Pyridine derivatives as KIF18A inhibitors

Abstract

Amide compounds of formula (I) as defined herein, and their synthetic intermediates, are said compounds capable of modulating the KIF18A protein, thereby influencing cell cycle and cell proliferation processes to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions comprising said compounds and methods for treating conditions associated with KIF18A activity.

Description

[0001] This invention relates to the field of pharmaceutical reagents, and more specifically, to compounds and compositions for regulating KIF18A, and to uses and methods for managing cell proliferation and treating cancer. Background Technology

[0002] Cancer is one of the most prevalent diseases afflicting humanity and a leading cause of death worldwide. Over the past few decades, numerous groups have invested significant time, effort, and resources in the search for effective treatments or cures for one or more of the many different cancers. However, to date, only a handful of available cancer treatments and therapies have offered a considerable degree of success.

[0003] Cancer is typically characterized by unregulated cell proliferation. Damage to one or more genes responsible for cellular pathways (controlling the progression of proliferation through the cell cycle and centrosome circulation) can lead to a loss of normal regulation of cell proliferation. These dysregulated genes can encode various tumor suppressors or oncogene proteins that participate in a series of events leading to unchecked cell cycle progression and cell proliferation. Various kinases and kinases have been identified as playing key roles in the regulation and progression of cell cycle and mitosis in both normally dividing cells and cancer cells.

[0004] Kinesins are molecular motors that play important roles in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins function in multiple aspects of spindle assembly, chromosome segregation, centrosome segregation, and dynamics (as reviewed in O. Rath and F. Kozielski, Nature Review Cancer, 12:527-39, 2012). Based on sequence homology within the so-called “motor domain,” human kinesins are classified into 14 subfamilies whose ATPase activity drives unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are responsible for cargo attachment; “cargo” can include any of a variety of membrane organelles, signal transduction scaffold systems, and chromosomes. Kinesins use ATP hydrolysis energy to move cargo along polarized microtubules. Therefore, kinesins are often referred to as “positive-terminal” or “negative-terminal” directional motors.

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a positive-end orientation motor. KIF18A is thought to influence the dynamics of the positive ends of centromere microtubules to control proper chromosome positioning and spindle tension. Depletion of human KIF18A in HeLa cervical cancer cells leads to longer spindles, increased chromosome oscillation in metaphase, and activation of mitotic spindle assembly checkpoints (MI Mayr et al., Current Biology 17, 488-98, 2007). KIF18A appears to be a potential target for cancer therapy. KIF18A is overexpressed in a variety of cancer types, including but not limited to colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, cervical cancer, and ovarian cancer. Furthermore, in cancer cell lines, gene deletion or knockout, or KIF18A inhibition, affects the mitotic spindle apparatus. In particular, inhibition of KIF18A has been found to induce mitotic arrest, a known vulnerability that can promote mitotic cell death through apoptosis, mitotic catastrophe, multiphase-driven lethality, or post-mitotic slippage death during interphase. Therefore, there is strong interest in finding inhibitors of the KIF18A protein.

[0006] Therefore, the inhibition of KIF18A ATPase activity is a promising approach for developing new anticancer agents. Summary of the Invention

[0007] One aspect of the present invention is a new class of compounds that, alone or in combination with microtubules, regulate the KIF18A protein to treat KIF18A-mediated symptoms and / or diseases, including cancer, inflammation, or ciliary pathology.

[0008] The compounds provided by this invention possess MT-based KIF18A-regulating activity, particularly KIF18A inhibitory activity. To this end, the invention also provides the use of these compounds and their pharmaceutically acceptable salts in the preparation and manufacture of pharmaceutical compositions or medicaments for the therapeutic, prophylactic, acute, or chronic treatment of KIF18A-mediated diseases and disorders (including, but not limited to, cancer). Therefore, the compounds of this invention can be used to manufacture anticancer drugs. The invention also provides methods for preparing compounds of formula I, and intermediates available in such methods.

[0009] In Example 1, the present invention provides a compound of formula (I):

[0010]

[0011] Or any pharmaceutically acceptable salt thereof, wherein:

[0012] X1 For N or -CR 3 ;

[0013] X 2 For N or -CR 4 ;

[0014] X 3 For N or -CR 1 ;

[0015] Where X 1 X 2 and X 3 Only one of them is N;

[0016] R 1 -ZR group 12 Where Z does not exist and is -C 0-4 Alkyl-NR 11 -C 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-, -C 0-4 Alkyl-(C=O)NR 11 -、-C-((C=O)-OR 11 )2-、-C 0-4 Alkyl-(C=O)-O-, -C 0-4 Alkyl-O-, -C 0-4 Alkyl-NR 11 (C=O)-、-C 0-4 Alkyl-NR 11 SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-SO2-, -NR 11 -C 0-4 Alkyl-O-, -C 0-4 Alkyl-S(=O)(=N) + (CH3)2)-, -C=N(OH)-, or -N=S(=O)<,

[0017] R 2 The group is -YR 13 Where Y does not exist and is -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-S=OC 0-4 Alkyl-, -C 0-4 Alkyl-SO2-C 0-4 Alkyl, -SO2NR 13c -C 0-4 Alkyl-, -SO2N(C1-4 alkyl)-, -SO2N(C 1-4 Alkyl-OC 1-4 alkyl)-, -C 0-4 Alkyl-S(=O)(=NH)-, -C 0-4 Alkyl-(C=O)-, -C 0-4 Alkyl-(C=O)-O-, -C 0-4 Alkyl-(C=O)NR 13c -、-NR 13c -、-OC 0-4 Alkyl group -, -N=S (=O)<, or -NR 13c -SO2-C 0-4 alkyl-;

[0018] R 3 H, halogen, C 1-4 Alkyl, or C 1-4 Halogenated alkyl groups;

[0019] R 4 H, halogen, C 1-8 Alkyl, or C 1-4 Halogenated alkyl groups;

[0020] R 5 H, halogen, C 1-8 Alkyl, or C 1-4 Halogenated alkyl groups;

[0021] R 6 H, halogen, CN, C 1-8 Alkyl, -OC 1-8 Alkyl, C 0-4 Alkyl-(C=O)-NH-C 0-4 Alkyl, C 1-4 Haloalkyl, -C 0-4 Alkyl-SO2NH-C 0-4 Alkyl, -C 0-4 Alkyl-SO2N(CH3)-C 0-4 Alkyl, or R 6a ;

[0022] R 7 H, halogen, CN, C 1-8 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-8 Alkyl, or R 7a ;

[0023] Alternatively, R 2 and R 7These can combine with their respective attached carbon atoms to form saturated, partially saturated, or unsaturated 5- or 6-membered monocyclic rings fused with a benzene ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic rings contain 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 rings are substituted with 0, 1, 2, or 3 groups selected from: F, Cl, Br, C 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OR a -OC 1-4 Halogenated alkyl groups, CN, -NR a R a Or oxygenation;

[0024] R 6a and R 7a Each independently selects from the group consisting of: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted with 0, 1, 2, or 3 groups selected from: F, Cl, Br, CN, C 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OC 1-4 Haloalkyl, -C(=O)R b -C 0-6 Alkyl-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 Alkyl NR a R a -OC 2-6 Alkyl OR 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)2NR a R a -NR a C 1-6 Alkyl NR a R a -NR a C 1-6 Alkyl OR a -C 0-6 Alkyl NR a R a -C 0-6 Alkyl OR a -C 1-6 Alkyl N(R) a )C(=O)R b -C 1-6 Alkyl OC(=O)R b -C 0-6 Alkyl C(=O)OR a and oxygenation;

[0025] R 8 H, halogen, C 1-4 Alkyl, or C 1-4 Halogenated alkyl groups;

[0026] L is -(C=O)-NR 10 -or-NR 10 -(C=O)-;

[0027] R 9 H, halogen, C 1-8 Alkyl, or C 1-4 Halogenated alkyl groups;

[0028] R 10 For H or C 1-4 alkyl;

[0029] R X Selected from H,

[0030] R Xa R Xb R Xc R Xd R Xe R Xf R Xg R Xh RXi R Xj R Xk and R Xl Each of them is H, halogen, R Xm 、or R Xn ;

[0031] Alternatively, R Xa and R Xb Yes, R Xc and R Xd Yes, R Xe and R Xf Yes, R Xg and R Xh Yes, R Xi and R Xj Yes, and R Xk and R Xl Each of the pairs can independently combine with their respective attached carbon atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring screwed onto an azircyclic butyl, pyrrolyl, piperidinyl, morpholinyl, or azircyclic heptyl ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0 N, O, and S atoms, and further, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OR a -OC 1-4 Halogenated alkyl groups, CN, -NR a R a Or oxygenation;

[0032] Or alternatively, R Xa and R Xb Yes, R Xc and R Xd Yes, R Xe and R Xf Yes, R Xg and R Xh Yes, R Xi and R Xj Yes, and R Xk and R Xl Each of the pairs can independently combine to form a double bond;

[0033] When R Xa R Xb R Xc R Xd R Xe R Xf R Xg R Xh R Xi RXj R Xk and R Xl When both are H, then the group ZR 12 For -NR 11 -R 12 And the group -YR 13 C 0-4 Alkyl-S(=O)2-R 13 or -SO2NR 13c -C 0-4 Alkyl-R 13 ;

