent Application Publication No. 566226, published October 20, 1993; International Patent Application Publication No. WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, published May 5, 1998; and International Patent Application Publication No. WO 96 / 33980, published October 3, 1996. European Patent Application Publication No. 30347; European Patent Application Publication No. 787772, published August 6, 1997; International Patent Application Publication No. WO 97 / 30034, published August 21, 1997; International Patent Application Publication No. WO 97 / 30044, published August 21, 1997; International Patent Application Publication No. WO 97 / 38994, published October 23, 1997; International Patent Application Publication No. WO 97 / 49688, published December 31, 1997; European Patent Application Publication No. 837063, published April 22, 1998; and International Patent Application Publication No. WO 98 / 02434, published January 22, 1998. International Publication No. WO 97 / 38983, published October 23, 1997; International Publication No. WO 95 / 19774, published July 27, 1995; International Publication No. WO 95 / 19970, published July 27, 1995; International Publication No. WO 97 / 13771, published April 17, 1997; International Publication No. WO 98 / 02437, published January 22, 1998; International Publication No. WO 98 / 02438, published January 22, 1998; International Publication No. WO 97 / 32881, published September 12, 1997 FRET; German Patent Application Publication No. 19629652, published January 29, 1998; International Publication No. WO 98 / 33798, published August 6, 1998; International Publication No. WO 97 / 32880, published September 12, 1997; International Publication No. WO 97 / 32880, published September 12, 1997; European Patent Application Publication No. 682027, published November 15, 1995; International Publication No. WO 97 / 02266, published January 23, 1997; International Publication No. WO 97 / 27199, published July 31, 1997;International Publication No. WO 98 / 07726, published February 26, 1998; International Publication No. WO 97 / 34895, published September 25, 1997; International Publication No. WO 96 / 31510, published October 10, 1996; International Publication No. WO 98 / 14449, published April 9, 1998; International Publication No. WO 98 / 14450, published April 9, 1998; International Publication No. WO 98 / 14451, published April 9, 1998; International Publication No. WO 95 / 09847, published April 13, 1995; International Publication No. WO 97 / 19065, published May 29, 1997 No. 5,656,643, published August 12, 1997; WO 99 / 35146, published July 15, 1999; WO 99 / 35132, published July 15, 1999; WO 99 / 07701, published February 18, 1999; and WO 92 / 20642, published November 26, 1992. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.

[0174] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, S. M., 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.

[0175] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0176] PI3K inhibitors include wortmannin, the 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 GDC0941, described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3 (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 (Axon 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one available from Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride available from Axon Medchem), PIK75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride available from Axon Medchem), PIK90 (Axon N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from 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), 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), 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.

[0177] AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Akt1 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., interferes with membrane localization of Akt; 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).

[0178] 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 FKBP12 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-hydroxyethyl) Rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in WO 05005434; U.S. Pat. No. 5,258,389; International Publication No. 94 / 090101, International Publication No. 92 / 05179, U.S. Patent No. 5,118,677, U.S. Patent No. 5,118,678, U.S. Patent No. 5,100,883, U.S. Patent No. 5,151,413, U.S. Patent No. 5,120,842, International Publication No. 93 / 111130, International Publication No. 94 / 02136, International Publication No. 94 / 02485, International Publication No. 95 / 140 23, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, derivatives disclosed in 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).

[0179] 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. Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (International Publication No. WO 2006 / 121168A1), each of which is expressly incorporated herein by reference. These include: Yervoy™ (ipilimumab) or tremelimumab (to CTLA-4), galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1), AMP224 (to B7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1), MEDI-570 (to ICOS), AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to LAG-3), BMS-663513 (to CD137), PF-05082566 (to CD137), CDX-1127 (to CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to OX40L), atacicept (to TACI), CP-870893 (to CD40), lucatumumab (to CD40), dacetuzumab (to CD40), muromonab-CD3 (to CD3), ipilimumab (to CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0180] GITR agonists include GITR fusion proteins described in U.S. Pat. No. 6,111,090box.c, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, WO 2010 / 003118 and WO 2011 / 090754, or GITR fusion proteins described in, for example, U.S. Pat. No. 7,025,962, European Patent No. 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, European Patent No. 1866339, WO 2011 / 028683, WO 2013 / 039954, These include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the anti-GITR antibodies described in WO 2005 / 007190, WO 2007 / 133822, WO 2005 / 055808, WO 99 / 40196, WO 2001 / 03720, WO 99 / 20758, WO 2006 / 083289, WO 2005 / 115451, U.S. Pat. No. 7,618,632, and WO 2011 / 051726.

[0181] The compounds described herein can be used in combination with the drugs disclosed herein or other suitable drugs, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with the other drugs described above. When used in combination therapy, the compounds described herein are administered simultaneously with the second drug or separately. This combination administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the drugs described above can be formulated together in the same dosage form and co-administered. Alternatively, the compounds of the present disclosure and any of the drugs described above can be administered simultaneously, where both drugs are in separate formulations. In another alternative, the compounds of the present disclosure can be administered followed by any of the drugs described above, or the reverse order can be used. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the drugs described above are administered within minutes, hours, or days.

[0182] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided foil packet. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing medical professional. [Example]

[0183] experiment Abbreviations: The following abbreviations may be used herein:

[0184] [Table 14]

[0185] [Table 15]

[0186] Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated. All microwave-assisted reactions were performed using a Smith Synthesizer™ from 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 measured by electrospray ionization technique. All examples were >90% purified as determined by high-performance liquid chromatography. Unless otherwise noted, reactions were carried out at room temperature.

[0187] In synthesizing the compounds of the present invention, the use of certain leaving groups may be desirable. The term "leaving group" ("LG") generally refers to a group displaceable by a nucleophile. Such leaving groups are well known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylates, tosylates), sulfides (e.g., SCH), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), and the like.

[0188] The following examples illustrate specific embodiments of the present invention, and are meant to be representative and are not intended to limit the scope of the claims in any way.

[0189] Note that when percent (%) is used with respect to a liquid, it refers to the volume percent of the solution. When used with a solid, it refers to the solid composition percent. Materials obtained from commercial sources were typically used without further purification. Reactions involving air- or moisture-sensitive reagents were typically performed under a nitrogen or argon atmosphere. Purity was determined using a high-performance liquid chromatography (HPLC) system equipped with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6 × 150 mm, 5 μm, 5–100% CH3CN in HO with 0.1% TFA, 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6 × 75 mm, 10–90% CH3CN in HO with 0.1% formic acid, 1.0 mL / min for 12 min) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed using prepacked silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). 1 H NMR was 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 reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or other internal standard in the appropriate solvent as specified. 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 determined on an Agilent 1100 Series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0190] General synthetic scheme Unless otherwise noted, starting materials and reagents used in preparing these compounds were purchased from Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. These compounds are available from commercial sources, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), and are prepared by methods known to those skilled in the art. These schemes are merely illustrative of some of the ways in which the compounds of the invention may be synthesized; various modifications to these schemes may be made and will be suggested to those skilled in the art having reference to this disclosure. The starting materials and intermediates, as well as the end products of the reactions, can be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0191] Unless indicated to the contrary, the reactions described herein are carried out at atmospheric pressure, at a temperature ranging from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably at about room (or ambient) temperature, e.g., about 20° C.

[0192] For clarity in this General Synthesis section, compounds of formula (I) as defined in the Summary of the Invention may be prepared by adding a ring Ar 1 and ring Ar 2 can be schematically depicted as including: [ka] wherein the group L is —NR 10 —(C═O)— or —(C═O)—NR 10 - and X 1 is N or -CR 3 and X 2 is N or -CR 4 and X 3 is N or -CR 1 and the ring Ar 1 is located to the left of the linker, and the ring Ar 2 is located to the right of the linker).

[0193] In general, compounds of formula (I) can be synthesized via three general steps: Step 1: Ring Ar 1 Compound preparation. Step 2: Ring Ar 2 Compound preparation. Step 3: Ring Ar 1 Compound ring Ar 2 Coupling to compounds.

[0194] The following general Schemes A-D are intended to provide guidance to a synthetic chemist of ordinary skill who will readily appreciate that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be modified as necessary and well within the skill and judgment of one of ordinary skill in the art.

[0195] In one embodiment, the following Schemes A to C illustrate the compound of formula (Ia): [ka] (wherein, preferably, R 5 is H), 10 -(C=O);X1 Ga-CR 4 and X 2 is N;X 3 Ga-CR 1 This provides a general preparation of compounds of formula (I)

[0196] Examples of compounds of formula (Ia) include, but are not limited to: [ka] (wherein, preferably, R 5 is H).

[0197] In another embodiment, the following Schemes A-C illustrate the compound of formula (Ic): [ka] Formula (I) (wherein L is -NR 10 -(C=O);X 1 is -N;X 2 Ga-CR 3 and X 3 Ga-CR 1 This provides a general preparation of compounds of formula (I)

[0198] Examples of compounds of formula (Ic) include, but are not limited to: [ka] Examples include:

[0199] Scheme A: Preparation of compound (Ia) or (Ic): According to Scheme A, in one embodiment, compounds of formula (I) disclosed herein can be synthesized as follows: Step 1a: Ring Ar 1 Compound preparation: [ka] Step A-1: ​​Ring Ar 1 Compound preparation: Compound A-1 (wherein, W 1where R is H) can be converted to the sulfonyl chloride by treatment with chlorosulfonic acid. 13 Further reaction with a base such as 2-(2-methyl-2-phenylpropanol) gives sulfonamide A-2. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride. R 13 Examples of amines include, but are not limited to, tert-butylamine, cyclopropylamine, cyclohexylamine, piperidine, or 4,4-difluoropiperidine.

[0200] Alternatively, compound A-1 (wherein W 1 is F) can be converted to the sulfonyl chloride by a two-step procedure, which involves treatment with benzyl mercaptan followed by oxidative chlorination with 1,3-dichloro-5,5-dimethylhydantoin. Compound A-1 is commercially available or can be synthesized by known methods by one skilled in the art.

[0201] Examples of compound A-1 include, but are not limited to, 1-methyl-3-nitrobenzene, 1-chloro-4-nitrobenzene, 1-methoxy-4-nitrobenzene, 1-methoxy-3-nitrobenzene, or 3,5-difluoronitrobenzene.

[0202] Compound A-2 can then be reacted with a suitable reducing agent, such as a palladium catalyst, such as Pd / C, and a hydrogen source in the presence of hydrogen gas to form compound A-3.

[0203] Step A-1-a: Ring Ar 1 Compound preparation: [ka] Alternatively, compound A-4 may be R 13After reacting with an amine reagent, metal-catalyzed amination can be followed, in which a suitable palladium or copper catalyst and base are used to form compound A-3 as defined in step A-1. An example of commercially available compound A-4 is 3-bromo-2-fluorobenzenesulfonyl chloride.

[0204] Step A-1-b: Ring Ar 1 Compound preparation: [ka] Alternatively, thiol compound A-5 can be prepared by a thiol alkylation reaction to give R 13 After reacting with the reagent, an oxidation reaction follows to give compound A-3 (wherein R 2 =SO2R 13 The R that can be used in this method 13 Examples of reagents include, but are not limited to, methylenecyclobutane, 2,2,2-trifluoroethyl 4-methylbenzenesulfonate, or cyclopent-2-enone.

[0205] Step A-1-c: Ring Ar 1 Compound preparation: [ka] Further alternatively, compound A-1 (wherein W 1 is halo, e.g., fluoro, chloro, or bromo, can be prepared by the addition of a suitable R 2 After reacting with the reagent, it can be reacted with a suitable reducing agent, such as a palladium catalyst, such as Pd / C, and a hydrogen source in the presence of hydrogen gas to form compound A-3.

[0206] Compound A-1 is commercially available or can be synthesized by known methods by one skilled in the art.

[0207] Examples of compound A-1 include, but are not limited to, 1-fluoro-3-nitrobenzene, 1,3-difluoro-5-nitrobenzene, 1-fluoro-3-methyl-5-nitrobenzene, or 2-bromo-1-fluoro-4-nitrobenzene.

[0208] R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethan-1-ol, or (6) 2-amino-3-methylpropan-1-ol.

[0209] Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0210] Step A-1-d: Ring Ar 1 Compound preparation: [ka] Further alternatively, compound A-1 as defined in step A-1c can be prepared in an amination reaction by reacting a suitable R 2 After reacting with the reagent, it can be reacted with a suitable reducing agent, such as a palladium catalyst, such as Pd / C, and a hydrogen source in the presence of hydrogen gas to form compound A-3.

[0211] Step A-2: Ring Ar 2 Compound preparation: In step A-2, compound A-6 (wherein W 2 and W 3 each independently is a halogen, such as fluoro, chloro, bromo, or iodo, XCompound A-7 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 in a suitable organic solvent such as NMP, acetonitrile, dioxane, DMF, DMSO, etc. [ka]

[0212] Step A-3: Ring Ar 1 Compound ring Ar 2 Coupling to the compound followed by R 1 Introduction: [ka] In step A-3, compound A-7 obtained from step A-2 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-3 to form compound A-8.

[0213] Alternatively, compound A-3 may be directly coupled with compound A-7 obtained from step A-2 in the presence of coupling reagents 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, thionyl chloride, carbonyldiimidazole, and polyphosphonic acid anhydride in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, and the like.

[0214] Those skilled in the art of synthetic chemistry will readily appreciate that other coupling agents may be used. Examples of suitable coupling agents include a metal catalyst and an R group 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. 1 In the presence of a reagent, a halogen group W can be converted by a conversion reaction such as metal-catalyzed sulfamidation, sulfination, or sulfonylation in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF, or methylene chloride. 3 Further manipulation of the formula (Ia) or (Ic) can be used to form compound (Ia) or (Ic). Those skilled in the art will readily understand that coupling reactions such as those shown in step A-3 can be carried out under a variety of known conditions.

[0215] Scheme B: Alternative preparation of compound (Ia) or (Ic): Step B-1: Ring Ar 1 Preparation of the compound: See steps A-1 to A-1-d in Scheme A above Step B-2: Ring Ar 2 Compound preparation: [ka] Scheme B provides an alternative method for forming compounds of formula (Ia) or (Ic) disclosed herein. After any of steps A-1 to A-1d described in Scheme A, a group R 1 Alternatively, in step B-2 rather than step B-3 as in Scheme A, ring Ar 2 According to step 2b, compound B-1 (wherein W 4 and W 5wherein each of W is independently a halogen, e.g., fluoro, chloro, bromo, or iodo) can be reacted with a suitable carboxylic acid protecting group (PG1 reagent) such as methyl iodide to form a methyl ester, or with other suitable protecting groups to form other esters, such as benzyl esters, in the presence of a base such as potassium carbonate in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or the like to form compound B-2, 4 and W 5 Each of these is as defined for Compound B-1. Compound B-2 can be prepared by reacting a suitable protected amine (PG 2 The compound B-3 can be formed by reacting with an R 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 in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or DMSO. X Reacting with a reagent to form compound B-4, 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, for example, as described in Greene's Protective Groups in Organic Synthesis.

[0216] Step B-3: Ring Ar 2 Ring Ar to Compound 1 Coupling of compounds and removal of protecting groups [ka] Step B-3 can be carried out under the same conditions as the coupling reaction described above in Step A-3.

[0217] Scheme C Step C-1: Ring Ar1 Preparation of the compound: See steps A-1 to A-1d in Scheme A above.

[0218] Step C-2: Ring Ar 2 Compound Preparation: Compound C-1 is commercially available or can be prepared according to methods known to those skilled in the art.

[0219] Step C-3: Ring Ar 2 Ring Ar to Compound 1 Coupling and R of compounds X Introduction of [ka] Commercially available compound C-1 (e.g., 2-fluoro-3-pyridinecarboxylic acid or 3-fluoroisonicotinic acid) 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-3 to form compound C-2.

[0220] Alternatively, compound C-1 can be directly coupled with compound A-3 obtained from step A-2 in the presence of a coupling reagent 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, thionyl chloride, carbonyldiimidazole, and polyphosphonic acid anhydride in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc. Compound C-2 can be prepared by reacting a compound C-2 with an R 3 -form 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 in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or DMSO. XUpon reaction with a reagent, compound (Ia) may be formed.

[0221] Scheme D In another embodiment, the compound of formula: [ka] Compounds of formula (I) represented by the formula (Ib), (Id), and (If) as defined herein above: [ka] Compounds realised as compounds of formula (I) can be synthesised according to Scheme D.

[0222] Step D-1: Ring Ar 1 Preparation of compounds: Ring Ar 1 One embodiment of the compound has the formula: [ka] In step D-1, compound D-1 (wherein W 5 is halo, for example fluoro or chloro) in the presence of a suitable base in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride, and the like, by reacting R 2 The compound D-1 can be reacted with a reagent to form compound D-2. Examples of compound D-1 include, but are not limited to, 3-fluorobenzoic acid or 3-fluoro-3-methylbenzoic acid. Examples of R2 reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazetidine hydrochloride. Examples of bases include, but are not limited to, diisopropylethylamine and potassium carbonate.

[0223] Compound D-1 is commercially available or can be prepared according to known methods and reagents by one of ordinary skill in the art.

[0224] Step D-2: Ring Ar 2 Compound preparation: [ka] In step D-2, compound D-3 (wherein W 6 is halo, e.g., fluoro, chloro, bromo, or iodo), can be prepared by the addition of R 3 to R 4, such as (1) 6-azaspiro[2.5]octane, (2) 4,4-dimethylpiperidine, (3) 3,4,4-trimethylpiperidine, (4) 4-methyl-6-azaspiro[2.5]octane, or (5) 7-azaspiro[3.5]nonane, in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, or methylene chloride. X The compound D-3 can be reacted with a reagent to form compound D-4. Examples of compound D-3 include, but are not limited to, 2-fluoropyridin-3-amine, 2-fluoro-6-methylpyridin-3-amine, 2-fluoro-5-methylpyridin-3-amine, 4-fluoropyridin-3-amine, or 6-bromo-2-fluoropyridin-3-amine.

[0225] Step D-3: Ring Ar 2 Ring Ar to Compound 1 Coupling of compounds. [ka] In step D-3, compound D-4 (wherein X 1 is N;X 2 Ga-CR 4 and X 3 is halo, e.g., fluoro, chloro, bromo, or iodo; 6 is reacted with compound D-2 in the presence of an activating agent such as T3P or HATU or TATU, and in the presence of DIPEA, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., to give compound (D-5) (wherein X 1 is N;X 2 Ga-CR 4 and X 3 W 6 ) can be formed.

[0226] The halo group W can then be converted by a transformation reaction such as SNAr, metal-catalyzed sulfamidation, sulfination, or sulfonylation in the presence of a metal catalyst and an R1 reagent such as (1) oxetan-3-amine, (2) 2-amino-2-methylpropan-1-ol, (3) (3-aminooxetan-3-yl)methanol, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropan-1-ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethan-1-ol, or (10) cyclopropanethiol in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, DMF, or the like. 6 can be further manipulated to form compound (Id) (wherein X 1 is N, X 2 is CR 4 , and X 3 is R 1 (It is).

[0227] [ka] Alternatively, compound D-4 (wherein X 1 Ga-CR 3 and X 2 is N;X 3 is halo, e.g., fluoro, chloro, bromo, or iodo; 7 is reacted with compound D-2 in the presence of an activating agent such as T3P or HATU or TATU, and in the presence of DIPEA, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., to give compound (D-5) (wherein X 1 Ga-CR 3 and X 2 is N;X 3 W 7 ) can be formed.

[0228] Next, a metal catalyst and R 1 such as (1) oxetan-3-amine, (2) 2-amino-2-methylpropan-1-ol, (3) (3-aminooxetan-3-yl)methanol, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropan-1-ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethan-1-ol, or (10) cyclopropanethiol are reacted with the reaction product. 1 In the presence of a reagent, a halo group W can be obtained by a conversion reaction such as SNAr, metal-catalyzed sulfoamidation, sulfination, or sulfonylation in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, or DMF. 7 Further manipulation of the compound (Id) (wherein X 1 Ga-CR 3 and X 2 is N;X 3 R 1 ) can be formed.

[0229] [ka] Further alternatively, compound D-4 (wherein X 1 Ga-CR 3 and X 2 is CR 4 and X 3 is N) is reacted with compound D-2 in the presence of an activating agent such as T3P or HATU or TATU, and in the presence of DIPEA in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc., to give compound (If) (wherein X 1 Ga-CR 3 and X 2 is CR 4 and X 3 is N) can be formed.

[0230] Those skilled in the art will readily appreciate that coupling reactions such as that shown in step D-3 can be carried out under a variety of known conditions.

[0231] Ring AR 1 Preparation of intermediates Intermediate 1: 3-amino-N-(tert-butyl)-5-methylbenzenesulfonamide. [ka] Step 1: To ice-cold 1-methyl-3-nitrobenzene (2.0 g, 14.58 mmol) was added chlorosulfonic acid (14.57 mL, 219 mmol) slowly over 15 minutes. The resulting mixture was heated at 80° C. for 3 hours. The reaction mixture was quenched with crushed ice and extracted with EtOAc (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-methyl-5-nitrobenzenesulfonyl chloride as a brown liquid. The crude sample was carried on immediately to the next step. 1 H NMR (400 MHz, chloroform-d) δ 8.70 (t, J = 1.9 Hz, 1H), 8.52-8.39 (m, 1H), 8.18 (t, J = 1.7 Hz, 1H), and 2.66 (s, 3H).

[0232] Step 2: To an ice-cold solution of 2-methylpropan-2-amine (1.09 g, 14.94 mmol) and DIPEA (3.56 mL, 20.37 mmol) in DCM (50 mL) was slowly added a solution of 3-methyl-5-nitrobenzene-1-sulfonyl chloride (crude) (3.2 g, 13.58 mmol) in dichloromethane (50 mL). After the addition, the reaction mixture was slowly warmed to ambient temperature, where it was stirred for 2 hours. Water (100 mL) was then added and stirred for 10 minutes. The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 10% EtOAc in petroleum ether to afford N-(tert-butyl)-3-methyl-5-nitrobenzenesulfonamide (1.9 g, 6.98 mmol, 51% yield) as a pale yellow solid. 1H NMR (300 MHz, chloroform-d) δ 8.56 (d, J = 5.8 Hz, 1H), 8.27-8.16 (m, 1H), 8.10-7.99 (m, 1H), 4.86 (s, 1H), 2.57 (s, 3H), and 1.42-1.12 (s, 9H). MS (ESI negative ion) m / z: 271.2 (M-1).

[0233] Step 3: A mixture of N-(tert-butyl)-3-methyl-5-nitrobenzenesulfonamide (1.9 g, 6.98 mmol) and 10% Pd / C (0.6 g, 0.56 mmol) in MeOH (50 mL) was stirred under a hydrogen atmosphere (approximately 14.5 psi—balloon pressure) for 3 hours and then filtered through a CELITE® pad. The pad was rinsed with methanol (150 mL). The filtrate was concentrated under reduced pressure to give a white residue. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with a gradient of 15–20% EtOAc in petroleum ether to give 3-amino-N-(tert-butyl)-5-methylbenzenesulfonamide (1.2 g, 4.95 mmol, 71% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.33-7.13(m,1H), 6.83(dq,J=4.7, 2.2Hz, 1H), 6.76(dd,J=3.8, 2.2Hz, 1H), 6.52(q,J=3.5, 2 .6Hz, 1H), 5.55-5.29(m,2H), 2.27-2.05(s,3H), and 1.20-0.98(s,9H).m / z(ESI):243.1(M+1).

[0234] [Table 16]

[0235] Intermediate 2: 3-amino-N-(tert-butyl)-5-fluorobenzenesulfonamide [ka] Step 1: To a mixture of 3,5-difluoronitrobenzene (1 mL, 8.80 mmol), potassium carbonate (0.59 mL, 9.68 mmol), and DMF (10 mL) at 0 °C, benzyl mercaptan (1.1 mL, 9.24 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and water was added (10 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was used without further purification.

[0236] Step 2: To a 100 mL round-bottom flask was added benzyl(3-fluoro-5-nitrophenyl)sulfane (1.63 g, 6.19 mmol), acetonitrile (12 mL), water (0.3 mL), and acetic acid (0.45 mL). The reaction mixture was cooled to 0 °C, and 1,3-dichloro-5,5-dimethylhydantoin (1.14 mL, 8.67 mmol) was added portionwise. Upon completion of the addition, the reaction mixture was stirred at 0 °C for 20 minutes, then diluted with saturated NaHCO and extracted with EtOAc. The organic extract was washed with water and dried over NaSO. The solution was filtered and concentrated under reduced pressure to give the crude material, 3-fluoro-5-nitrobenzene-1-sulfonyl chloride (1.48 g, 6.19 mmol, 100% yield), as a white solid, which was used without further purification. m / z (ESI): 240.2 (M+1).

[0237] Step 3: To a 100 mL round-bottom flask was added 3-fluoro-5-nitrobenzene-1-sulfonyl chloride (1.66 g, 6.92 mmol), tert-butylamine (0.51 mL, 6.92 mmol), DIPEA (1.81 mL, 10.38 mmol), and dichloromethane (10 mL). The mixture was stirred at room temperature for 3 hours, diluted with saturated NaHCO3, and extracted with dichloromethane (6 mL). The organic extract was washed with water and dried over Na2SO4. The solution was filtered and concentrated under reduced pressure to give the crude material as a white oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with a gradient of 0% to 25% EtOAc in heptane to give N-(tert-butyl)-3-fluoro-5-nitrobenzenesulfonamide (1.02 g, 3.70 mmol, 53% yield) as a white solid. m / z(ESI):290.2(M+Na).