[0034] When L is -NR 10 -(C=O)- and X 1 When L is N; or when L is -(C=O)-NR 10 -and X 2 When R is N; then X for Alternatively, R Xa and R Xb Each of them can combine with the carbon atoms to which they are attached to form a cyclopropyl, cyclobutyl, or cyclopentyl ring screwed onto the piperidinyl ring;

[0035] R 11 and R 13c Each independently is H or C 1-8 alkyl;

[0036] R 12 H, halogen, CN, -OH, R 12a 、or R 12b ;

[0037] R 13 H, halogen, CN, R 13a or R 13b ;

[0038] R Xm and R 12a and R 13a Each of these is independently selected, in each case, from the group consisting of: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2, 3, or 4 groups selected from: F, Cl, Br, C 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OR a -OC 1-4 Haloalkyl, CN, -C(=O)R b -C(=O)ORa -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 Alkyl NR a R a -OC 2-6 Alkyl OR 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 Alkyl NR a R a -NR a C 2-6 Alkyl OR a -C 1-6 Alkyl NR a R a -C 1-6 Alkyl OR a -C 1-6 Alkyl N(R) a )C(=O)R b -C 1-6 Alkyl OC(=O)R b -C 1-6 Alkyl C(=O)NR a R a -C1-6 Alkyl C(=O)OR a Oxygenated, or saturated, partially saturated or unsaturated 3-, 4-, or 5-membered monocyclic rings;

[0039] R Xn R 12b and R 13b Each of these groups is independently selected from the following groups in each case: selected from F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)OR a -C 0-6 Alkyl OR a -OC 1-4 Haloalkyl, CN, NH2, NH(CH3), N(CH3)2, -(C=O)NR a -NR a (C=O)C 0-4 Alkyl group, -S(=O)2R a C-shaped monocyclic rings with 0, 1, 2, 3, 4, or 5 substituents, whether saturated, partially saturated, or unsaturated. 1-6 alkyl;

[0040] R a H or R independently in each case b ;and

[0041] R b C is independent in each case. 1-6 alkyl, phenyl, or benzyl, wherein the C 1-6 The alkyl group is substituted by 0, 1, 2, or 3 of the following substituents: halogen, -OH, -OC. 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl group, -OC (=O)C 1-4 Alkyl, or -N(C) 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl group is substituted with 0, 1, 2 or 3 of the following substituents: halogen, C 1-4 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl group, -OC (=O)C 1-4 Alkyl, or -N(C) 1-4 Alkyl)C 1-4 alkyl.

[0042] In Example 2, the present invention provides a compound, wherein R X Selected from H,

[0043] Where R Xa R Xb R Xc and R Xd Each of them is H, halogen, R Xm 、or R Xn ;

[0044] Alternatively, R Xa and R Xb Yes, and R Xc and R Xd Each of the pairs can independently combine with its respective attached carbon atom to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring screwed to a pyrrolidinyl, piperidinyl, or morpholinyl ring; wherein the 3-, 4-, 5-, or 6-membered monocyclic ring contains 0 N, O, and S atoms, and further, wherein the 3-, 4-, 5-, or 6-membered monocyclic ring is substituted with 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C. 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OR a -OC 1-4 Halogenated alkyl groups, CN, -NR a R a Or oxygenation;

[0045] Or alternatively, R Xa and R Xb or R Xc and R Xd Each of the pairs can independently combine to form a double bond.

[0046] In Example 3, the present invention provides a compound, wherein R X for

[0047] In Example 4, the present invention provides a compound, wherein R X for

[0048] In Example 5, the present invention provides a compound, wherein R X for

[0049] In Example 6, the present invention provides a compound, wherein R Xa R Xb R Xc and R Xd Each of the following is selected from:

[0050] a) H, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, or cyclopropyl; or

[0051] b) Alternatively, R Xa and R Xb Yes, and R Xc and R Xd Each of the pairs can independently combine with their respective attached carbon atoms to form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring, wherein each ring is screwed to a pyrrolidinyl, piperidinyl, or morpholinyl ring; and wherein each of the rings is substituted by 0, 1, 2, or 3 groups selected from the following: F, Cl, Br, C. 1-6 Alkyl, C 1-4 Halogenated alkyl or methoxy; or

[0052] c) Alternatively, R Xa and R Xb or R Xc and R Xd Each of the pairs can independently combine to form >C=CH or >C=CH-CH3; and

[0053] Where R Xe R Xf R Xg R Xh R Xi R Xj R Xk and R Xl Each of them is H, F, or methyl.

[0054] In Example 7, the present invention provides a compound, wherein L is -NR. 10 -(C=O)-.

[0055] In Example 8, the present invention provides a compound wherein L is -(C=O)-NR. 10 -

[0056] In Example 9, the present invention provides a compound, wherein L is -NR. 10 -(C=O); X 1 For -CR 4 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For -CR 1 ; Possesses formula (Ia):

[0057] In sub-example 9a, the present invention provides a compound having formula (Ia-1):

[0058]

[0059] In Example 10, the present invention provides a compound wherein L is -(C=O)-NR. 10 -;X 1 For -CR4 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For -CR 1 ; with formula (Ib):

[0060]

[0061] In sub-example 10a, the present invention provides a compound having formula (Ib-1):

[0062]

[0063] In Example 11, the present invention provides a compound, wherein L is -NR. 10 -(C=O); X 1 -N; X 2 For -CR 3 And X 3 For -CR 1 ; with formula (Ic):

[0064]

[0065] In sub-example 11a, the present invention provides a compound having formula (Ic-1):

[0066]

[0067] In Example 12, the present invention provides a compound wherein L is -(C=O)-NR. 10 -;X 1 -N; X 2 For -CR 3 And X 3 For -CR 1 ; with formula (Id):

[0068]

[0069] In sub-example 12a, the present invention provides a compound having formula (Id-1):

[0070]

[0071] In Example 13, the present invention provides a compound, wherein L is -NR. 10 -(C=O); X 1 For -CR 4 ;X 2 For -CR 3 And X 3 For N; it has the formula (Ie):

[0072]

[0073] In Example 14, the present invention provides a compound wherein L is -(C=O)-NR. 10 -;X 1 For -CR 4 ;X 2 For -CR 3 And X 3 Let N be the number of elements; and let it have the following expression (If):

[0074]

[0075] In Example 15, the present invention provides a compound, wherein R 10 It is H or methyl.

[0076] In Example 16, the present invention provides a compound, wherein R X Selected from H,

[0077] In Example 17, the present invention provides a compound, wherein R X for

[0078] In sub-example 17a, the present invention provides a compound, wherein R X for

[0079] In Example 18, the present invention provides a compound wherein Z is absent, or is -NH-, -(C=O)-, -CH(CH3)-(C=O)NH-, -C-((C=O)-O-(CH3))2, -C-((C=O)-O-(CH3)3)2, -CH(CH3)-(C=O)-O-, -C(CH3)2-(C=O)-O-, -(C=O)-O-, -N(CH3)-, -O-, -NH(C=O)-, -(C=O)NH, -CH2-(C=O)-O-, -CH2NCH3-, -NCH3-, -CH2-(C=O)-NH-, -NHSO2-, -CH2SO2-, -NHCH2-, or -NHCH2CH2-O-.

[0080] In sub-example 18a, the present invention provides a compound in which Z is absent.

[0081] In Example 19, the present invention provides a compound, wherein R 12 Selected from:

[0082] a)H, F, Cl, Br, OH, or CN;

[0083] 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 Alkyl; or

[0084] c) A saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 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, wherein the ring is 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.

[0085] In Example 20, the present invention provides a compound, wherein R 12 Selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridine, oxadiazolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolyl, dioxopentyl, morpholinyl, phenyl, Each R 12 It is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, methyl, ethyl, CN, -CF3, -CH2OH, -CH2CH2OH, -OH, -OCH3, -COOH, -CONH2, COOCH3, -CONH(CH3), -NH2, -SO2CH3, or oxo.

[0086] In Example 21, the present invention provides a compound, wherein R 1 -ZR group 12 Where Z is absent, is -NH-, -O-, -NHSO2-, or -CH2SO2-; and R 12 It is H, pyrrolidinyl, oxetyl, cyclopropyl, or cyclobutyl, or R 12 C is a carbon atom substituted with 0, 1, 2 or 3 OH, CF3 or -CH2OH groups. 1-6 alkyl.

[0087] In Example 22, the present invention provides a compound wherein Y is absent, or is -S-, -SO2-, -SO2CH2-, -SO2CH(CH3)-, -SO2NH-, -SO2NHCH2-, -SO2N(CH2CH3)-, -SO2N(CH3)-, -SO2N(CH2C≡CH)-, SO2N(CH2CH2OCH3)-, -S(=O)(=NH)-, -C=O-, -CH2-(C=O)-, -(C=O)-O-, -CH2(C=O)-O-, -(C=O)NH-, -(C=O)-N(CH3)-, -CH2-(C=O)-NH-, -NH-, -O-, -N=S(=O)<, or -NHSO2-.

[0088] In sub-example 22a, the present invention provides a compound in which Y is absent.