[0238] Step 4: To a 25 mL glass vial was added iron (299 mg, 5.43 mmol), ammonium chloride (48 mg, 0.905 mmol), N-(tert-butyl)-3-fluoro-5-nitrobenzenesulfonamide (500 mg, 1.81 mmol), and EtOH (6 mL), followed by 0.5 mL of water. The reaction mixture was stirred at 80 °C for 1 hour, cooled to room temperature, filtered over CELITE®, and the solvent was removed under reduced pressure. The reaction mixture was diluted with saturated NH Cl (10 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (10 mL) and dried over Na SO . The solution was filtered and concentrated under reduced pressure to give the crude material as a white oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 0% to 40% EtOAc in heptane to afford 3-amino-N-(tert-butyl)-5-fluorobenzenesulfonamide (334 mg, 1.35 mmol, 75% yield) as a white solid. 1H NMR (400MHz, chloroform-d)δ 6.99(t,J=1.76Hz, 1H), 6.93(td,J=1.91, 8.12Hz, 1H), 6.51(td,J=2.35, 10.17Hz, 1H), 4.52(s,1H), 1.26(s,9H).m / z(ESI):247.1(M+1).

[0239] Intermediate 3: 3-amino-N-(tert-butyl)-2-fluorobenzenesulfonamide. [ka] Step 1: To a solution of 3-bromo-2-fluorobenzenesulfonyl chloride (4.0 g, 14.62 mmol) in dichloromethane (40 mL) under a nitrogen atmosphere, triethylamine (6.12 mL, 43.9 mmol) and tert-butylamine (2.33 mL, 21.94 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (30 mL), and the biphasic mixture was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with 5% to 8% EtOAc in hexanes to afford 3-bromo-N-(tert-butyl)-2-fluorobenzenesulfonamide (3.5 g, 77% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 8.01-7.95(m,2H), 7.85-7.80(m,1H), 7.36-7.31(m,1H), 1.13(s,9H).m / z(ESI):308.1[M-1].

[0240] Step 2: To a solution of 3-bromo-N-(tert-butyl)-2-fluorobenzenesulfonamide (3.2 g, 10.32 mmol) in ethylene glycol (5 mL) under a nitrogen atmosphere, N1,N2-dimethylethane-1,2-diamine (0.091 g, 1.032 mmol), potassium carbonate (0.28 g, 2.06 mmol), copper(I) oxide (0.074 g, 0.516 mmol), and aqueous ammonia (7.5 mL) were added. The reaction vessel was closed and stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by silica gel chromatography eluting with 25% to 35% EtOAc in hexanes to give 3-amino-N-(tert-butyl)-2-fluorobenzenesulfonamide (0.90 g, 3.65 mmol, 35% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6): δ 7.56(s,1H), 6.98-6.88(m,3H), 5.50(s,2H), 1.12(s,9H).m / z(ESI):247.2[M+1].

[0241] Intermediate 4: 3-((1-methylcyclobutyl)sulfonyl)aniline [ka] Step 1: To a mixture of 3-aminobenzenethiol (3.0 g, 23.96 mmol) and methylenecyclobutane (2.94 g, 43.1 mmol) in diethyl ether (30.0 mL), concentrated H2SO4 (3.83 mL, 71.9 mmol) was carefully added and stirred at room temperature for 45 min. The reaction mixture was quenched by pouring into cold saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic extracts were washed with cold water (5 × 50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 1% to 15% EtOAc in hexanes to give 3-((1-methylcyclobutyl)thio)aniline (3.2 g, 69% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d): δ 7.02-6.95 (m, 1H), 6.63 (s, 1H), 6.55-6.45 (m, 2H), 2.27-2.14 (m, 2H), 2.08-1.84 (m, 4H), 1.45 (m, 3H). No visible NH protons. m / z (ESI): 194.2 [M+1].

[0242] Step 2: To a solution of 3-((1-methylcyclobutyl)thio)aniline (3.0 g, 15.52 mmol) in tetrahydrofuran (30 mL) was added Boc anhydride (7.21 mL, 31.0 mmol) and triethylamine (3.24 mL, 23.28 mmol) at room temperature and stirred for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 8% EtOAc in hexanes to afford tert-butyl (3-((1-methylcyclobutyl)thio)phenyl)carbamate (3.2 g, 70% yield) as a white solid. 1H NMR (300MHz, chloroform-d):δ 7.44-7.33(m,2H), 7.30-7.20(m,1H), 7.10(d,J=7.6Hz, 1H), 6.50(s,1H), 2.42-2 .26(m,2H), 2.16-1.93(m,4H), 1.57(s,9H), 1.54(s,3H).m / z(ESI):294.2[M+1].

[0243] Step 3: To a solution of tert-butyl (3-((1-methylcyclobutyl)thio)phenyl)carbamate (2.0 g, 6.82 mmol) in methanol (40 mL) and water (20 mL), oxone (9.22 g, 15.00 mmol) was added and stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7 with 10% aqueous NaHCO (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (100 mL), dried over 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 eluting with a gradient of 1% to 40% EtOAc in hexanes to afford tert-butyl (3-((1-methylcyclobutyl)sulfonyl)phenyl)carbamate (1.8 g, 81% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 9.78(s,1H), 8.05(s,1H), 7.78-7.68(m,1H), 7.53(d,J=8.0Hz, 1H), 7.39(d,J=7.8Hz, 1H), 2.72-2.64(m ,2H), 2.00(dt,J=10.8, 7.8Hz, 1H), 1.91-1.68(m,3H), 1.49(s,9H), 1.35(s,3H).m / z(ESI):326.1[M+1].

[0244] Step 4: To a solution of tert-butyl (3-((1-methylcyclobutyl)sulfonyl)phenyl)carbamate (1.8 g, 5.53 mmol) in 1,4-dioxane (20 mL) was added HCl (4 M in 1,4-dioxane, 6.91 mL, 27.7 mmol) at 0 °C and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure and adjusted to pH 7-8 with 10% aqueous NaHCO3. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (100 mL) to give 3-((1-methylcyclobutyl)sulfonyl)aniline (1.05 g, 84% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.34-7.21(m,1H), 7.00(s,1H), 6.93-6.79(m,2H), 5.66(s,2H), 2.73-2.59(m, 2H), 2.07-1.93(m,1H), 1.85-1.76(m,3H), 1.35(s,3H).m / z(ESI):226.1[M+1].

[0245] Intermediate 5: 3-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)aniline. [ka] Step 1: To a solution of 2,2,2-trifluoroethan-1-ol (5.0 g, 50.0 mmol) in dichloromethane (300 mL), triethylamine (4.64 mL, 33.3 mmol) and p-toluenesulfonyl chloride (6.35 g, 33.3 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was quenched with water (200 mL) and extracted with dichloromethane (2 x 500 mL). The combined organic extracts were washed with water, dried over NaSO, filtered, and concentrated under reduced pressure to give 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (5 g, 59% yield) as an off-white solid. 1H NMR (400MHz, chloroform-d): δ 8.85(d,J=8.5Hz, 2H), 8.43(d,J=8.5Hz, 2H), 5.38(q,J=10.2Hz, 2H), 3.50(s,3H).m / z(ESI):255.1[M+1].

[0246] Step 2: To a solution of 3-aminobenzenethiol (4.43 g, 35.4 mmol) in THF (225 mL) was added sodium hydride (1.77 g, 44.3 mmol) at 0 °C and stirred for 30 min. Next, 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (9.0 g, 35.4 mmol) was added, and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with water, dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 5% to 10% EtOAc in hexanes to give 3-((2,2,2-trifluoroethyl)thio)aniline (5 g, 68% yield) as a light brown oil. 1 H NMR (300MHz, DMSO-d6):δ 6.99(d,J=7.7Hz, 1H), 6.66-6.58(m,2H), 6.47(d,J=8.0Hz, 1H), 5.22(s,2H), 3.87(q,J=10.2Hz, 2H).m / z(ESI):208.2[M+1].

[0247] Step 3: To a solution of 3-((2,2,2-trifluoroethyl)thio)aniline (5.0 g, 24.13 mmol) in tetrahydrofuran (50 mL), triethylamine (6.73 mL, 48.3 mmol) and BocO (8.40 mL, 36.2 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column eluted with a gradient of 5% to 8% EtOAc in hexanes to afford tert-butyl (3-((2,2,2-trifluoroethyl)thio)phenyl)carbamate (4.2 g, 57% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6):δ 9.43(s,1H), 7.62(s,1H), 7.33(d,J=8.4Hz, 1H), 7.27-7.21(m,2H), 3.93(q,J=10.0Hz, 2H), 1.48(s,9H).m / z(ESI):308.1[M+1].

[0248] Step 4: To a solution of tert-butyl (3-((2,2,2-trifluoroethyl)thio)phenyl)carbamate (4.2 g, 13.67 mmol) in methanol (40 mL) and water (20 mL), oxone (9.24 g, 30.1 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The reaction mixture was neutralized with 10% aqueous NaHCO3 and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with water (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (3-((2,2,2-trifluoroethyl)sulfonyl)phenyl)carbamate (3.2 g, 69% yield) as a white solid. 1H NMR (300MHz, DMSO-d6):δ 9.86(s,1H), 8.22(s,1H), 7.70(d,J=7.2Hz, 1H), 7.64-7.56(m,2H), 4.92(q,J=10.0Hz, 2H), 1.49(m,9H).m / z(ESI):338.0[M-1].

[0249] Step 5: To a solution of tert-butyl (3-((2,2,2-trifluoroethyl)sulfonyl)phenyl)carbamate (8.5 g, 25.05 mmol) in dry tetrahydrofuran (50 mL) was added methyl iodide (15.66 mL, 250 mmol) and HMPA (43.6 mL, 250 mmol) at 0 °C. The reaction mixture was cooled to -78 °C, and LDA (2 M solution in THF, 31.3 mL, 62.6 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 30 min and allowed to warm to room temperature. The reaction mixture was diluted with saturated aqueous NH4Cl (100 mL) and extracted with diethyl ether (3 x 250 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with 5% to 7% EtOAc in hexanes to afford tert-butyl (3-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)carbamate (1.9 g, 21% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 9.86(s,1H), 8.15(s,1H), 7.80(d,J=8.7Hz, 1H), 7.62-7.58(m,1H), 7.50(d,J=7.9Hz, 1H), 1.58-1.43(m,15H).m / z(ESI):366.2[M-1].

[0250] Step 6: To a solution of tert-butyl (3-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)carbamate (1.8 g, 4.90 mmol) in 1,4-dioxane (20 mL) was added hydrochloric acid (4 N solution in 1,4-dioxane, 12.3 mL, 49.0 mmol) at 0 °C and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and adjusted to pH 7-8 with 10% aqueous NaHCO3. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by Isolera-Biotage eluting with 17%-19% EtOAc in hexanes to give 3-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)aniline (0.9 g, 69% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ 7.30(d,J=7.9Hz, 1H), 7.08(s,1H), 7.00-6.89(m,2H), 5.75(s,2H), 1.49(s,6H).m / z(ESI):268.1[M+1].

[0251] Intermediate 6: 3-((3,3-difluorocyclopentyl)sulfonyl)aniline. [ka] Step 1: To a solution of 3-aminobenzenethiol (10.0 g, 80 mmol) in acetone (160 mL) was added Boc anhydride (37.1 mL, 160 mmol) and 10% aqueous NaCO solution (20 mL, 160 mmol). The reaction mixture was stirred at room temperature for 18 h, quenched with water (250 mL), and extracted with EtOAc (3 × 250 mL). The combined organic extracts were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by flash chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 1% to 15% EtOAc in hexanes to afford tert-butyl (3-mercaptophenyl)carbamate (11 g, 61% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 13.1 (s, 1H), 7.56 (s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 7.31 (dd, J = 7.6, 7.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 1.52 (s, 9H).

[0252] Step 2: A mixture of tert-butyl (3-mercaptophenyl)carbamate (10.0 g, 44.4 mmol) and cyclopent-2-enone (14.58 g, 178 mmol) was stirred for 24 hours at 120° C. The reaction mixture was absorbed directly onto a plug of silica gel and purified by silica gel chromatography eluting with 9% to 12% EtOAc in hexanes to give tert-butyl (3-((3-oxocyclopentyl)thio)phenyl)carbamate (10.0 g, 73% yield) as a colorless viscous oil. 1 H NMR (300 MHz, chloroform-d) δ 7.54 (s, 1H), 7.28-7.17 (m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 3.94 (t, J = 8.0 Hz, 1H), 2.71-2.58 (m, 1H), 2.45-2.20 (m, 4H), 2.12-1.97 (m, 1H), 1.53 (s, 9H). m / z (ESI): 308.6 [M+1].

[0253] Step 3: To a solution of tert-butyl (3-((3-oxocyclopentyl)thio)phenyl)carbamate (5.0 g, 16.27 mmol) in MeOH (100 mL) was added a solution of oxone (22 g, 35.8 mmol) in water (50 mL) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was extracted with DCM (3 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to afford tert-butyl (3-((3-oxocyclopentyl)sulfonyl)phenyl)carbamate (4.5 g, crude) as a pale yellow oil, which was carried on directly to the next step. 1 H NMR (400MHz, DMSO-d6)δ 9.84(s,1H), 8.14(s,1H), 7.71(d,J=7.92Hz, 1H), 7.60-7.53(m,1H), 7.4 8(d,J=7.7Hz, 1H), 4.08(t,J=7.4Hz, 1H), 2.45-2.16(m,6H), 1.50(s,9H).