[0089] In Example 23, the present invention provides a compound, wherein R 13 Selected from:

[0090] a) H, halogen, or CN;

[0091] b)R 13a Selected from saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, wherein the ring is substituted with 0, 1, 2, or 3 groups selected from: F, Cl, Br, methyl, ethyl, isopropyl, CHF2, CF3, CH2OH, -OH, -OCH3, -NH2, -NH(CH3), oxo, cyclopropyl, or cyclobutyl; or

[0092] c)R 13b C substituted with 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, -OH, -CF3, cyclopropyl or cyclobutyl 1-6 alkyl.

[0093] In Example 24, the present invention provides a compound, wherein R 13a Selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, imidazoalkyl, oxazolyl, phenyl, pyrrolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperidinyl, azacyclobutane, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, oxadiazolyl, tetrazolyl, pyridinyl.

[0094] Each of them is independently substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3, -OCH3, -CH2CH2OCH3, or oxo.

[0095] In Example 25, the present invention provides a compound, wherein R 13b Selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl or neopentyl, each of which is independently substituted by 0, 1, 2 or 3 groups selected from: F, CF3, OH or cyclopropyl.

[0096] In Example 26, the present invention provides a compound, wherein R 2 The group is -YR 13 Where Y is nonexistent, is -SO2-, or -SO2NH-; and R 13 For tert-butyl, or R 13a Selected from cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl, wherein each of the R... 13a It is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, methyl, or CF3.

[0097] In Example 27, the present invention provides a compound, wherein R 2 The group is -YR 13 Where Y is -SO2- and R 13 It is cyclopropyl, cyclobutyl, cyclopentyl, morpholino, or piperidinyl, each of which is substituted by 0, 1, 2, or 3 methyl groups.

[0098] In Example 28, the present invention provides a compound, wherein R 3 It can be H, F, or methyl.

[0099] In Example 29, the present invention provides a compound, wherein R 4 It can be H, F, Cl, cyclopropyl, -(C=O)CH3 or CF3.

[0100] In Example 30, the present invention provides a compound, wherein R 4 For H.

[0101] In Example 31, the present invention provides a compound, wherein R 5 For H.

[0102] In Example 32, the present invention provides a compound, wherein R 6 It can be H, F, Br, methyl, CN, methoxy, cyclopropyl, -(C=O)NH2, -CF3, furanyl, pyridyl, morpholinyl, or -SO2NHC(CH3)3.

[0103] In Example 33, the present invention provides a compound, wherein R 6 It can be H or F.

[0104] In Example 34, the present invention provides a compound, wherein R 7 It can be H, F, Br, Cl, CN, methyl, methoxy, cyclopropyl, or R. 2 and R 7 They can combine with the carbon atoms to which they are attached to to form functional groups:

[0105] In Example 35, the present invention provides a compound, wherein R 7 It can be H, F, or methyl.

[0106] In Example 36, the present invention provides a compound, wherein R 8 It can be H, F, or methyl.

[0107] In Example 37, the present invention provides a compound, wherein R 8 For H.

[0108] In Example 38, the present invention provides a compound, wherein R 9 For H.

[0109] In Example 39, the present invention provides a compound, wherein R 10 For H.

[0110] In Example 40, the present invention provides a compound or any pharmaceutically acceptable salt thereof, selected from:

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] In Example 41, the present invention provides a compound or any pharmaceutically acceptable salt thereof, selected from:

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] ; or any pharmaceutically acceptable salt thereof.

[0130] Another aspect of the invention is a pharmaceutical composition comprising a novel class of compounds or pharmaceutically acceptable salts thereof, which can be used alone or in combination with microtubules to form a binding complex to modulate the KIF18A protein.

[0131] In Example 42, the present invention provides a pharmaceutical composition comprising a compound according to any one of Examples 1-41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0132] Another aspect of the invention is a method for treating a condition that can be treated with a KIF18a inhibitor, the method comprising administering to a patient in need a therapeutically effective amount of a novel compound or a pharmaceutically acceptable salt thereof, which can be used alone or in combination with microtubules to form a binding complex to modulate the KIF18A protein.

[0133] In Example 43, the present invention provides a method for treating a condition that can be treated with a KIF18a inhibitor, the method comprising administering to a patient in need a therapeutically effective amount of a compound according to Examples 1-41 or a composition according to Example 42.

[0134] In Example 44, the present invention provides a method according to Example 43, wherein the disease is a cancer selected from the group consisting of: (a) solid tumors or hematopoietic tumors selected from the group consisting of: bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, 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, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) hematopoietic tumors selected from the group consisting of: leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, etc. T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pilocellular lymphoma, and Burkett's lymphoma; (c) hematopoietic tumors of the following bone marrow lineages: acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (d) stromal tumors of the following fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous systems of the following astrocytomas, neuroblastomas, gliomas, and schwannomas; or (f) melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0135] In sub-example 44a, the present invention provides a method according to example 43, wherein the disease 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, 2010.09; 31(9):1676-84. doi:10.1093 / carcin / bgq134.Epub 2010Jul 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.

[0136] In Example 45, the present invention provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound according to Examples 1-41 or a composition according to Example 42.

[0137] In Example 46, the present invention provides a method for treating cell proliferation disorders in a subject, the method comprising administering to a subject in need a therapeutically effective amount of a compound according to Examples 1-41 or a composition according to Example 42.

[0138] In Example 47, the present invention provides a method for inhibiting KIF18A in cells, the method comprising contacting the cells with a compound according to Examples 1-41 or a pharmaceutically acceptable salt thereof or a composition according to Example 42.

[0139] Another aspect of the invention is a method for preparing a new class of compounds or pharmaceutically acceptable salts thereof, which can be used alone or in combination with microtubules to regulate KIF18A protein.

[0140] In Example 48, the present invention provides a method for preparing compounds of formula (I) as described herein.

[0141] In Example 49, the present invention provides an intermediate compound for use in a method for preparing compounds of formula (I) as described herein. Detailed Implementation

[0142] This invention includes all pharmaceutically acceptable isotopically labeled compounds of this invention, wherein one or more atoms are replaced by atoms having the same number of atoms but with an atomic mass or mass number different from those normally found in nature.

[0143] Examples of isotopes suitable for inclusion in the compounds of this invention include, but are not limited to, isotopes of hydrogen, such as... 2 H and 3 H; isotopes of carbon, such as 11 C 13 C and 14 C; isotopes of chlorine, for example 38 Cl; isotopes of fluorine, for example 18 F; Isotopes of iodine, for example 123 I and 125 I; Isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O、 17 O and 18 O; isotopes of phosphorus, such as 32 Isotopes of P and sulfur, for example 35 S.

[0144] Certain isotope-labeled compounds of the present invention, such as compounds incorporating radioisotopes, can be used in drug and / or substrate tissue distribution studies. Given their ease of incorporation and ready-to-use detection methods, radioisotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) It is especially suitable for this purpose.

[0145] Use heavier isotopes (e.g., deuterium, i.e.) 2H) substitution can provide certain therapeutic advantages derived from higher metabolic stability (e.g., prolonged in vivo half-life or reduced dose requirements), and is therefore preferred in some cases.

[0146] Using positron emission of isotopes, such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0147] The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the appended examples and preparations, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0148] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, such as D2O, d6-acetone, and d6-DMSO.

[0149] Specific embodiments of the present invention include compounds exemplified in the following examples, as well as their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives.

[0150] Unless otherwise stated, the following definitions apply to terms appearing in this specification and claims:

[0151] “C α-β "Alkyl" refers to an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched, linear, or any combination of these three arrangements, where α and β represent integers. Alkyl groups described in this section may also contain one or two double or triple bonds. The name C0 alkyl indicates a direct bond. 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0152]

[0153] The term "benzo[a]" alone or in combination refers to a divalent group C4H4=, one of which is represented as -CH=CH-CH=CH-. When attached to another ring at the ortho position, it forms a benzene ring—for example, tetrahydronaphthalene, indole, etc.

[0154] The terms "oxo" and "thio" refer to =O (e.g., carbonyl) and =S (e.g., thiocarbonyl), respectively.

[0155] "Halogen" or "halogen" refers to halogen atoms selected from F, Cl, Br, and I.

[0156] “C α-β"Halogenated alkyl" means an alkyl group as described above, wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.

[0157] N(R a )R a Groups, etc., include two of them R a Substituents that together form a ring (optionally containing N, O, or S atoms) and include, for example:

[0158]

[0159] Group N(C) α-β Alkyl)C α-β Alkyl groups (where α and β are as defined above) include two of their carbon atoms. α-β Alkyl groups together form substituents that form a ring (optionally containing N, O, or S atoms) and include, for example:

[0160]

[0161] "Bicyclic" refers to a group having two connecting rings. A bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, one, two, or three heteroatoms, such as N, O, or S). Both rings can be aliphatic (e.g., naphthane and norbornane), aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene).

[0162] The double ring includes:

[0163] (a) Spirocyclic compounds in which the two rings share a single monatomic atom (a spiroatomic atom, which is usually a quaternary carbon). Examples of spirocyclic compounds include, but are not limited to:

[0164]

[0165] (b) Fused bicyclic compounds in which the two rings share two adjacent atoms. In other words, the rings share a single covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thuenene and naphthane). Examples of fused bicyclic compounds include, but are not limited to:

[0166]

[0167]

[0168] as well as

[0169] (c) Bridged bicyclic compounds in which the two rings share three or more atoms, separated by a bridge consisting of at least one atom at the two bridgehead atoms. For example, norbornane, also known as bicyclic [2.2.1]heptane, can be considered as a pair of cyclopentane rings, each ring sharing three of its five carbon atoms. Examples of bridged bicyclic compounds include, but are not limited to:

[0170]

[0171] Unless otherwise stated, "carbon ring" or "of carbon rings" refers to a ring contained on its own or in combination with other terms, indicating "C". α-β Alkyl groups are cyclic forms. Examples of carbocyclic compounds include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, and cyclohexylene.

[0172] "Heterocyclic" or "heterocyclic" means a ring comprising at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocyclic rings that may appear in the claims include, but are not limited to, the following:

[0173]

[0174]

[0175] "Pharmaceutically acceptable salt" means a salt prepared by conventional means and is well known to those skilled in the art. "Pharmaceutically acceptable salt" includes 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, etc. When the compounds of the present invention contain an acidic functional group such as a carboxyl group, then suitable pharmaceutically acceptable cation pairs of the carboxyl group are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium, quaternary ammonium cations, etc. For further examples of "pharmaceutically acceptable salts," see below and Berge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66:1 (1977).

[0176] "Saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents that are completely unsaturated with hydrogen, and substituents that are partially saturated with hydrogen.

[0177] "Leaving group" generally refers to a group that is readily replaced 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, trifluoromethanesulfonates, toluenesulfonates, etc. Preferred leaving groups are indicated herein where appropriate.

[0178] "Protecting group" generally refers to a group well-known in the art that prevents selected reactive groups such as carboxyl, amino, hydroxyl, and mercapto groups from undergoing undesirable reactions, such as nucleophilic, electrophilic, oxidative, and reductive reactions. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenyl and substituted cycloalkenyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, etc. Examples of aralkyl groups include, but are not limited to, benzyl, o-methylbenzyl, triphenylmethyl, and diphenylmethyl, which may optionally be substituted with halogens, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, etc., as well as salts (such as phosphate and ammonium salts). Examples of aryl groups include phenyl, naphthyl, indanyl, anthracene, 9-(9-phenylfluorenyl), phenanthryl, durenyl, etc. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl groups preferably have 6 to 10 carbon atoms, including but not limited to cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl, and arylalkoxycarbonyl groups include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthalyl, etc. Mixtures of protecting groups can be used to protect the same amino group; for example, a primary amino group can be protected by both an arylalkyl and an arylalkoxycarbonyl group. Amino protecting groups can also form heterocycles with the nitrogen to which they are attached, such as 1,2-bis(methylene)benzene, phthalimide, succinimide, maleimide, etc., and these heterocyclic groups can further comprise adjacent aryl and cycloalkyl rings. Furthermore, the heterocyclic group can be mono-, di-, or tri-substituted, such as nitrophthalimide. Amino groups can also prevent undesirable reactions, such as oxidation, by forming addition salts (e.g., hydrochloride, p-toluenesulfonic acid, trifluoroacetic acid, etc.). Many amino protecting groups are also suitable for protecting carboxyl, hydroxyl, and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable for protecting hydroxyl and mercapto groups, such as tert-butyl groups.

[0179] 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 amino groups provides mono- or di-silylamino groups. Silylation of amino alcohols can lead to N,N,O-trimethylsilyl derivatives. Removal of silyl functionality from silyl ether functional groups is readily accomplished by treatment with, for example, metal hydroxides or ammonium fluoride reagents, either as a standalone reaction step or in situ during the reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or combinations thereof with imidazole or DMF. Methods for the silylation of amines and the removal of silylation protecting groups are well known to those skilled in the art. Methods for preparing these amine derivatives from the corresponding amino acids, amino acid amides, or amino acid esters are also well known to those skilled in the art of organic chemistry, including amino acid / amino acid ester or amino alcohol chemistry.

[0180] Protecting groups are removed under conditions that do not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. Preferred methods involve the removal of protecting groups, for example, by palladium carbonyl hydrolysis in a suitable solvent system (such as alcohols, acetic acid, etc., or mixtures thereof). Tert-butoxycarbonyl protecting groups can be removed using inorganic or organic acids (such as HCl or trifluoroacetic acid) in a suitable solvent system (e.g., dioxane or dichloromethane). The resulting amino salt can be readily neutralized to give a free amine. Carboxyl protecting groups (e.g., methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, etc.) can be removed under hydrolytic and hydrogenolytic conditions well known to those skilled in the art.

[0181] It should be noted that the compounds of the present invention may contain groups that can exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted heteroaryl groups (Y' = O, S, NR), etc., as illustrated in the following examples:

[0182]

[0183] Although this document names, describes, displays and / or claims a form, all tautomers are intended to be inherently included in this name, description, display and / or claim.

[0184] This invention also considers prodrugs of the compounds of the invention. A prodrug is an active or inactive compound that, after administration to a patient, is chemically modified into the compounds of the invention through physiological processes in vivo, such as hydrolysis and metabolism. The suitability and techniques relating to the preparation and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek, Drug Metabolism Reviews 165 (1988) and Bundgaard, Design of Prodrugs, Elsevier (1985). Examples of 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., neopentyloxymethyl). Amines have been masked as arylcarbonyloxymethyl-substituted derivatives, which are cleaved in vivo by esterases, releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Similarly, drugs containing acidic NH groups (such as imidazole, imide, indole, etc.) have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4 / 11 / 81) discloses the Mannich base hydroxamic acid prodrug, its preparation, and its uses.

[0185] This specification and claims contain a list of categories (sometimes referred to as the Markush groups) using the language “selected from…and…” and “for…or…”. When this language is used in this application, unless otherwise stated, it is intended to include the group as a whole, or any individual member thereof, or any subgroup thereof. The use of this language is for shorthand purposes only and is not intended to limit the removal of individual elements or subgroups as needed.

[0186] Drug composition, administration and route of administration

[0187] This document also provides pharmaceutical compositions comprising compounds as disclosed herein and pharmaceutically acceptable excipients, such as diluents or carriers. Compounds and pharmaceutical compositions suitable for use in this invention include those that can be administered in an effective amount to achieve their intended purpose. The administration of the compound will be described in more detail below.

[0188] The appropriate formulation of a pharmaceutical preparation can be determined by a technician based on the route of administration and the required dosage. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th edition, Mack Publishing Co., Easton, PA, 1990). The formulation can affect the physical state, stability, or rate of release and clearance of the administered drug. Depending on the route of administration, the appropriate dosage can be calculated based on body weight, body surface area, or organ size. Those skilled in the art can refine the calculations necessary to determine the appropriate therapeutic dosage in a conventional manner without conducting excessive experimentation, particularly based on the dosage information and measurements disclosed herein and pharmacokinetic data available from animal or human clinical trials.

[0189] The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse reactions, allergic reactions, or other adverse effects when administered to animals or humans. As used herein, "pharmaceutically acceptable" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. Such excipients are well known in the art for use with pharmaceutically active substances. Their use in therapeutic compositions should be considered unless any conventional media or agents are incompatible with the therapeutic composition. Complementary active ingredients may also be incorporated into the composition. In an exemplary embodiment, the formulation may comprise 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 hydrogen 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-cysteine ​​dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, α-tocopherol acetate, sodium chloride, nicotinamide, mixed tocopherols, calcium pantothenate, ketone sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, β-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0190] Compounds can be present in pharmaceutical compositions as pharmaceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" include, for example, base addition salts and acid addition salts.

[0191] Pharmaceutically acceptable base addition salts can be formed using metals or amines (e.g., alkali metals and alkaline earth metals or organic amines). Pharmaceutically acceptable salts of compounds can also be prepared using pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal cations, alkaline earth metal cations, ammonium cations, and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium, or ferric iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucosamine, and procaine.

[0192] Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, salts of formic acid, acetic acid, citric acid, oxalic acid, tartaric acid or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; and salts of organic formic acid, sulfonic acid, thioic acid or phosphonic acid, or N-substituted aminosulfonic 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, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, and 2-phenoxy Salts of benzoic acid, 2-acetoxybenzoic acid, primordial acid, nicotinic acid, or isonicotinic acid; and salts of amino acids, such as the 20 α-amino acids involved in protein synthesis in nature, such as glutamic acid or aspartic acid; and salts of 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-phosphoglyceric acid or 3-phosphoglyceric acid, glucose-6-phosphate, N-cyclohexylaminosulfonic acid (used for the formation of cyclohexylaminosulfonate), or salts of other acidic organic compounds, such as ascorbic acid.

[0193] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, such as by conventional methods of mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, encapsulation, trapping, or lyophilization. Appropriate formulations depend on the chosen route of administration.

[0194] For oral administration, suitable compositions can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients (e.g., carriers) well known in the art. Such excipients and carriers enable the formulation of the compounds of the present invention into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient to be treated. Pharmaceutical formulations for oral use can be obtained by adding a solid excipient as disclosed herein to a compound, optionally grinding the resulting mixture, and, if desired, processing the granular mixture with the addition of a suitable excipient to obtain a tablet or sugar-coated pill core. Suitable excipients include, for example, fillers and cellulose formulations. Disintegrants may be added if desired. Pharmaceutically acceptable ingredients for various types of formulations are well known and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavoring agents, coating materials, preservatives, dyes, thickeners, excipients, antimicrobial agents, antioxidants, and carriers for various types of formulations.