[0254] Step 4: To a solution of tert-butyl (3-((3-oxocyclopentyl)sulfonyl)phenyl)carbamate (1.65 g, 4.86 mmol) in DCM (20 mL) was added DAST (1.606 mL, 12.15 mmol) at −78° C. under a nitrogen atmosphere and stirred at −78° C. for 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with 1 N aqueous NaOH (10 mL), diluted with water (25 mL), and extracted with DCM (3×50 mL). The combined organic extracts were washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with 6% to 8% EtOAc in hexanes to afford tert-butyl (3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)carbamate (0.95 g, 54% yield) as a colorless viscous oil. 1H NMR (300MHz, DMSO-d6):δ 9.84(s,1H), 8.14(s,1H), 7.70(d,J=7.8Hz, 1H), 7.61-7.43(m,2H), 4.13-3 .98(m,1H), 2.41-1.95(m,6H), 1.49(s,9H).MS (ESI, anion) m / z:360.2[M-1].

[0255] Step 5: To a solution of tert-butyl (3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)carbamate (1.0 g, 2.8 mmol) in 1,4-dioxane (10 mL) was added HCl (4 M solution in dioxane, 10 mL, 40.0 mmol) at 0 °C and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in water (15 mL), adjusted to pH 7 with 10% aqueous NaHCO, diluted with HO (20 mL), and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine solution (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was adsorbed onto a plug of silica gel and purified by silica gel chromatography eluting with 20% to 25% EtOAc in hexanes to give 3-((3,3-difluorocyclopentyl)sulfonyl)aniline (250 mg, 35% yield) as a viscous oil. 1 H NMR (400 MHz, MeOD): δ 7.27 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 3.90-3.84 (m, 1H), 2.51-2.05 (m, 6H). No visible NH protons. MS (ESI, positive ion) m / z: 262.1 [M+1].

[0256] Intermediate 7: (R)-3-fluoro-5-(2-methylmorpholino)aniline. [ka] Step 1: A mixture of 1,3-difluoro-5-nitrobenzene (3.0 g, 18.86 mmol, Apollo Scientific), (R)-2-methylmorpholine (2.289 g, 22.63 mmol, Arbor Chemicals), and DIPEA (6.59 mL, 37.7 mmol) in 1,4-dioxane (30.0 mL) was stirred in a microwave at 100° C. for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a gradient of 0% to 40% EtOAc in petroleum ether to afford (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.5 g, 6.24 mmol, 33% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.54(d,J=2.3Hz,1H),7.38(dt,J=8.4,2.1Hz,1H),7.27(dt,J=12.3,2.3H z,1H),3.92(ddd,J=11.5,3.7,1.4Hz,1H),3.80(dt,J=12.2,2.2Hz,1H),3 .68(ddt,J=12.2,3.1,1.6Hz,1H),3.53-3.67(m,2H),2.79(td,J=11.9,3. 6Hz,1H),2.41-2.49(m,1H),1.16(d,J=6.2Hz,3H).m / z(ESI):241.1(M+H) + .

[0257] Step 2: To a solution of (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholino (1.8 g, 7.49 mmol) in MeOH (10 mL) and THF (10 mL), Pd on carbon (0.5 g, 4.70 mmol, Hindustan platinum) was added and stirred under H pressure (14 psi) for 16 h. The reaction mixture was filtered through a bed of CELITE®, washed with MeOH, and the combined filtrates were concentrated to give (R)-3-fluoro-5-(2-methylmorpholino)aniline (1.1 g, 5.23 mmol, 70% yield) as a beige solid. 1H NMR(400MHz,DMSO-d6):δ ppm 5.90(d,J=12.5Hz,2H),5.78(d,J=11.0Hz,1H),5.19(d,J=7.9Hz,2H),3. 86(dd,J=11.2,3.4Hz,1H),3.57(dtd,J=14.7,11.5,10.0,4.3Hz,2H),3. 43(d,J=11.6Hz,1H),3.33(m,1H),2.58(td,J=11.7,3.3Hz,1H),2.27(q, J=10.9,10.3Hz,1H),1.13(dd,J=9.6,5.7Hz,3H).m / z(ESI):211.2(M+H) + .

[0258] Intermediate 8: (R)-4-fluoro-3-(2-methylmorpholino)aniline [ka] Step 1: A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Scientific), (R)-2-methylmorpholine (1.94 g, 19.23 mmol, Arbor Chemicals), Pd(OAc) (0.36 g, 1.63 mmol), CsCO (8.89 g, 27.3 mmol), and Xantphos (0.87 g, 1.50 mmol) in dioxane (15 mL) was heated at 100 °C for 16 h. The reaction mixture was filtered through a bed of CELITE® and washed with EtOAc. The filtrate was washed with water, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% EtOAc in hexane to give (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol, 21% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6):δ ppm 7.89(ddd,J=8.9,3.9,2.8Hz,1H),7.79(dd,J=7.6,2.8Hz,1H),7.46(dd,J=12.2,8.9Hz,1H),3.90(ddd,J=11.5,3.2,1.5Hz,1H),3.68-3 .77(m,2H),3.27-3.40(m,2H),2.85(td,J=11.6,3.2Hz,1H),2.56(dd,J=11.6,10.0Hz,1H),1.15(d,J=6.3Hz,3H).m / z(ESI):241.1(M+H) + .

[0259] Step 2: To a solution of (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol) in MeOH (10 mL) and THF (10 mL) was added Pd on carbon (0.35 g, 3.29 mmol, Hindustan platinum), and the reaction mixture was stirred under H pressure (14 psi) for 16 h. The reaction mixture was filtered through a bed of CELITE®, washed with MeOH, and the filtrate was concentrated to give (R)-4-fluoro-3-(2-methylmorpholino)aniline as a beige solid, which was used directly in the next step without purification. 1 H NMR(400MHz,DMSO-d6):δ ppm 6.75(dd,J=12.9,8.5Hz,1H),6.22(dd,J=7.7,2.6Hz,1H),6.10(dt,J=8.6,3.1Hz,1H),4.84(s,2H),3.79-3.87(m,1H),3.58-3. 72(m,2H),3.07-3.20(m,2H),2.61(td,J=11.5,3.2Hz,1H),2.32(t,J=10.7Hz,1H),1.10(d,J=6.3Hz,3H).m / z(ESI):211.2(M+H) + .

[0260] Ring AR 2 Preparation of intermediates: Intermediate 9: 6-Fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid [ka] A 250 mL round-bottom flask was charged with 2,6-difluoronicotinic acid (5.0 g, 31.5 mmol), 6-azaspiro[2.5]octane (3.8 g, 34.6 mmol), and 1,4-dioxane (60 mL). DIPEA (6.6 mL, 37.9 mmol) was added, and the light brown solution was stirred at room temperature for 18 hours. The mixture was concentrated, and the residue was diluted with EtOAc (80 mL) and then washed with water (2 × 10 mL), followed by brine (10 mL). The organic phase was reduced to approximately 50 mL, and some solid began to precipitate. The suspension was allowed to stand for 18 hours. The solid was collected to give the title compound (2.35 g) as a yellow solid. The mother liquor was concentrated, and a minimal amount of EtOAc was added to dissolve all residue. The volume was reduced to approximately 20 mL, and the second crop was collected to give the title compound (2.23 g) as a yellow solid. This procedure was repeated to give a third crop of the title compound (1.10 g). All three batches were combined to give 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (5.68 g, 72% yield). 1 H NMR (400MHz, chloroform-d) δ 10.50(s,1H), 8.68(t,J=8.2Hz, 1H), 7.00(dd,J=3.1, 8.4Hz, 1H), 3.19(t,J=5.6Hz, 4H), 1.69(br s,4H), 0.47(s,4H).m / z(ESI):251.0(M+H) + .

[0261] [Table 17]

[0262] Intermediate 10: 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1: To a stirred solution of methyl 2-chloro-6-methylnicotinate (5.0 g, 26.9 mmol) in carbon tetrachloride (50 mL), AIBN (0.442 g, 2.69 mmol) and N-bromosuccinimide (4.79 g, 26.9 mmol) were added and stirred at 70 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with dichloromethane (2 × 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give methyl 6-(bromomethyl)-2-chloronicotinate (5 g, crude product) as a pale yellow oil. The crude product was carried forward without purification. MS (ESI, positive ion) m / z: 264 [M+1].

[0263] Step 2: To a solution of methyl 6-(bromomethyl)-2-chloronicotinate (5.9 g, 22.31 mmol) in DMF (50 mL) was added sodium methanesulfinate (2.73 g, 26.8 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine solution (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60–120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (120 g) eluting with a gradient of 1%–50% EtOAc in hexanes to afford methyl 2-chloro-6-((methylsulfonyl)methyl)nicotinate (4.0 g, 68% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d): δ 8.25(d,J=7.9Hz, 1H), 7.54(d,J=7.9Hz, 1H), 4.45(s,2H), 3.99(s,3H), 3.00 s, 3H).MS(ESI, cation) m / z:264.1[M+1].

[0264] Step 3: In a microwave reaction vessel (20 mL), a solution of methyl 2-chloro-6-((methylsulfonyl)methyl)nicotinate (2.0 g, 7.58 mmol) and 6-azaspiro[2.5]octane (1.012 g, 9.10 mmol) in dimethyl sulfoxide (10 mL) was added and heated for 1 h at 140 °C in a microwave reactor (Biotage microwave initiator+). The reaction mixture was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (80 g) eluting with a gradient of 1% to 40% EtOAc in hexanes to afford methyl 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.4 g, 45% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d):δ 7.99(d,J=7.7Hz, 1H), 6.83(d,J=7.7Hz, 1H), 4.29(s,2H), 3.91(s,3H), 3.57-3.40( m,4H), 3.01(s,3H), 1.52-1.39(m,4H), 0.38(s,4H).MS (ESI, cation) m / z:339.2[M+1].

[0265] Step 4: To a solution of methyl 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.4 g, 4.14 mmol) in ethanol (10 mL) and water (10 mL), sodium hydroxide (0.496 g, 12.41 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol. The aqueous layer was neutralized to pH 7 with 1.5 N HCl solution and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with brine solution (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was absorbed onto a plug of silica gel (60-120 mesh) and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 1% to 6% MeOH in DCM to afford 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (680 mg, 51% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d6)δ 13.29(s,1H), 7.95(d,J=7.6Hz, 1H), 6.91(d,J=7.6Hz, 1H), 4.53(s,2H), 3.45 -3.36(m,4H), 1.48-1.37(m,4H), 0.35(s,4H).MS (ESI, anion) m / z:323.2[M-1].

[0266] Intermediate 11: 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1: 2,6-Difluoronicotinic acid (10.6 g, 66.6 mmol) and thionyl chloride (35 mL, 480 mmol) were combined under nitrogen and heated to gentle reflux for 2 hours. The solution was concentrated to dryness under reduced pressure. Toluene (100 mL) was added to the crude product, which was evaporated to dryness once more. The crude acid chloride was dissolved in DCM (50 mL) under nitrogen and cooled in an ice bath. A mixture of triethylamine (25 mL, 180 mmol) and benzyl alcohol (7.25 mL, 70.1 mmol) in DCM (50 mL) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 30 minutes. 0.1 N HCl (100 mL) was then added, and the phases were mixed and separated. The organic phase was removed, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to give benzyl 2,6-difluoronicotinate, which was used without further purification. m / z(ESI):250.0(M+H) + .

[0267] Step 2: 4,4-Dimethyloxazolidin-2-one (0.80 g, 6.95 mmol) was dissolved in THF (15 mL) under nitrogen. Potassium t-butoxide (0.75 g, 6.68 mmol) was added, and the suspension was stirred at room temperature for 5 minutes. A solution of benzyl 2,6-difluoronicotinate (1.60 g, 6.42 mmol) in N,N-dimethylacetamide (40 mL) was added, and the mixture was stirred at room temperature for 10 minutes. Water (75 mL), EtOAc (150 mL), and saturated ammonium chloride (25 mL) were added, and the phases were mixed and separated. The organic phase was removed, washed with brine (50 mL), and evaporated to dryness under reduced pressure. Purification by silica gel chromatography (heptane to EtOAc gradient) afforded benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-fluoronicotinate (1.82 g, 5.29 mmol, 82% yield) as a white solid.

[0268] Step 3: Benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-fluoronicotinate (1.81 g, 5.23 mmol) was dissolved in NMP (20 mL). Cesium carbonate (2.00 g, 6.14 mmol) and 6-azaspiro[2.5]octane (0.60 g, 5.40 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water (100 mL) and EtOAc (150 mL) were added, and the phases were mixed and separated. The organic phase was removed, washed with brine, and evaporated to dryness under reduced pressure. Purification using silica gel chromatography (0% to 40% EtOAc in heptane) afforded benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.77 g, 4.06 mmol, 78% yield) as a milky white oil. m / z (ESI): 436.1 (M+H). + .

[0269] Step 4: Benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.77 g, 4.06 mmol) was dissolved in EtOAc (30 mL) and transferred to a pressure vessel. Ethanol (60 mL) was added, followed by 5% palladium on carbon (dry weight, 50% water, 0.250 g, 0.117 mmol). The suspension was stirred under 40 psi of hydrogen for 15 minutes. The mixture was filtered through a pad of CELITE®, and the solid was washed with EtOAc (50 mL). The combined filtrates were evaporated to dryness under reduced pressure to give 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (1.15 g, 3.33 mmol, 82% yield) as a white solid. m / z (ESI): 346.0 (M+H). + .

[0270] [Table 18]

[0271] Intermediate 12: 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid [ka] Step 1: A mixture of methyl 2,6-dichloronicotinate (5.0 g, 24.3 mmol, Combi-Blocks), DIPEA (4.7 mL, 26.7 mmol), and 6-azaspiro[2.5]octane (2.70 g, 24.27 mmol, AstaTech, Inc.) in acetonitrile (50 mL) was stirred at room temperature for 24 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (0% to 30% EtOAc in heptane) to give methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (4.34 g, 15.46 mmol, 64% yield). m / z (ESI): 281.0 (M+H). + .

[0272] Step 2: A mixture of methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (4.10 g, 14.60 mmol), tributyl(1-ethoxyvinyl)tin (5.80 g, 16.06 mmol, Aldrich), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.41 g, 0.58 mmol, Aldrich) in toluene (30 mL) was stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature, treated with HCl (4 M in dioxane, 18.25 mL, 73.00 mmol), and stirred for 2 h. The reaction mixture was then filtered through a pad of CELITE® and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3, dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0% to 30% EtOAc in heptane) to give methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (2.75 g, 9.54 mmol, 65% yield). 1H NMR (400MHz, DMSO-d6) δ ppm 8.02(d,J=7.8Hz, 1H), 7.28(d,J=7.6Hz, 1H), 3.84(s,3H), 3.38-3.51(m,4H), 2.57(s,3H), 1.33-1.53(m,4H), 0.35(s,4H).

[0273] Step 3: To a stirred solution of methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (2.50 g, 8.67 mmol) in tetrahydrofuran (1 mL) was added (trifluoromethyl)trimethylsilane (1.54 mL, 10.40 mmol, Aldrich) at 0 °C. After the addition, the mixture was stirred for 2 h. The solid was filtered off, washed with EtOAc, and concentrated. Purification by silica gel chromatography eluting with 0% to 30% EtOAc in heptane gave methyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinate (2.87 g, 8.01 mmol, 92% yield). 1 H NMR (400MHz, chloroform-d) δ ppm 8.05(d,J=7.8Hz, 1H), 6.85(d,J=7.8Hz, 1H), 6.01(s,1H), 3.91(s,3H), 3.39-3 .56(m,4H), 1.69(s,3H), 1.45-1.53(m,4H), 0.38(s,4H).m / z(ESI):359.0(M+H) + .

[0274] Step 4: To a stirred solution of methyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinate (2.87 g, 8.01 mmol) in MeOH (20 mL) at room temperature, aqueous NaOH (8.0 mL of a 5 M solution, 40.0 mmol) was added. After the addition, the reaction mixture was stirred for 3 days. The reaction mixture was concentrated, diluted with HO, and acidified with 5 N aqueous HCl (to pH 4). The precipitated solid was collected, washed with HO, and dried to give 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid (2.70 g, 98% yield). 1 H NMR (400MHz, DMSO-d6) δ ppm 13.23(br s,1H), 7.97(d,J=7.8Hz, 1H), 7.15(d,J=7.8Hz, 1H), 6.62(s,1H), 3.36-3.43 (m,4H), 1.65(s,3H), 1.33-1.44(m,4H), 0.33(s,4H).m / z(ESI):345.0(M+H) + .

[0275] AR 1 and AR 2 Coupling of intermediates Intermediate 13: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A 250 mL round-bottom flask was charged with 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (2.0 g, 8.00 mmol, Intermediate 9) and DCM (30 mL). Oxalyl dichloride (6.00 mL, 11.99 mmol) was added to the reaction mixture at room temperature, followed by a few drops of DMF. The mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure. The residue was redissolved in DCM (30 mL) and treated with 3-amino-N-(tert-butyl)benzenesulfonamide (1.80 g, 7.90 mmol), followed by DIPEA (6.98 mL, 40.0 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over NaSO, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 5% to 50% EtOAc in heptane to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-fluoro-2-(spiro[2.5]octan-6-yl)nicotinamide (3.02 g, 82% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d) δ=11.33(s,1H), 8.54(t,J=8.3Hz, 1H), 8.27(t,J=1.9Hz, 1H), 7.93(dd,J=1.1, 8.1Hz, 1H), 7.70-7.65(m,1H), 7.55-7 .47(m,1H), 6.78(dd,J=3.3, 8.4Hz, 1H), 4.62(s,1H), 3.32-3.25(m,4H), 1.61-1.56(m,4H), 1.29(s,9H), 0.41(s,4H).m / z(ESI):461.1(M+H) + .

[0276] [Table 19]

[0277] Intermediate 14: 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide [ka] To a solution of 2-fluoro-3-pyridinecarboxylic acid (1.0 g, 7.09 mmol) in DCM (9 mL) was added oxalyl dichloride (0.80 mL, 9.01 mmol) and catalytic DMF. The reaction mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue was redissolved in DCM (10 mL) and treated with 3-(piperidine-1-sulfonyl)-phenylamine (0.78 mL, 4.16 mmol) and then sodium bicarbonate (0.405 mL, 10.40 mmol). The reaction mixture was stirred at room temperature for 16 hours, after which it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 0% to 50% EtOAc in hexanes to afford 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (1.16 g, 77% yield) as a white solid. 1 H NMR (chloroform-d) δ:8.60-8.74(m,2H), 8.36-8.50(m,1H), 8.04(s,1H), 7.95(d,J=7.0Hz, 1H), 7.52-7.65(m ,2H), 7.41-7.50(m,1H), 3.02-3.10(m,4H), 1.61-1.71(m,4H), 1.40-1.50(m,2H).m / z(ESI):364.1(M+H) + .

[0278] [Table 20]

[0279] [Table 21]

[0280] Intermediate 15: 3-(2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)benzenesulfonyl chloride [ka] A 150 mL round-bottom flask was charged with N-(3-(benzylthio)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (3.01 g, 7.01 mmol, Intermediate 14-14), ACN (28 mL), aqueous HO (0.7 mL), and acetic acid (1.4 mL). The reaction mixture was cooled to 0 °C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.66 g, 8.42 mmol) was added. The reaction was stirred at 0 °C for 3 h, warmed to room temperature, and partitioned between saturated NaHCO (ca. 40 mL) and EtOAc (40 mL). The organic layer was removed, washed with water, and dried. The crude mixture was purified by Biotage (SNAP50, Ultra, eluent 5% to 40% EtOAc in heptane) to give 3-(2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)benzenesulfonyl chloride (2.01 g, 71% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ=12.51(br s,1H), 8.66(s,1H), 8.59-8.47(m,2H), 8.00(d,J=8.2Hz, 1H), 7.81(d,J=7 .8Hz, 1H), 7.70-7.61(m,1H), 7.29(s,1H), 3.29(t,J=5.4Hz, 4H), 1.66(br s,4H), 0.45(s,4H).MS (ESI, cation) m / z:406.1[M+1]. [Example]

[0281] Example 100: 2-(4,4-dimethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide. [ka] To a solution of 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (44 mg, 0.12 mmol, Intermediate 14) in ACN (1 mL) was added 4,4-dimethylpiperidine hydrochloride (33 mg, 0.22 mmol) and DIPEA (50 μL, 0.29 mmol). The reaction mixture was stirred at 85° C. for 4 hours and allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×5 mL). The combined organic extracts were concentrated under reduced pressure, adsorbed onto a plug of silica gel, and chromatographed through a silica gel column eluting with 0–60% EtOAc in heptane to give 2-(4,4-dimethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (35 mg, 0.08 mmol, 33% yield). 1 H NMR (chloroform-d) δ: 12.27(br s,1H), 8.42-8.61(m,2H), 8.14(d,J=7.0Hz, 1H), 7.91~8.04(m,1H), 7.63(d,J=5.9Hz, 1H), 7.48-7.57(m,2H), 3.20(br m / z(ESI):457.2(M+H) + .

[0282] [Table 22]

[0283] [Table 23]

[0284] [Table 24]

[0285] [Table 25]

[0286] Example 101: N-(3-(N-cyclopropylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A glass vial was charged with 3-(2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)benzene-1-sulfonyl chloride (0.049 g, 0.12 mmol, Intermediate 15), cyclopropylamine (0.01 g, 0.19 mmol), and DCM (1 mL). To the reaction mixture, DIPEA (0.065 mL, 0.37 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the crude product was purified by silica gel chromatography (10% to 70% EtOAc in heptane) to give N-(3-(N-cyclopropylsulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (43 mg, 84% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ=12.15(br s,1H), 8.50(d,J=6.3Hz, 2H), 8.39(s,1H), 7.94(d,J=8.0Hz, 1H), 7.69(d,J=7.8Hz, 1H), 7.61-7.53(m,1H), 7.24(t,J=6.0Hz, 1H), 5. 00(s,1H), 3.28(t,J=5.3Hz, 4H), 2.32(d,J=4.1Hz, 1H), 1.63(s,4H), 0.75-0.59(m,4H), 0.43(s,4H).MS(ESI, cation) m / z:427.1[M+1].

[0287] [Table 26]

[0288] [Table 27]

[0289] Example 102: (R)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] A glass vial was charged with N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.080 g, 0.17 mmol, Intermediate 13), DMSO (2 mL), (R)-3-pyrrolidinol (0.028 g, 0.33 mmol), and DIPEA (0.091 mL, 0.52 mmol). The mixture was stirred at 110 °C for 5 h and cooled to room temperature. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography with a gradient of 30% to 100% EtOAc in heptane to afford (R)-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (71 mg, 77% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6)δ 11.14(s,1H), 8.32(s,1H), 7.81-7.88(m,2H), 7.46-7.57(m,3H), 6.16(d,J=8.61Hz, 1H), 4.97(d,J=3.33Hz, 1H), 4.39(br s,1H), 3.45-3.59(m,3H), 3.39(br d,J=8.61Hz, 1H), 3.15-3.24(m,4H), 1.97-2.10(m,1H), 1.85-1.95(m,1H), 1 .42-1.50(m,4H), 1.12(s,9H), 0.30(s,4H).MS(ESI, cation) m / z:582.2[M+1].

[0290] [Table 28]

[0291] [Table 29]

[0292] [Table 30]

[0293] [Table 31]

[0294] [Table 32]

[0295] Example 103: N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] A glass vial was charged with N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (95 mg, 0.21 mmol, Intermediate 13-1), 1-amino-2-methyl-propan-2-ol (0.037 mL, 0.41 mmol), DIPEA (0.036 mL, 0.21 mmol), and DMSO (3 mL). The mixture was stirred at 85 °C for 24 h and cooled to room temperature. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography with a gradient of 0% to 100% EtOAc:EtOH (3:1) in heptane to give N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (84 mg, 77% yield). 1 H NMR(DMSO-d6)δ:11.25(s,1H), 8.39(s,1H), 7.96(d,J=8.0Hz, 1H), 7.75(d,J=8.4Hz, 1H), 7.58-7.68(m,1H), 7.53(d,J=7.8Hz, 1H), 6.98(br s,1H), 6.31(d,J=8.4Hz, 1H), 4.57(s,1H), 3.73(t,J=7.7Hz, 1H), 3.32(s, 2H), 3.16(d,J=4.7Hz, 4H), 1.74-1.98(m,4H), 1.51-1.72(m,4H), 1.46(br s,4H), 1.13(s,6H), 0.31(s,4H).MS(ESI, cation) m / z:527.2[M+1].

[0296] [Table 33]

[0297] [Table 34]

[0298] [Table 35]

[0299] [Table 36]

[0300] Example 104: N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxetan-3-yloxy)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] A mixture of N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (100 mg, 0.22 mmol, Intermediate 13-1), DIPEA (387 μL, 2.19 mmol), and 3-hydroxyoxetane (64.8 μL, 0.87 mmol) was heated at 100 °C for 24 h. HO was added, and the solid was collected, dried, and purified by silica gel column chromatography (0–50% EtOAc / heptane) to give N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxetan-3-yloxy)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (33 mg, 0.065 mmol, 30% yield). 1 H NMR(DMSO-d6)δ:10.65(s,1H), 8.35(br s,1H), 7.99(d,J=7.8Hz, 1H), 7.82(d,J=8.0Hz, 1H), 7.61-7.68(m,1H), 7.52-7.60(m,1H), 6.37(d,J=8.2Hz, 1H), 5.52-5.62(m,1H), 4. 90(t,J=6.7Hz, 2H), 4.61(t,J=6.3Hz, 2H), 3.73(dt,J=15.2, 7.6Hz, 1H), 3.33(s,4H), 1.85(d,J=5.3Hz, 4H), 1.50-1.70(m,4H), 1.36(br s,4H), 0.29(s,4H).MS (ESI, cation) m / z:512.2[M+1].