[0195] When a therapeutically effective amount of the compound disclosed herein is administered orally, the composition is typically in the form of a solid (e.g., tablet, capsule, pill, powder, or lozenge) or a liquid formulation (e.g., aqueous suspension, solution, elixir, or syrup).

[0196] When administered in tablet form, the composition may additionally contain functional solids and / or solid carriers, such as gelatin or excipients. Tablets, capsules, and powders may contain about 1% to about 95% of the compound, and preferably about 15% to about 90% of the compound.

[0197] When applied in liquid or suspension form, a functional liquid and / or liquid carrier, such as water, petroleum, or oil of animal or plant origin, may be added. The liquid form of the composition may further contain aqueous saline solution, sugar alcohol solution, dextrose or other sugar solution, or glycol. When applied in liquid or suspension form, the composition may contain about 0.5% to about 90% by weight of the compounds disclosed herein, and preferably about 1% to about 50% by weight of the compounds disclosed herein. In one intended embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For application in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to application.

[0198] When a therapeutically effective amount of the compounds disclosed herein is administered via intravenous, transdermal, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions should take into account pH, isotonicity, stability, etc., and be within the scope of the art. In addition to the compounds disclosed herein, preferred compositions for intravenous, transdermal, or subcutaneous injection typically contain an isotonic agent. Such compositions can be administered by preparing a solution suitably mixed with a surfactant (e.g., hydroxypropyl cellulose) in water for use as a free base or a pharmacologically acceptable salt. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and in oils. Under normal storage and use conditions, these formulations may optionally contain preservatives to prevent microbial growth.

[0199] Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, the form must be sterile and the flowability must be sufficient to allow for easy injection. It must be stable under manufacturing and storage conditions and must resist microbial (e.g., bacterial and fungal) contamination by optionally including preservatives. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one considered embodiment, the carrier is non-aqueous or substantially non-aqueous. Appropriate flowability can be maintained, for example, by using coatings, such as lecithin; in dispersion embodiments, by maintaining the desired particle size of the compound; and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenols, sorbic acid, thimerosal, etc. In many embodiments, including isotonic agents (e.g., sugars or sodium chloride) is preferred. Extended absorption of injectable compositions can be achieved by using absorption delay agents (e.g., aluminum monostearate and gelatin) in the composition.

[0200] Sterile injectable solutions are prepared by incorporating the active compound in the desired amount into a suitable solvent containing, as needed, various other components listed above, followed by filtration and sterilization. Dispersions are typically prepared by incorporating various sterilized active ingredients and other desired components from those listed above into a sterile medium containing a base dispersion medium. In embodiments for preparing sterile powders for sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any other desired components from its pre-sterilely filtered solution.

[0201] Slow-release or sustained-release formulations can also be prepared to achieve controlled release of the active compound upon contact with bodily fluids in the gastrointestinal tract and to provide substantially constant and effective levels of the active compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. Additionally, slow-release methods can promote absorption through saturable or restrictive pathways within the gastrointestinal tract. For example, for this purpose, the compound can be encapsulated in a polymer matrix of a biodegradable polymer, a water-soluble polymer, or a mixture of both, and optionally a suitable surfactant. In this case, encapsulation can mean incorporating microparticles into the polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsion-coated droplets via known dispersion or emulsion coating techniques.

[0202] For administration by inhalation, the compounds of the present invention are conveniently delivered from pressurized packaging or nebulizers using a suitable propellant in the form of an aerosol spray. In embodiments of pressurized aerosols, a valve can be provided to determine the dosage unit for delivery of a metered amount. Capsules and cartridges, such as gelatin, for use in inhalers or blowpipes can be formulated as powder mixtures containing the compound with a suitable powder matrix (e.g., lactose or starch).

[0203] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus or continuous infusion). Injectable formulations can be presented in unit dosage forms (e.g., in ampoules or in multi-dose containers) and contain preservatives. Compositions can take the form of, for example, suspensions, solutions, or emulsions in oily or aqueous media, and may contain formulations such as suspending agents, stabilizers, and / or dispersants.

[0204] Pharmaceutical formulations for parenteral administration include aqueous solutions of compounds in a water-soluble form. Alternatively, suspensions of the compounds can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils or synthetic fatty acid esters. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or reagents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention may be in powder form for preparation with a suitable mediator (e.g., sterile, pyrogen-free water) prior to use.

[0205] The compounds disclosed herein can also be formulated into rectal compositions, such as suppositories or retention enemas (e.g., containing a conventional suppository matrix). In addition to the formulations previously described, the compounds can also be formulated as long-acting preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives (e.g., as slightly soluble salts).

[0206] Specifically, the compounds disclosed herein can be administered orally, buccally, or sublingually in the form of tablets containing excipients (e.g., starch or lactose), or in capsules or ovules alone or in combination with excipients, or in elixirs or suspensions containing flavoring agents or coloring agents. Such liquid formulations can be prepared with pharmaceutically acceptable additives (e.g., suspensions). The compounds can also be administered parenterally, such as intravenously, intramuscularly, subcutaneously, or intracoronaryly. For parenteral administration, the compounds are preferably used in the form of a sterile aqueous solution, which may contain other substances, such as salts or sugar alcohols (e.g., mannitol) or glucose, to make the solution isotonic with blood.

[0207] For veterinary use, the compounds disclosed herein are administered as suitably acceptable formulations according to standard veterinary practice. Veterinarians can readily determine the most suitable dosing regimen and route of administration for a particular animal.

[0208] In some embodiments, all necessary components for treating KIF18A-related disorders using compounds as disclosed herein (alone or in combination with another agent or intervention conventionally used to treat this disease) may be packaged into a kit. Specifically, the present invention provides a kit for a therapeutic intervention for a disease comprising a packaged kit of pharmaceuticals, including the compounds disclosed herein and buffer solutions and other components for preparing said pharmaceuticals in a deliverable form; and / or a means for delivering such pharmaceuticals; and / or any agent for combination therapy with the compounds disclosed herein; and / or instructions for the treatment of the disease packaged with the pharmaceuticals. The instructions may be affixed to any tactile medium, such as printed paper, or computer-readable magnetic or optical media, or instructions referencing a remote computer data source (e.g., a World Wide Web webpage accessible via the Internet).

[0209] "Therapeutic effective amount" means the amount that effectively treats or prevents the development of existing symptoms in a treated subject or alleviates existing symptoms. In particular, the determination of an effective amount is entirely within the capabilities of those skilled in the art, based on the detailed disclosure provided herein. Generally, a "therapeutic effective dose" refers to the amount of compound that results in the desired effect. For example, in a preferred embodiment, a therapeutically effective amount of the 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 group.

[0210] The amount of compound administered can depend on the subject being treated, the subject's age, health status, sex, and weight, the type of concurrent treatment (if any), the severity of the condition, the nature of the desired effect, the manner and frequency of treatment, and the prescribing physician's judgment. The frequency of administration can also depend on the pharmacodynamic effect on arterial oxygen partial pressure. Although individual needs vary, determining the optimal range of effective amounts of the compound is within the scope of the art. Such dosages can be administered as a single dose or can be divided into multiple doses.

[0211] When used herein, the terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals 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, liver cancer, breast cancer, colon cancer, and head and neck cancer, ovarian cancer, and endometrial cancer. Although the term “cancer” is not limited to any particular form of the disease as used herein, the methods of the present invention are considered particularly effective in identifying cancers with or dependent on unregulated KIF18A levels, which are essential for proper chromosome segregation and survival in mammals.

[0212] As used herein, the term "treat (treating)" refers to a therapy, including but not limited to curative therapy, preventative therapy, and preventive treatment. Preventive treatment typically involves the complete prevention of the onset of an individual's disease or the delay of the onset of an individual's disorder in the preclinical, apparent stage.

[0213] As used herein, the terms “patient,” “subject,” or “mammal” refer to any “patient,” “subject,” or “mammal,” including humans, cattle, horses, dogs, and cats. In one embodiment of the invention, the mammal is a human.

[0214] The term “includes / contains” means open-ended, including one or more of the specified components, but excluding other elements.

[0215] The term “Formula I” includes any subformula.

[0216] Methods using KIF18A inhibitors

[0217] This disclosure provides compounds generally possessing MT-based KIF18A regulatory activity, particularly inhibitory activity. In one embodiment of the invention, a method for modulating the KIF18A protein in a subject is provided, the method comprising administering an effective dose of a compound of formula I to the subject. 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 tumors. The compounds can also be used for ciliate-related diseases and for ablation of haploid germ cell populations that can be used as male contraceptives.

[0218] Furthermore, the compounds of the present invention can be used, but are not limited to, for the prevention or treatment of cancer and other KIF18A-mediated diseases or conditions. For example, the compounds of the present invention can be used to treat a variety of solid tumors or hematopoietic tumors, such as cancers 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); lymphoid hematopoietic tumors (including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair loss...). Cellular lymphoma and Burkert lymphoma; hematopoietic tumors of the bone marrow lineage (including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of stromal origin (including fibrosarcoma and rhabdomyosarcoma, as well as 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, or Kaposi's sarcoma).