[0301] [Table 37]

[0302] Example 105: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1: A 100 mL round-bottom flask was charged with 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (549 mg, 1.59 mmol, Intermediate 11) and DCM (8 mL). Oxalyl dichloride (1.43 mL, 2.86 mmol, 2 M in DCM) was added to the reaction mixture at room temperature, followed by a few drops of DMF. The mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue was redissolved in DCM (10 mL) and treated with 3-amino-N-(tert-butyl)benzenesulfonamide (0.38 mL, 1.67 mmol) and DIPEA (1.39 mL, 7.95 mmol). The reaction mixture was stirred at room temperature for 18 hours, after which it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 0% to 60% EtOAc in heptane to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (703 mg, 1.26 mmol, 80% yield) as a pale yellow solid. MS (ESI, positive ion) m / z: 556.1 [M+1].

[0303] Step 2: A glass vial was charged with N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (703 mg, 1.26 mmol), MeOH (2 mL), and sodium hydroxide (1.26 mL, 6.33 mmol, 5N). Stirred at 70 °C for 1 h, cooled to room temperature, and the solvent was removed under reduced pressure. The residue was partitioned between half-saturated NH Cl (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with water (20 mL) and dried over Na SO . The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column eluting with a gradient of 0% to 60% EtOAc in heptane to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (485 mg, 0.92 mmol, 72% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm 11.21(s,1H), 8.32(t,J=1.45Hz, 1H), 7.84(dt,J=7.88, 1.45Hz, 1H), 7.71(d,J=8.7 1Hz, 1H), 7.50-7.57(m,2H), 7.49(dt,J=7.88, 1.45Hz, 1H), 6.60(s,1H), 6.28(d,J=8 .50Hz, 1H), 4.81(t,J=5.70Hz, 1H), 3.59(d,J=5.81Hz, 2H), 3.11-3.17(m,4H), 1.44- 1.51(m,4H), 1.36(s,6H), 1.12(s,9H), 0.31(s,4H).MS(ESI, cation) m / z:530.2[M+1].

[0304] [Table 38]

[0305] [Table 39]

[0306] [Table 40]

[0307] [Table 41]

[0308] [Table 42]

[0309] Example 106: N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxypropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] A mixture of N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (100 mg, 0.219 mmol, Intermediate 13-1), DIPEA (141 mg, 1.09 mmol), and 2-amino-1,3-propanediol hydrochloride (56 mg, 0.44 mmol) in DMSO (1 mL) was heated at 85° C. for 16 h. The reaction mixture was allowed to cool to room temperature, HO was added, and the precipitated solid was collected by filtration. The crude solid was purified by silica gel chromatography (0 to 50% EtOAc:EtOH (3:1) in heptane) to give N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxypropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (48 mg, 0.09 mmol, 41% yield). 1H NMR(DMSO-d6)δ:11.23(s,1H), 8.38(s,1H), 7.92-7.99(m,1H), 7.73(d,J=8.6Hz, 1H), 7.59-7.68(m,1H), 7.52(d,J=8.2Hz, 1H), 6.78(br s,1H), 6.26(d,J=8.6Hz, 1H), 4.63(t,J=5.5Hz, 2H), 3.92-4.07(m,1H), 3.66-3.80(m,1H), 3.47-3.63(m,4H), 3.07- 3.23(m,4H), 1.77-1.95(m,4H), 1.52-1.69(m,4H), 1.38-1.50(m,4H), 0.31(s,4H).MS(ESI, cation) m / z:529.1[M+1].

[0310] [Table 43]

[0311] Examples 107-1 and 107-2: (R)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide and (S)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide [ka] A 100 mL round-bottom flask was charged with 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid (0.87 g, 2.52 mmol, Intermediate 12) and DCM (8 mL). Oxalyl dichloride (2.52 mL, 5.05 mmol, 2 M in DCM) was added to the reaction mixture at room temperature, followed by a few drops of DMF. The mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. The residue was redissolved in DCM (10 mL) and treated with 3-amino-N-(tert-butyl)benzenesulfonamide (0.576 g, 2.52 mmol) and DIPEA (2.20 mL, 12.62 mmol). The reaction mixture was stirred at room temperature for 18 hours, after which it was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 10% to 60% EtOAc in heptane to give racemic N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide. 1 H NMR (400 MHz, chloroform-d) δ 11.19 (s, 1H), 8.52 (d, J = 8.02 Hz, 1H), 8.26 (s, 1H), 7.94 (dd, J = 1.17, 8.22 Hz, 1H), 7.68 (d, J = 7.82 Hz, 1H), 7.47-7.54 (m, 1H), 7.37 (d, J = 8.02 Hz, 1H), 5.85 (s, 1H), 4.79 (br s, 1H), 3.29-3.38 (m, 4H), 1.76 (s, 3H), 1.57-1.65 (m, 4H), 1.28 (s, 9H), 0.42 (s, 4H). MS (ESI, positive ion) m / z: 555.2 [M+1]. This material was separated by preparative SFC using an ADH column (250 × 21 mm, 5 microns) with a mobile phase of 80% liquid CO and 20% MeOH and a flow rate of 75 mL / min to give:

[0312] Example 107-1: (R)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide. First eluting peak; ee>99.5%. 1 H NMR (400 MHz, chloroform-d) δ 11.21 (s, 1H), 8.53 (d, J = 8.02 Hz, 1H), 8.27 (t, J = 1.66 Hz, 1H), 7.94 (dd, J = 1.17, 8.22 Hz, 1H), 7.68 (d, J = 8.02 Hz, 1H), 7.48-7.55 (m, 1H), 7.37 (d, J = 8.02 Hz, 1H), 5.85 (s, 1H), 4.69 (s, 1H), 3.30-3.38 (m, 4H), 1.77 (s, 3H), 1.61 (br d,J=5.28Hz, 4H), 1.28(s,9H), 0.43(s,4H).MS(ESI, cation) m / z:555.2[M+1].

[0313] Example 107-2: (S)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide. Second eluting peak; ee>99.5%. 1 H NMR (400 MHz, chloroform-d) δ 11.23(s,1H), 8.54(d,J=8.02Hz, 1H), 8.28(t,J=1.76Hz, 1H), 7.93(dd,J= 1.17, 8.22Hz, 1H), 7.69(d,J=7.82Hz, 1H), 7.49-7.56(m,1H), 7.38(d,J=7 .83Hz, 1H), 5.85(s,1H), 4.61(s,1H), 3.31-3.39(m,4H), 1.77(s,3H), 1.6 0-1.66(m,4H), 1.29(s,9H), 0.43(s,4H).MS(ESI, cation) m / z:555.2[M+1].

[0314] Stereochemistry was arbitrarily assigned.

[0315] [Table 44]

[0316] Examples 109-1 and 109-2: (S)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide and (R)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1: A 100 mL round-bottom flask was charged with N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (1.00 g, 2.09 mmol, Intermediate 13-2), AmPhos (0.151 g, 0.21 mmol), tributyl(1-ethoxyvinyl)stannane (0.85 mL, 2.51 mmol), and toluene (10 mL). The reaction mixture was stirred at 90 °C for 30 min. The mixture was cooled to room temperature, treated with HCl / dioxane (2 mL, 4 M), and stirred at room temperature for 30 min. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2 × 10 mL). The organic phase was concentrated, and the crude product was purified by Biotage (SNAP25, Ultra, eluent: 0% to 50% EtOAc in heptane) to give 6-acetyl-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.85 g, 84% yield). 1H NMR (400MHz, DMSO-d6) δ=10.79(s,1H), 8.31(s,1H), 7.95(d,J=7.4Hz, 1H), 7.87(d,J=2.9Hz, 1H), 7.60-7.52 (m,3H), 7.42(d,J=7.4Hz, 1H), 3.49-3.40(m,4H), 2.61(s,3H), 1.43-1.35(m,4H), 1.11(s,9H), 0.29(s,4H).

[0317] Step 2: A 20 mL scintillation vial was charged with trimethylsulfoxonium iodide (0.201 g, 0.914 mmol) and DMSO (1.5 mL). To this mixture was added potassium tert-butoxide (0.093 g, 0.83 mmol), and the mixture was stirred at room temperature for 30 minutes. Next, 6-acetyl-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.399 g, 0.82 mmol) in 1.0 mL of DMSO was added, and the yellow solution was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water (15 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic extracts were washed with brine (30 mL) and dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2 x 5 mL). The organic phase was concentrated to carry over the crude product. MS (ESI, positive ion) m / z: 499.2 [M+1].

[0318] Step 3: A 150 mL round-bottom flask was charged with N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(2-methyloxiran-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (2.19 g, 3.95 mmol), dioxane (12 mL), and water (12 mL). Hydrochloric acid (2.0 mL, 8.00 mmol) was then added, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with water and dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2 × 10 mL). The combined organic extracts were concentrated and purified by Biotage (SNAP100, Ultra, eluent: 40% to 100% EtOAc in heptane) to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (1.14 g, 56% yield). 1 H NMR (400 MHz, chloroform-d) δ 11.52 (s, 1H), 8.50 (d, J = 8.02 Hz, 1H), 8.27 (t, J = 1.66 Hz, 1H), 7.94 (dd, J = 1.08, 8.12 Hz, 1H), 7.67 (d, J = 8.02 Hz, 1H), 7.49-7.54 (m, 1H), 7.33 (d, J = 7.82 Hz, 1H), 4.68 (s, 1H), 4.61 (s, 1H), 3.81-3.90 (m, 1H), 3.72-3.80 (m, 1H), 3.26-3.34 (m, 4H), 2.46 (br MS (ESI, positive ion) m / z: 517.2 [M+1]. This material was separated by preparative SFC using an OX-H column (250 × 21 mm, 5 microns) with a mobile phase of 40% liquid CO and 60% MeOH (20 mM NH) and a flow rate of 50 mL / min to give the following:

[0319] Example 109-1: (S)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. First eluting peak; ee>99.5%. 1 H NMR (400 MHz, chloroform-d) δ = 11.49 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.95 (dd, J = 1.1, 8.1 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.55-7.47 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H) ), 4.78(s,1H), 3.89-3.83(m,1H), 3.79-3.72(m,1H), 3.29(t,J=5.4Hz, 4H), 1.63-1 .56(m,4H), 1.53(s,3H), 1.28(s,9H), 0.41(s,4H).MS(ESI, cation) m / z:517.2[M+1].

[0320] Example 109-2: (R)—N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. Second eluting peak; ee>99.5%. 1 H NMR (400 MHz, chloroform-d) δ = 11.50 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.25 (s, 1H), 7.95 (dd, J = 1.1, 8.1 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.54-7.47 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.81 (s, 1H), 4.69 ( dt,J=2.0, 4.1Hz, 1H), 3.89-3.81(m,1H), 3.79-3.72(m,1H), 3.32-3.24(m,4H), 2.80-2.36(m, 1H), 1.62-1.56(m,4H), 1.53(s,3H), 1.28(s,9H), 0.41(s,4H).MS(ESI, cation) m / z:517.2[M+1].

[0321] Stereochemistry was arbitrarily assigned.

[0322] Example 110: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A glass vial was charged with 6-bromo-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (96 mg, 0.185 mmol, Intermediate 13-3), methanesulfonamide (21 mg, 0.23 mmol), CuI (14 mg, 0.07 mmol), and potassium phosphate (129 mg, 0.61 mmol). The vial was evacuated and refilled with N. This procedure was repeated four more times, and DMF (1 mL) was added, followed by (1r,2r)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.017 mL, 0.11 mmol). The vial was closed, and the reaction mixture was stirred at 100° C. for 4 h. The mixture was diluted with EtOAc (4 mL) and filtered through a pad of CELITE®. The filtrate was washed with water (2 × 5 mL) and concentrated. The crude product was purified by Biotage (SNAP10, Ultra, eluent: 40% to 90% EtOAc in heptane) to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (41 mg, 42% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ=11.23(s,1H), 8.40(d,J=8.3Hz, 1H), 8.27(s,1H), 7.91(br d,J=8.1Hz, 1H), 7.66(d,J=7.7Hz, 1H), 7.55-7.47(m,1H), 6.86(d,J=8.3Hz, 1H), 4.66(s,1H), 3.38(s,3H), 3.32-3.22(m,4H), 1.60(br d,J=4.6Hz, 4H), 1.29(s,9H), 0.41(s,4H).MS(ESI, cation) m / z:536.2[M+1].

[0323] Example 111: 6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(4-methyl-3-(oxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] Step 1: A mixture of N-(3-bromo-4-methylphenyl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.5 g, 1.195 mmol, Intermediate 13-5), 2-amino-2-methyl-1-propanol (0.23 mL, 2.39 mmol), and DIPEA (0.62 mL, 3.59 mmol) in DMSO (6 mL) was heated at 140 °C for 24 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over NaSO, and filtered. The filtrate was concentrated and purified by silica gel chromatography (0–70% EtOAc / heptane) to give N-(3-bromo-4-methylphenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.26 g, 0.53 mmol, 45% yield). MS (ESI, positive ion) m / z: 487.1 / 489.1 [M+1].

[0324] Step 2: A pressure vial was charged with N-(3-bromo-4-methylphenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.050 g, 0.10 mmol), palladium tetrakis (0.024 g, 0.021 mmol), and 2-(tri-n-butylstannyl)oxazole (0.028 mL, 0.13 mmol). The vial was purged with N for several minutes, and 1,4-dioxane (1 mL) was added. The vial was closed and heated at 120° C. for 24 h. The reaction mixture was concentrated and then purified by preparative HPLC to give 6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(4-methyl-3-(oxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (15 mg, 0.032 mmol, 31% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d) δ ppm 0.42(s,4H)1.45(s,6H)1.65(br s,4H)2.69(s,3H)3.22(t,J=5.38Hz, 4H)3.75(s,2H)4.72(br s,1H)5.19(br s,1H)6.27(d,J=8.61Hz,1H)7.27-7.34(m,2H)7.67(dd,J=8.31,2.25Hz,1H)7.74(s,1H)8 .24(d,J=8.41Hz, 1H)8.44(d,J=2.15Hz, 1H)11.76(s,1H).MS(ESI, cation) m / z:476.1[M+1].

[0325] [Table 45]

[0326] [Table 46]

[0327] Example 112: N-(3-(N-(tert-butyl)sulfamoyl)-5-(furan-2-yl)phenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] Step 1: To a 5 mL microwave reaction tube was added N-(3-bromo-5-(N-(tert-butyl)sulfamoyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.084 g, 0.13 mmol, Intermediate 13-4), furan-2-ylboronic acid (0.034 g, 0.31 mmol), Pd(PPh3)4 (10 mg, 8.22 μmol), and sodium carbonate (0.20 mL, 0.40 mmol, 2 M) in dioxane (2 mL). The mixture was degassed by bubbling Ar through the reaction mixture for 5 minutes. The tube was subjected to microwave irradiation at 120 °C for 30 minutes. The mixture was cooled to room temperature and partitioned between water (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic phases were washed with water (15 mL) and saturated aqueous sodium chloride solution (15 mL). The organic phase was dried by passing through a Chem Elut extraction cartridge eluting with EtOAc (2 × 5 mL). The organic phase was concentrated, and the crude product was purified by Biotage Ultra (eluent: acetone in heptane 20% to 70%) to give N-(3-(N-(tert-butyl)sulfamoyl)-5-(furan-2-yl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (34 mg, 41% yield). 1H NMR (400MHz, chloroform-d)δ 11.95(s,1H), 8.52(d,J=8.61Hz, 1H), 8.40(s,1H), 8.04(s,1H), 7.94(s,1H), 7.90(d,J=8.61Hz, 1H), 7.53(d,J=1.37Hz, 1H), 6.83(d,J=3.33Hz, 1H), 6.54(dd,J=1.76, 3.33Hz, 1H), 4.54(s,1H), 4.15(s,2H), 3.24(t,J=5.38Hz, 4H), 1.79(s,6H), 1.67(br s,4H), 1.31(s,9H), 0.45(s,4H).MS(ESI, cation) m / z:622.0[M+1].

[0328] Step 2: A glass vial was charged with N-(3-(N-(tert-butyl)sulfamoyl)-5-(furan-2-yl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (34 mg, 0.054 mmol), MeOH (2 mL), and NaOH (0.1 mL, 0.5 mmol, 5 M). The reaction mixture was stirred at 70 °C for 1 h. The mixture was cooled to room temperature and concentrated. The residue was partitioned between half-saturated NH4Cl (3 mL) and EtOAc (3 mL). The aqueous phase was extracted with EtOAc (3 mL). The combined organic phases were concentrated and the crude product was purified by Biotage (SNAP10, Ultra, eluent: 30% to 100% EtOAc in heptane) to give N-(3-(N-(tert-butyl)sulfamoyl)-5-(furan-2-yl)phenyl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (27 mg, 84% yield) as a white solid. 1H NMR (400MHz, DMSO-d6)δ 11.24(s,1H), 8.32(s,1H), 8.08(s,1H), 7.84(d,J=1.17Hz, 1H), 7.80(s,1H), 7.70(d,J=8.61Hz, 1H), 7.62(s,1H), 6.96 (d,J=3.33Hz, 1H), 6.66(dd,J=1.76, 3.33Hz, 1H), 6.61(s,1H), 6.27(d,J=8.61Hz, 1H), 4.83(t,J=5.58Hz, 1H), 3.59(br d,J=5.48Hz, 2H), 3.12-3.19(m,4H), 1.47(br s,4H), 1.36(s,6H), 1.14(s,9H), 0.30(s,4H).MS(ESI, cation) m / z:596.3[M+1].

[0329] [Table 47]

[0330] Example 113: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] To a solution of 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (0.1 g, 0.308 mmol, Intermediate 10) in DMF (2 mL) was added HATU (0.176 g, 0.462 mmol) and diisopropylethylamine (0.135 mL, 0.771 mmol) at 0 °C and stirred for 10 min. 3-Amino-N-(tert-butyl)benzenesulfonamide (0.070 g, 0.308 mmol) was added to the reaction mixture and stirred at room temperature for 24 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 × 15 mL). The organic layer was washed with brine solution (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using a gradient of 50% EtOAc in hexanes to afford the title compound (68 mg, 28% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6):δ 10.76(s,1H), 8.32(s,1H), 7.93-7.81(m,2H), 7.62-7.51(m,3H), 7.02(d,J=7.7Hz, 1H), 4.57(s,2H), 3.36(t ,J=7.6Hz, 4H), 3.13(s,3H), 1.36(t,J=7.6Hz, 4H), 1.11(s,9H), 0.28(s,4H).MS(ESI, cation) m / z:535.2[M+1].

[0331] Example 114: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)isonicotinamide [ka] To a solution of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3-fluoroisonicotinamide (1.43 g, 4.07 mmol, Intermediates 14-16) in DMSO (1 mL) was added 6-azaspiro[2.5]octane (0.68 g, 6.10 mmol) and CsCO (4.64 g, 14.24 mmol). The reaction mixture was stirred at 100 °C for 18 h and allowed to cool to room temperature. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 5 mL). The combined organic extracts were concentrated under reduced pressure, adsorbed onto a plug of silica gel, and chromatographed through a silica gel column eluting with 0–60% EtOAc in heptane to give N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-3-(6-azaspiro[2.5]octan-6-yl)isonicotinamide (0.28 g, 0.64 mmol, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ: 11.14(s,1H), 8.54(s,1H), 8.37(d,J=4.9Hz, 1H), 8.32(s,1H), 7.86-7.93(m,1H), 7.55-7.64(m,3H), 7.53(d,J=4.9Hz, 1H), 3.08-3.14(m,4H), 1.41(br t, J=4.9Hz, 4H), 1.11(s,9H), 0.28(s,4H).m / z(ESI):443.5(M+H) + .

[0332] [Table 48]

[0333] Example 115: N-(3-(3,3-difluoropiperidine-1-carbonyl)-4-methylphenyl)-3-(6-azaspiro[2.5]octan-6-yl)isonicotinamide [ka] Step 1: To a solution of methyl 5-(3-fluoroisonicotinamido)-2-methylbenzoate (0.82 g, 2.84 mmol, Intermediate 14-8) in dioxane-CHCN (2:1, 5 mL) was added 6-azaspiro[2.5]octane (0.38 g, 3.41 mmol) and DIPEA (0.55 g, 4.27 mmol). The reaction mixture was stirred at 170 °C for 1 h under microwave irradiation. The mixture was adsorbed onto a plug of silica gel and chromatographed through a silica gel column eluting with 25-45% EtOAc in heptane to give methyl 5-(3-(6-azaspiro[2.5]octan-6-yl)isonicotinamido)-2-methylbenzoate (0.80 g, 2.11 mmol, 74% yield) as an off-white solid. m / z (ESI): 380.1 (M+H). + .

[0334] Step 2: A mixture of methyl 5-(3-(6-azaspiro[2.5]octan-6-yl)isonicotinamido)-2-methylbenzoate (0.80 g, 2.11 mmol), anhydrous lithium hydroxide (0.22 g, 5.27 mmol) in THF (3 mL), HO (3 mL), and MeOH (1 mL) was heated at 50° C. for 3 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was treated with 1 N HCl (10 mL), and the yellow precipitate was filtered off, washed with water, and dried. 5-(3-(6-azaspiro[2.5]octan-6-yl)isonicotinamido)-2-methylbenzoic acid dihydrochloride (0.72 g, 1.64 mmol, 78% yield) was obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6)δ 10.99(br s,1H), 8.59(s,1H), 8.42(d,J=5.28Hz, 1H), 8.27(d,J=2.35Hz, 1H), 7.66-7.82(m,2H), 7.28-7.38(m,1H) , 3.69-5.21(m,3H), 3.11-3.26(m,4H), 2.5(s,3H), 1.31-1.49(m,4H), 0.32(s,4H).m / z(ESI):366.0(M+H) + .

[0335] Step 3: A mixture of 5-(3-(6-azaspiro[2.5]octan-6-yl)isonicotinamido)-2-methylbenzoic acid dihydrochloride (50 mg, 0.11 mmol), triethylamine (80 μL, 0.6 mmol), and 3,3-difluoropiperidine hydrochloride (27 mg, 0.17 mmol) in 0.5 mL of DMF was treated with T3P (50 wt % in EtOAc) (0.27 mL, 0.46 mmol), and the mixture was stirred at 45 °C for 2 h. It was diluted with EtOAc and washed with 1 N NaOH, followed by brine. The organic layer was concentrated, and the residue was purified by reverse-phase HPLC (10–90% [0.1% TFA] in CH3CN in 0.1% TFA in water) to afford the title compound (45 mg, 0.06 mmol, 57% yield) as a yellow fluffy powder. 1 H NMR (400MHz, DMSO-d6)δ 10.97(br s,1H), 8.58(s,1H), 8.41(d,J=4.89Hz, 1H), 7.53-7.74(m,3H), 7.32(d,J=8.41Hz, 1H), 4.25(br s, 3H), 3.71(br s,1H), 3.50(br s,1H), 3.22(t,J=4.89Hz, 1H), 3.16(t,J=4.99Hz, 4H), 2.19(s,3H), 2.03-2.15(m,2H), 1.73(m,1H), 1.62(br s,1H), 1.24-1.42(br s,4H), 0.32(s,4H).m / z(ESI):469.2(M+H) + .

[0336] [Table 49]

[0337] Further Examples The following Examples 116 to 128 can be prepared according to procedures similar to those of the above examples by using commercially available starting materials, or according to procedures well known to those skilled in the art.

[0338] [Table 50]

[0339] [Table 51]

[0340] Biological Examples The following assays were used to test exemplary compounds of the invention. Data for these examples, tested according to the procedures below, are presented in Table A below.

[0341] KIF18A enzyme assay: A microtubule-stimulated ATPase activity assay is 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 (1-467 His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography by 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 the ADP formed from the ATPase reaction. A reaction buffer is prepared [(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 porcine microtubules (Cytoskeleton Inc)]. Compounds and KIF18A protein (30 nM) are added to the prepared reaction buffer and incubated at room temperature for 15 minutes, followed by the addition of ATP (K mAdd 5 μl of ADP-Glo™ Reagent to 2.5 μl of the reaction mixture and incubate at room temperature for an additional 15 minutes. Add 10 μl of ADP-Glo™ Detection Reagent and incubate at room temperature for 40 minutes. Read luminescence using an EnVision microplate reader (Perkin Elmer Inc) equipped with an ultra-luminescence module. Fit concentration-response curves and determine IC using Genedata Screener Software (Standard 15.0.1, Genedata Inc) equipped with a 4-parameter logistic regression fitting model. 50 The following judgment was made.

[0342] Table A provides the compounds exemplified in this application as representative compounds of the present invention and their priority document data as follows: compound names (named by ACD software or ChemDraw (Professional 15.0)) and biological data (IC 50 (Unit: μM). Ex.# indicates the example number.

[0343] [Table 52]

[0344] [Table 53]

[0345] [Table 54]

[0346] [Table 55]

[0347] [Table 56]

[0348] [Table 57]

[0349] [Table 58]

[0350] [Table 59]

[0351] [Table 60]

[0352] 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 recognize that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the above description is intended to be illustrative, and not limiting. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0353] 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.