[0219] The compounds of the present invention can also be used to treat cancer-related indications, such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic malignancies (including leukemia and lymphoma), pleural or pericardial effusions caused by tumors, and malignant ascites.

[0220] Based on their ability to regulate kinins and influence angiogenesis, the compounds of this invention can also be used for the treatment and therapy of proliferative diseases. In particular, these compounds can be used to treat inflammatory diseases, especially those affecting the musculoskeletal system, such as various inflammatory rheumatoid diseases, particularly chronic polyarthritis, including rheumatoid arthritis, juvenile arthritis, or psoriatic arthritis; tumor-associated syndromes or tumor-related inflammatory diseases, turbid effusions, collagen diseases such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma, or mixed collagen diseases; post-infectious arthritis (where no living pathogenic organism is found in or at the site of infection), seronegative spondyloarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis, or arthropathy; or any further combinations thereof.

[0221] The compounds of this invention can also be used as active agents against conditions such as arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary artery and lateral cerebral processes, colloidal ischemic angiogenesis, wound healing, peptic ulcers, Helicobacter pylori-related diseases, fractures, cat scratch fever, flushing, neovascular glaucoma, and retinopathy (e.g., retinopathy associated with diabetic retinopathy or macular degeneration). Furthermore, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers, and hyperproliferative disorders (e.g., thyroid hyperplasia (especially Graves' disease)) and cysts (e.g., vascular hyperplasia of the ovarian stroma, a characteristic feature of polycystic ovary syndrome (Stein-Leventhal syndrome)), because such diseases require vascular cell proliferation for growth and / or metastasis.

[0222] These compounds can be used not only for human treatment but also for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals and rodents. For example, the compounds provided by this invention can be used to treat animals including horses, dogs, and cats.

[0223] combination

[0224] Although the compounds of the present invention can be administered or applied as the sole active pharmaceutical ingredient, they can also be used in combination with one or more compounds of the present invention or in combination with other agents. When administered in combination, the therapeutic agents can be formulated into separate compositions, which can be administered simultaneously or sequentially at different times, or the therapeutic agents can be given as a single composition.

[0225] In defining the use of the compounds and another pharmaceutical agent of the present invention, the phrase “combination therapy” (or “group therapy”) is intended to include sequential administration of each agent in a manner that provides a beneficial combination of pharmaceutical effects, and is also intended to include co-administration of the agents in a substantially simultaneous manner, for example, in a single capsule having a fixed proportion of these active agents or in multiple separate capsules of each agent.

[0226] Specifically, the application of the compounds of the present invention can be combined with other therapies known to those skilled in the art for the prevention or treatment of cancer, such as radiotherapy, small molecule targets (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies with tumor or cytotoxic agents (e.g., naked and drug-conjugated), and immunotherapy antibodies (checkpoint inhibitors, bispecific T-cell conjugates).

[0227] If formulated into a fixed dosage, such combination products utilize the compounds of the present invention within an acceptable dosage range. When the combination formulation is unsuitable, the compounds of Formula I may also be administered sequentially with known anticancer agents or cytotoxic agents. The present invention is not limited to the order of administration; the compounds of the present invention may be administered before, simultaneously with, or after the administration of known anticancer agents or cytotoxic agents.

[0228] There are a large number of anticancer agents available for commercial use, clinical evaluation, and preclinical development, which can be selected for the treatment of tumors through combination drug chemotherapy. These agents are divided into several major categories, such as antibiotics, alkylated and alkyl-like agents, antimitotic agents, small molecule targeted agents, antimetabolites, hormones, immunomodulators, antiangiogenic agents, interferon agents, and miscellaneous agents.

[0229] This disclosure also provides methods for combination therapy, wherein agents known to modulate other pathways or other components of the same pathway, or even overlapping sets of target enzymes, are used in combination with compounds of this disclosure or pharmaceutically acceptable salts thereof. In one aspect, such therapy includes, but is not limited to, combinations of one or more compounds of this disclosure with chemotherapeutic agents, therapeutic antibodies, small molecule targets, and radiation therapy to provide synergistic or additive therapeutic effects.

[0230] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds disclosed herein. In some embodiments, the chemotherapeutic agents are selected from the group consisting of: antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, bioreaction modifiers, antihormonal agents, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, such as... (imatinib mesylate) (carfilzomib) (bortezomib), Casodex (bicalutamide) Gefitinib and Adriamycin, as well as a variety of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimine and methylamelamine, including hexamethylmelamine, triethylene ethylmelamine, triethylene ethylphosphamide, triethylenethiophosphamide, and trimethylolomelamine; nitrogen mustards such as chlorambucil, naphthiamethoxam, cholophosphamide, estradiol, ifosfamide, dichloromethyldiethylamine, and mechlorethamine oxide. Hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trafosamide, uracil mustard; nitrosoureas, such as carmustine, chloramphenicol, formustine, lomustine, nimustine, ramustine; antibiotics, such as aclacinomysin, actinomycin, autramycin, diazoserine, bleomycin, cactinomycin, calicheamicin, carabicin, erythromycin, carzinophilin, Casodex™ Chromomycin, cyproterone, doxorubicin, detoxin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, isorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogamycin, oligomycin, pepromycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptomycin, streptozotocin, tuberculin, ubenimex, fenestrated statin, zolrubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteroxate, trimethoprim; purine analogs, such as fludarabine, 6-mercaptopurine, thioimide, thioguanine;Pyrimidine analogues, such as azacitidine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enoxabin, and fluorouridine; androgens such as capesterolone propionate, dromostanolone propionate, cyclothionol, meandrolone, and testosterone; antiadrenergic drugs, such as aminoglutethimide, mitotane, and trilosterone; and folic acid supplements, such as frolinic acid. acid); glucuronolactone; aldehyde phosphoramide glycoside; aminolevulinic acid; acridine; bestrabucil; bifenthrin; edatraxate; defofamine; colchicine; diazinon; elfomithine; elifonitrile; etoglucopyranoside; gallium nitrate; hydroxyurea; lentinan; chlordamine; mitoxantrone; mitoxantrone; mopiperol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid (acid); 2-ethylhydrazine; procarbazine; PSK; propylimine; cizonan; germanium spiroamine; Alternaria alternifolia ketoacid; triaminequinone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromoeugenol; piperobromo; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as taxol and docetaxel, albumin-bound taxol (Nab-paclitaxel); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0231] Suitable chemotherapeutic cell opsonizers also include antihormonal agents used to modulate or inhibit the effects of hormones on tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex™), raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trivoxifen, keoxifene, and LY. 117018, Onasone and toremifene (Falletone); and antiandrogens such as flutamide, nilumid, bicalutamide, leuprorelin and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; danomycin; aminopterin; xeloda; ibandronate; topotecan; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO),

[0232] If needed, the compounds or pharmaceutical compositions disclosed herein may be used in combination with commonly prescribed anticancer drugs, such as... Abraxane ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygerdomyl, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiourea, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, antitumor drugs, antitumorigenic herbs, Apaziquone, Atipremod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthioninesulfoximine), CBV (chemotherapy), Calyculin, cell cycle nonspecific antitumor agents, dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquida ( Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Talazoparib, Niraparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A) Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatintetranitrate, tri(2-chloroethyl)amine, troxacitabine, uramustine, vadimozan, vinflunine, ZD6126 or zosuquidar, CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, Kisqali; abemaciclib, Verzenio).

[0233] This disclosure further relates to methods for inhibiting abnormal cell growth or treating hyperplasia disorders in mammals using a combination of the compounds or pharmaceutical compositions provided herein with radiotherapy. Techniques for administering radiotherapy are known in the art, and these techniques can be used in the combination therapies described herein. The administration of the compounds disclosed herein in such combination therapies can be determined as described herein.

[0234] Radiation therapy can be administered through one or a combination of several methods, including but not limited to external beam therapy, internal radiation therapy, implantation radiation, stereotactic radiosurgery, whole-body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term “brachytherapy” refers to radiation therapy delivered by a spatially confined radioactive material inserted into or near a lesion site in the body, such as a tumor or other proliferative tissue. The term is intended to include, without limitation, 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 Lu). Suitable radiation sources used as cytomodulation agents in this disclosure include both solid and liquid forms. By way of non-limiting examples, the radioactive source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192 as solid sources, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays. The radioactive material can also be a fluid prepared from any solution of one or more radionuclides (e.g., a solution of I-125 or I-131), or the radioactive fluid can be generated using a suitable fluid slurry containing small particles of a solid radionuclide (e.g., Au-198, Y-90). Furthermore, one or more radionuclides can be embedded in gels or radioactive microspheres.

[0235] The compounds or pharmaceutical compositions disclosed herein may be used in combination with a certain amount of one or more substances selected from the following: anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0236] Antiangiogenic agents can be used in combination with the compounds disclosed herein and the pharmaceutical compositions described herein. These antiangiogenic agents are, for example, MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, vardicoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in the following patents: WO 96 / 33172, WO 96 / 27583, European Patent Publication EP 0818442, European Patent Publication EP1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, European Patent Publication 606046, European Patent Publication 931788, WO 90 / 05719, WO 99 / 52910, WO99 / 52889, WO 99 / 29667, WO 1999007675, European Patent Publication EP 1786785, European Patent Publication EP 1181017, and US Patent Publication. The following patents are incorporated herein by reference in their entirety: 20090012085, US Publication No. 5863 949, US Publication No. 5861510, and European Patent Publication No. EP 0780386. Preferred MMP-2 and MMP-9 inhibitors are those with minimal or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors that may be used in this disclosure are AG-3340, RO 32-3555, and RS 13-0830.