Claims

1. Formula I: 【Chemical 1】 or any pharmaceutically acceptable salt thereof, wherein: X １ is -CR ３ and X ２ is N, X ３ is -CR １ and R １ is the group -Z-R １２ where Z is absent, -C ０～４ alk-NR １１ -C ０～４ alk-, -C ０～４ alk-(C=O)-, -C ０～４ alk-(C=O)NR １１ -, -C-((C=O)-O-R １１ ) ２ -, -C ０～４ alk-(C=O)-O-, -C ０～４ alk-O-, -C ０～４ alk-NR １１ (C=O)-, -C ０～４ alk-NR １１ SO ２ -C ０～４ alk-, -C ０～４ alk-S-, -C ０～４ alk-S(=O)-,-C ０～４ alk-SO ２ -, -NR １１ -C ０～４ alk-O-, -C ０～４ alk-S(=O)(=N ＋ (CH ３ ) ２ )-, -C=N(OH)-, or -N=S(=O)<; R ２ is a group -Y-R １３ where Y is absent or -C ０～４ alk-SO ２ -C ０～４ alk-, R ３ is H, halo, C １～４ alk, or C １～４ Helloalk, R ５ is H, halo, C １～８ alk, or C １～４ Helloalk, R ６ H, halo, CN, C １～８ alk, -O-C １～８ alk, C ０～４ alk-(C=O)-NH-C ０～４ alk, C １～４ Haloalk, -C ０～４ alk-SO ２ NH-C ０～４ alk, -C ０～４ alk-SO ２ N (CH ３ )-C ０～４ alk, or R ６ａ and R ７ H, halo, CN, C １～８ alk, C １～４ Haloalk, -O-C １～８ alk, or R ７ａ and Or, R ２ and R ７ can combine with the carbon atoms bonded to each of them to form a saturated, partially saturated, or unsaturated 5- or 6-membered monocyclic ring fused to a phenyl ring, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein the 5- or 6-membered monocyclic ring does not contain any of 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 ６ａ and R ７ａ each independently contains, in each occurrence, 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, CN, C １～６ alk, C １～４ Helloalk, -OC １～４ Haloalk, -C(=O)R ｂ , -C ０－６ alk-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 , -N(R ａ ) C(=O)R ａ , -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 １～６ alkNR ａ R ａ , -NR ａ C １～６ alkOR ａ , -C ０－６ alkNR ａ R ａ , -C ０－６ alkOR ａ , -C １～６ alkN(R ａ ) C(=O)R ｂ , -C １～６ alkOC(=O)R ｂ , -C ０－６ alkC(=O)OR ａ and oxo; R ８ is H, halo, C １～４ alk, or C １～４ Helloalk, L is -NR １０ -(C=O)- (wherein N is attached to the left phenyl ring in formula (I) and C=O is the linking group attached to the right ring in formula (I)); R ９ is H, halo, C １～８ alk, or C １～４ Helloalk, R １０ is H or C １～４ alk, R Ｘ teeth, 【Chemistry 2】 and R Ｘａ , R Ｘｂ , R Ｘｃ or R Ｘｄ Each of the groups is H, halo, R Ｘｍ , or R Ｘｎ and Or, R Ｘａ and R Ｘｂ can independently combine with the carbon atom bonded to each of them to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepanyl ring, wherein said 3-, 4-, 5-, or 6-membered monocyclic ring contains zero N, O, and S atoms, and further wherein said 3-, 4-, 5-, or 6-membered monocyclic ring does not contain any of F, Cl, Br, C, １～６ alk, C １～４ Haloalk, -OR ａ , -OC １～４ Haloalk, CN, -NR ａ R ａ or oxo; Additionally or alternatively, R Ｘａ and R Ｘｂ each of the pairs can independently combine to form a double bond, R １１ are independently H or C １～８ alk, R １２ is H, halo, CN, -OH, R １２ａ , or R １２ｂ and R １３ is H, halo, CN, R １３ａ , or R １３ｂ and R Ｘｍ , and R １２ａ , and R １３ａ each independently contains, in each occurrence, 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and 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 a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring substituted with 0, 1, 2, 3, or 4 groups selected from , oxo, or a saturated, partially saturated, or unsaturated 3-, 4-, or 5-membered monocyclic ring; R Ｘｎ , R １２ｂ , and R １３ｂ is independently, at each occurrence, F, Cl, Br, —CH ２ F, -CHF ２ , -CF ３ , -C(=O)OR ａ , -C ０－６ alkOR ａ , -OC １～４ Haroalk, CN, NH ２ , NH(CH ３ ), N(CH ３ ) ２ , —(C═O)NR ａ , -NR ａ (C=O)C ０～４ alk, -S (=O) ２ R ａ or a saturated, partially saturated or unsaturated 3-, 4- or 5-membered monocyclic ring. １～６ alk is selected from the group consisting of 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 with 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, wherein C ０ alk means a direct bond).

2. R Ｘａ , R Ｘｂ , R Ｘｃ , and R Ｘｄ Each of the a) H, F, Cl, methyl, ethyl, propyl, isopropyl, -CH ２ F, -CHF ２ , -CF ３ or cyclopropyl; b) or R Ｘａ and R Ｘｂ and R Ｘｃ and R Ｘｄ can independently combine with the carbon atom to which each is bonded to form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring, wherein each ring is spiro to the pyrrolidinyl ring, piperidinyl ring, or morpholinyl ring, and each of the rings is selected from the group consisting of F, Cl, Br, C １～６ alk, C １～４ substituted with 0, 1, 2 or 3 groups selected from haloalk, or methoxy; c) or R Ｘａ and R Ｘｂ The pair is combined to form >C=CH or >C=CH-CH ３ 2. The compound of claim 1, which is capable of forming:

3. L is -NR １０ -(C=O), and X １ Ga-CR ４ and X ２ is N and X ３ Ga-CR １ and formula (Ia): 【Chemistry 3】 wherein R ４ is H, halo, C １～８ alk, or C １～４ The compound of claim 1 or 2, wherein the compound is haloalk.

4. R １０ The compound of any one of claims 1 to 3, wherein is H or methyl.

5. R Ｘ but, 【Chemistry 4】 The compound according to any one of claims 1 to 4, selected from:

6. R Ｘ but, 【Chemistry 5】 The compound according to any one of claims 1 to 5,

7. Z is absent, —NH—, —(C═O)—, —CH(CH ３ )-(C=O)NH-, -C-((C=O)-O-(CH ３ )) ２ , -C-((C=O)-O-(CH ３ ) ３ ) ２ , -CH(CH ３ )-(C=O)-O-, -C(CH ３ ) ２ -(C=O)-O-, -(C=O)-O-, -N(CH ３ )-, -O-, -NH(C=O)-, -(C=O)NH, -CH ２ -(C=O)-O-, -CH ２ NCH ３ -, -NCH ３ -, -CH ２ -(C=O)-NH-, -NHSO ２ -, -CH ２ SO ２ --NHCH ２ - or -NHCH ２ CH ２ The compound according to any one of claims 1 to 6, wherein the aryl group is -O-.

8. R １２ but, a) H, F, Cl, Br, OH, or CN; b) F, Cl, Br, -CF ３ , -CH ２ OH, -OH, -OCH ３ , -C(=O)OH, -C(=O)OCH ３ , -C(=O)NH, -C(=O)NCH ３ , -NHC(=O)H, -NHC(=O)CH ３ , -NCH ３ C(=O)CH ３ , -NH ２ , -NH(CH ３ ), or -N(CH ３ ) ２ C substituted with 0, 1, 2 or 3 groups selected from １～６ alk, or c) containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, CN, methyl, ethyl, -CF ３ , -CH ２ OH, -CH ２ CH ２ OH, -OH, -OCH ３ , -NH ２ , -NH(CH ３ ), -N(CH ３ ) ２ , —C(═O)NH ２ , -C(=O)OH, -C(=O)OCH ３ , -SO ２ CH ３ a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring substituted with 0, 1, 2, 3, or 4 groups selected from -, or oxo; The compound according to any one of claims 1 to 7, selected from:

9. R １２ cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, dioxolanyl, morpholinyl, phenyl, 【Chemistry 6】 where each R １２ is F, Cl, Br, methyl, ethyl, CN, -CF ３ , -CH ２ OH, -CH ２ CH ２ OH, -OH, -OCH ３ , -COOH, -CONH ２ , COOCH ３ , -CONH(CH ３ ), -NH ２ , -SO ２ CH ３ 9. The compound of claim 1, substituted with 0, 1, 2 or 3 groups selected from:

10. R １ The group -Z-R １２ wherein Z is absent, —NH—, —O—, or —NHSO ２ - or -CH ２ SO ２ - and R １２ is H, pyrrolidinyl, oxetanyl, cyclopropyl, or cyclobutyl, or R １２ is 0, 1, 2 or 3 OH, CF ３ , or -CH ２ C substituted with OH group １～６ The compound according to any one of claims 1 to 9, wherein the compound is alk.

11. Y is absent or -SO ２ The compound according to any one of claims 1 to 10, wherein

12. R １３ but, a) H, halo, or CN; b) containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and including F, Cl, Br, methyl, ethyl, isopropyl, CHF ２ , C.F. ３ , C.H. ２ OH, -OH, -OCH ３ , -NH ２ , -NH(CH ３ R is selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or a 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring substituted with 0, 1, 2, or 3 groups selected from oxo, cyclopropyl, or cyclobutyl; １３ａ , or c) F, Cl, Br, -OH, -CF ３ substituted with 0, 1, 2, 3, 4, or 5 groups selected from cyclopropyl, cyclopropyl, or cyclobutyl; １～６ R selected from alk １３ｂ The compound according to any one of claims 1 to 11, selected from:

13. R １３ａ each independently represents F, Cl, methyl, ethyl, isopropyl, CHF ２ , C.F. ３ , C.H. ２ CF ３ , -OCH ３ , -CH ２ CH ２ OCH ３ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, imidazolidinyl, oxazolyl, phenyl, pyrrolidinyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperidinyl, azetidinyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, substituted by 0, 1, 2 or 3 groups selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, imidazolidinyl, oxazolyl, phenyl, pyrrolidinyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperidinyl, azetidinyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, 【Chemistry 7】 The compound according to any one of claims 1 to 12, selected from:

14. R １３ｂ However, each is independently F, CF ３ 14. The compound of any one of claims 1 to 13, wherein the substituted aryl group is selected from methyl, ethyl, isopropyl, isobutyl, tert-butyl, or neopentyl, substituted with 0, 1, 2, or 3 groups selected from , OH, or cyclopropyl.

15. R ２ is a group -Y-R １３ wherein Y is absent or -SO ２ - and R １３ is tert-butyl, or R is selected from cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl １３ａ wherein R １３ａ each of which is F, Cl, Br, methyl, or CF ３ The compound of any one of claims 1 to 14, substituted with 0, 1, 2 or 3 groups selected from:

16. R ２ is a group -Y-R １３ where Y is -SO ２ - and R １３ The compound of any one of claims 1 to 15, wherein is cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl, each substituted with 0, 1, 2, or 3 methyl groups.

17. R ３ The compound of any one of claims 1 to 16, wherein is H, F or methyl.

18. R ４ The compound of any one of claims 1 to 17, wherein is H.

19. R ５ The compound of any one of claims 1 to 18, wherein is H.

20. R ６ is H, F, Br, methyl, CN, methoxy, cyclopropyl, -(C=O)NH ２ , -CF ３ , furanyl, pyridinyl, morpholinyl, or —SO ２ NHC (CH ３ ) ３ The compound according to any one of claims 1 to 19,

21. R ６ The compound according to any one of claims 1 to 20, wherein is H or F.

22. R ７ is H, F, Br, Cl, CN, methyl, methoxy, cyclopropyl, or R ２ and R ７ in combination with the carbon atoms to which they are each bonded to form the group: 【Chemistry 8】 22. The compound according to any one of claims 1 to 21, which is capable of forming

23. R ７ The compound of any one of claims 1 to 22, wherein is H, F, or methyl.

24. R ８ The compound of any one of claims 1 to 23, wherein is H, F, or methyl.

25. R ８ The compound of any one of claims 1 to 24, wherein is H.

26. R ９ The compound of any one of claims 1 to 25, wherein is H.

27. R １０ The compound of any one of claims 1 to 26, wherein is H.

28. below: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 28. The compound of any one of claims 1 to 27, selected from the group consisting of: or any pharmaceutically acceptable salt thereof.

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

30. 30. The pharmaceutical composition of claim 29 for use in a method for treating a condition that can be treated with a KIF18A inhibitor.

31. 31. The pharmaceutical composition of claim 30, wherein the condition is selected from cancer, psoriasis, atopic dermatitis, an autoimmune disease, or inflammatory bowel disease; the cancer is melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia; the autoimmune disease may be an autoimmune disease of the central nervous system selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, Reiter's syndrome, autoimmune lymphoproliferative syndrome (ALPS), also known as Canal-Smith syndrome, or multiple sclerosis, myasthenia gravis, and encephalomyelitis; and the inflammatory bowel disease may be ulcerative colitis or Crohn's disease.

32. 30. The pharmaceutical composition of claim 29 for use in a method for reducing the size of a solid tumor in a subject.

33. 30. The pharmaceutical composition of claim 29 for use in a method for treating a cell proliferative disorder in a subject.

34. 30. The pharmaceutical composition of claim 29 for use in a method of inhibiting KIF18A in a cell.

35. The condition is (a) a solid tumor or a blood-borne tumor selected from bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a lymphoid tumor 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 Burkitt's lymphoma; The pharmaceutical composition of claim 30, wherein the cancer is selected from the group consisting of (a) hematological malignancies, (b) hematopoietic malignancies of the myeloid cell lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia, (c) hematopoietic malignancies of the myeloid cell lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndromes, 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 neurilemmoma, or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

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