[0237] The compounds of this invention can also be used in co-treatment with other antitumor agents, such as acemannan, arubicin, interleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminolevulinic acid, arubicin, acridine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, bromouridine, capecitabine, simvastatin, cetrorexate, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, and denileukin. Diftitox, Deslorelin, Dexrazoxen, Dilazep, Docetaxel, Diococcalciferol, Deoxyfluorouridine, Doxorubicin, Bromocriptine, Carmustine, Cytarabine, Fluorouracil, HIT (Diclofenac), Interferon-α, Doxorubicin, Doxorubicin, Retinoic Acid, Edifosine, Ezocuronium, Eflornithine, Ethiributyrol, Epirubicin, Erythropoietin β, Etoposide Phosphate, Exemestane, Exisulind, Fazodazole, Filgrastim, Finasteride, Fludarabine Phosphate, Formestane, Formosine, Gallium Nitrate, Gemcitabine, Gemtuzumab, Omzolidine abzogamicin), gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin, imiquimod, interferon-α, interferon-α, natural interferon-α-2, interferon-α-2a, interferon-α-2b, interferon-α-N1, interferon-α-n3, interferon alfacon-1, interferon α, natural interferon β, interferon β-1a, interferon β-1b, interferon γ, natural interferon γ-1a, interferon γ-1b, interleukin-1β, iodobenzylguanidine, irinotecan, isoladine, lanreotide, LC9018 (Yakult Group), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte α-interferon, Leuprorelin, Levamisole + Fluorouracil, Liarozole, Lobaplatin, Clonidamine, Lovastatin, Masrophenone, Melarsone, Metoclopramide, Mifepristone, Mitefosine, Milistatin, Mismatched double-stranded RNA, Mitoguanidine, Dibromoceroxyl, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis-Stimulating Protein, NSC 631570 Octreotide, Oprelvekin, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, Pegylated Interferon-α-2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti-thymocyte Polyclonal Antibody, Pegylated Interferon-α-2a, Porphyrin Sodium, Raloxifene, Raltitrexed, Rasburiembodiment, Rhenium Ethidone (Re 186), RII Retinoylphenol (RII) Retinamide, Rituximab, Romotide, Samarium (153Sm), Sargramostim, Cizonan, Sobuzosen, Sonermin, Strontium Chloride-89, Suramin, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecoxide, Thalidomide, Thymofasin, Thyroxine alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, tresmin, retinoic acid, tralosterol, trimethoprim, triptorelin, tumor necrosis factor alpha, natural ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizine, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), Cetuximab, Decitabine, Dexaminoglutethimide, Diazinon, EL 532 (Elan), EM 800 (Endorecherche), Enuracil, Ethanidazole, Fenretinide, Filgrastim SD01 (Amgen), Fulvestrant, Gallotabine, Gastrin 17 Immunogen, HLA-B7 Gene Therapy (Vical), Granulocyte-Macrophage Colony-Stimulating Factor, Histamine Dihydrochloride, Tiimomab, Ilomasta, IM 862 (Cytran), Interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131MAb (Techniclone), polymorphic epithelial mucin-yttrium-90MAb (Antisoma), marimastat, minoli, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubecitabine, satraplatin, sodium phenylacetate, sparfosicacid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl tin.etiopurpurin, terazamine, cancer vaccine (Bamira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0238] The compounds of this invention can be further used in conjunction with VEGFR inhibitors. Other compounds described in the following patents and patent applications may be used in combination therapies: US 6,258,812, US 2003 / 0105091, WO 01 / 37820, US 6,235,764, WO 01 / 32651, US 6,630,500, US 6,515,004, US 6,713,485, US 5,521,184, US 5,770,599, US 5,747,498, WO 02 / 68406, WO 02 / 66470, WO 02 / 55501, WO 04 / 05279, WO04 / 07481, WO 04 / 07458, WO 04 / 09784, WO 02 / 59110, WO 99 / 45009, WO 00 / 59509, WO 99 / 61422, US 5,990,141, WO 00 / 12089 and WO 00 / 02871.

[0239] In some embodiments, the combination comprises a combination of the composition of the present invention with at least one anti-angiogenic agent. Agents include, but are not limited to, chemical compositions synthesized in vitro, antibodies, antigen-binding regions, radionuclides, and combinations thereof, and conjugates. Agents may be agonists, antagonists, allosteric modulators, toxins, or more generally, may be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), thereby promoting cell death or inhibiting cell growth.

[0240] Exemplary anti-angiogenic agents include ERBITUX TM (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding domains that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen-binding domains that specifically bind to VEGF, or soluble VEGF receptors or their ligand-binding domains) (e.g., AVASTIN) TM or VEGF-TRAP TM) and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to them), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them) (e.g., Vectibix (panitumumab), IRESSA) TM (Gefitinib), TARCEVA TM (Erlotinib), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to or to their receptors (e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them). The pharmaceutical compositions of the present invention may also comprise one or more agents that specifically bind to and inhibit the activity of growth factors (e.g., antibodies, antigen-binding regions, or soluble receptors), such as antagonists of hepatocyte growth factor (HGF, also known as scattering factor), and antibodies or antigen-binding regions that specifically bind to their receptor “c-met.”

[0241] Other anti-angiogenic agents include alemtuzumab (Campath), IL-8, β-FGF, Tek antagonists (Ceretti et al., U.S. Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., those that specifically bind to antibody or antigen-binding domains, or soluble TWEAK receptor antagonists; see Wiley, U.S. Patent No. 6,727,225), and ADAM disintegrin domains that antagonize the binding of integrin to its ligands (Fanslow et al., U.S. Publication No. 2002 / 0162712). 042368), antibodies or antigen-binding regions that specifically bind to anti-eph receptors and / or anti-ephrin (US Patent Nos. 5,981,245, 5,728,813, 969,110; 6,596,852; 6,232,447; 6,057,124 and members of their patent families), anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands), and 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 to them).

[0242] Other 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, US5712291); ilomastat (Arriva, USA, US 5892112); emaxanib (Pfizer, USA, USA). 5792783); 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 Co., Ltd., Japan) 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); Transmetastatin (EntreMed, USA); Angiogenesis Inhibitor (Tripep, Sweden); Serine Protease Inhibitor (maspin) (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Fluroxypyr (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan). 02233610); Platelet-4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, α5β3 integrin, second-generation (Applied Molecular Evolution, USA and MedImmune, USA); Gene therapy, retinopathy (Oxford Biotechnology, UK). BioMedica, UK); Zekran hydrochloride (USA) (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneron, USA); rBPI 21 and BPI-derived anti-angiogenic agents (XOMA, USA);PI 88 (Progen, Australia); cilengitide (pINN) (Merck KGaA, Germany; Technical University of Munich, Germany; Scripps Clinic and Research Foundation, USA); cetuximab (INN) (Aventis, France); AVE 8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children's Hospital, USA); ATN 161 (Attenuon, USA); Angiostatin (Boston Children's Hospital, USA); 2-Methoxyestradiol (Boston Children's Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Vatalani (pINN) (Novartis, Switzerland and Schering, Germany) AG, Germany); Tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); Curcumin (Yonsei University, South Korea);Vaccines, gene-based: VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California at San Diego, USA); PX 478 (ProlX, USA); transferstatin (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidine promoters (Dimensional Pharmaceuticals, USA); motuporamine C (University of British Columbia, Canada); CDP 791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Vaccines, angiogenesis inhibitors (EntreMed, USA); Urokinase plasminogen activator inhibitors (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitors (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea);GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); Intraocular drug delivery system, 2-methoxyestradiol (EntreMed, USA); Picatinyl ester (anginex) (Maastricht University, Netherlands) University, Netherlands and University of Minnesota, USA; ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor necrosis factor-alpha inhibitor (National Institute on Aging, USA); SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA). Children's Hospital (USA) and EntreMed (USA); MAb, KDR (ImClone Systems (USA)); MAb, α5β1 (Protein Design (USA)); KDR kinase inhibitors (Celltech Group (UK) and Johnson & Johnson (USA)); GFB 116 (South Florida University (USA) and Yale University (USA)); CS 706 (Sankyo (Japan)).Constatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea). Korea); MAb, vascular endothelial growth factor (Xenova, UK); irsogladine (INN) (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (pINN) (Genaera, USA); RPI 4610 (Sirna, USA); cancer therapy (Marinova, Australia); heparinase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); and honokiol (Emory University, USA). University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan);VEGF receptor modulators (Pharmacopeia, USA); VE-cadherin-2 antagonists (ImClone Systems, USA); angiogenesis inhibitors (National Institutes of Health, USA); vaccines, Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); tumor suppressor (TumStatin, Beth Israel Hospital, USA); short soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co., USA); Tie-2 ligands (Regeneron, USA); and thromboretin 1 inhibitors (Allegheny Health, Education and Research Foundation, USA).

[0243] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, and hydroxychloroquine (Plaquenil). TM ), bafilomycin A1, 5-amino-4-imidazolamide ribonucleoside (AICAR), okadaic acid, autophagy-inhibiting alginate toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels such as adenosine, LY204002, N6-mercaptopurine ribonucleoside, and vincristine. Additionally, antisense or siRNAs that inhibit protein expression, including but not limited to ATG5 (which is involved in autophagy), can be used.

[0244] Other pharmaceutically active compounds / pharmaceuticals that can be used to treat cancer and can be used in combination with one or more compounds of the present invention include: epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; anxistatin; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706 or pharmaceutically acceptable salts thereof.

[0245] In some embodiments, the compositions provided herein are administered in combination with chemotherapeutic agents. Suitable chemotherapeutic agents may include natural products such as vinca alkaloids (e.g., vincristine, vinorelbine, and vinorelbine), paclitaxel, epidipodophyllotoxin (e.g., etoposide and teniposide), antibiotics (e.g., dextrin (actinomycin D), doxorubicin, doxorubicin, and idarubicin), anthracycline antibiotics, mitoxantrone, bleomycin, procainoxantrone (scintillan), mitomycin, and enzymes (e.g., L-asparaginase, which is systemically metabolized). L-Asparagine and deprive cells that do not have the ability to synthesize their own asparagine, antiplatelet agents, antiproliferative / antimitotic alkylating agents (e.g., nitrogen mustard, such as dichloromethyldiethylamine, cyclophosphamide and analogues, melphalan and chlorambucil), ethyleneimine and methylmelamine (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-03). 32991, dinaciclib, P27-00, AT-7519, RGB286638 and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogues and streptozotocin), triazine-dacarbazine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogues (e.g., methotrexate), pyrimidine analogues (e.g.) Examples of inhibitors include fluorouracil, fluorouracil, and cytarabine; purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine); aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole); platinum coordination complexes (e.g., cisplatin and carboplatin); procarbazine; hydroxyurea; mitotane; aminoglutethimide; histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, aspirin, and hydroamic acid). (e.g., acid), vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., tesimolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis), PI3Kδ inhibitors (e.g., GS-1101 and TGR-1202), PI3Kδ and γ inhibitors (e.g., CAL-130), multi-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g.,Estrogens and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprorelin, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS) 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzartolin), FTIs (e.g., Zarnestra), TM Anti-CD138 (e.g., BT062), Torc1 / 2 specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targets (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib, talazoparib, niraparib, and veliparib (ABT-888)), and BCL-2 antagonists. Other chemotherapeutic agents may include dichloromethyldiethylamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, noviben, sorafenib, or any analogues or derivative variants of the foregoing.

[0246] The compounds of this invention can also be used in combination with radiotherapy, hormone therapy, surgery and immunotherapy, which are well known to those skilled in the art.

[0247] In some embodiments, the pharmaceutical compositions provided herein are administered in combination with steroids. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, aclomethasone, alpha-pregnant hormone, ansine, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocotropin, chlorprednisolone, corticosteroids, cortisone, cortisol, difucoxetine, desonide, hydroxymethasone, dexamethasone, diflorasone, diflucortolone, difuprednate, glycyrrhetinic acid, fluzacrolide, flucloronide, flumethasone, flunisolone, fluocinolone acetonide, fluocinolone acetate, fluocortinbutyl, fluocinolone, fluorometholone, and fluperolone. Acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, horseprednione, methylprednisolone, methylprednisolone, mometasone furoate furoate), peramisone, prednicarbamate, prednisolone, prednisolone 2,5-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, limexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts and / or derivatives. In one particular embodiment, the compounds of the present invention may also be used in combination with other pharmaceutically active agents for the treatment of nausea.Examples of medications that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0248] The compounds or pharmaceutical compositions disclosed herein may also be used in combination with one or more substances selected from the following: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and immunotherapies, including anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

[0249] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful EGFR antibody inhibitors include cetuximab (Erbitux), panitumumab (Vectib), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently, lapatinib (TykerB). See, for example, 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.

[0250] Non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, and all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European Patent Application EP 520722, published December 30, 1992; European Patent Application EP 566226, published October 20, 1993; PCT International Publication WO 96 / 33980, published October 31, 1996; US Patent No. 5,747,498, granted May 5, 1998; PCT International Publication WO 96 / 30347, published October 3, 1996; European Patent Application EP 787772, published August 6, 1997; PCT International Publication WO 97 / 30034, published August 21, 1997; PCT International Publication WO PCT International Publication WO 97 / 30044, published August 21, 1997; PCT International Publication WO 97 / 38994, published October 23, 1997; PCT International Publication WO 97 / 49688, published December 31, 1997; European Patent Application EP 837063, published April 22, 1998; PCT International Publication WO 98 / 02434, published January 22, 1998; PCT International Publication WO 97 / 38983, published October 23, 1997; PCT International Publication WO 95 / 19774, published July 27, 1995; PCT International Publication WO 95 / 19970, published July 27, 1995; PCT International Publication WO WO 97 / 13771, published April 17, 1997; PCT International Publication WO 98 / 02437, published January 22, 1998; PCT International Publication WO 98 / 02438, published January 22, 1998; PCT International Publication WO 97 / 32881, published September 12, 1997; German Application DE 19629652, published January 29, 1998; PCT International Publication WO 98 / 33798, published August 6, 1998; PCT International Publication WO 97 / 32880, published September 12, 1997; PCT International Publication WO 97 / 32880, published September 12, 1997; European Patent Application EP 682027, published November 15, 1995; PCT International Publication WO WO 97 / 02266, published on January 23, 1997; PCT International Publication WO 97 / 27199, published on July 31, 1997; PCT International Publication WO 98 / 07726, published on February 26, 1998; PCT International Publication WO 97 / 34895, published on September 25, 1997.PCT International Publication WO 96 / 31510′, published on October 10, 1996; PCT International Publication WO 98 / 14449, published on April 9, 1998; PCT International Publication WO 98 / 14450, published on April 9, 1998; PCT International Publication WO 98 / 14451, published on April 9, 1998; PCT International Publication WO 95 / 09847, published on April 13, 1995; PCT International Publication WO PCT International Publication WO97 / 19065, published May 29, 1997; PCT International Publication WO98 / 17662, published April 30, 1998; U.S. Patent No. 5,789,427, granted August 4, 1998; U.S. Patent No. 5,650,415, granted July 22, 1997; U.S. Patent No. 5,656,643, granted August 12, 1997; PCT International Publication WO99 / 35146, published July 15, 1999; PCT International Publication WO99 / 35132, published July 15, 1999; PCT International Publication WO99 / 07701, published February 18, 1999; and PCT International Publication WO92 / 20642, published November 26, 1992. Other non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in Traxler, P., 1998, Exp. Opin. Ther. Patents [Expert Commentary on Therapeutic Patents] 8(12):1599-1625.

[0251] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligands. Non-limiting examples of antibody-based EGFR inhibitors include those described in the following literature: 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, SM et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X. et al., 1999, Cancer Res. 59:1236-1243. Therefore, EGFR inhibitors can be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, ibid.), or Mab C225 (ATCC accession number HB-8508), or antibodies or antibody fragments with their binding specificity.

[0252] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0253] PI3K inhibitors include, but are not limited to, womanpem, 17-hydroxywomanpem analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methanesulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT publications WO 09 / 036,082 and WO 09 / 055,730), and 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT publication WO 06 / 044453). 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (described in PCT Publication No. WO 2008 / 070740), LY294002 (2-(4-morpholino)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI103 hydrochloride (3-[4-(4-morpholinopyridino-[3′,2′:4,5]furano[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75(N′-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfonyl-hydrazide hydrochloride, available from Exxon Medical Chemicals), PIK 90(N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Exxon Medical Chemicals), GDC-0941 dimethylsulfonate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine dimethylsulfonate, available from Exxon Medical Chemicals), AS-2524 24 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidin-2,4-dione, available from Exxon Medical Chemicals, Inc.) and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one, available from Exxon Medical Chemicals, Inc.), XL-765 and XL-147.Other PI3K inhibitors include demethoxyviridin, perifoxine, 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.

[0254] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibiting Akt1) (Barnett et al. (2005) Biochem.J. [Journal of Biochemistry], 385(Pt.2), 399-408); Akt-1-1,2 (inhibiting Ak1 and 2) (Barnett et al. (2005) Biochem.J. [Journal of Biochemistry], 385(Pt.2), 399-408); and API-59CJ-Ome (e.g., Jin et al. (2004) Br.J. Cancer [British Cancer Journal]). [Journal of Cancer] 91, 1808-12); 1-H-imidazo[4,5-c]pyridyl compounds (e.g., WO05011700); indole-3-methanol and its derivatives (e.g., US Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. [Journal of Nutrition] 134 (12 Supplement), 3493S-3498S); perifosine (e.g., interfering with Akt membrane localization; Dasmahapatra et al., (2004) Clin. Cancer Res. [Clinical Cancer Research] 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs [Research Drug Expert Review] 13, 787-97); and triciribine (TCN or API-2 or NCI identification: NSC154020; Yang et al., (2004), Cancer Res. [Cancer Research] 64, 4394-9).

[0255] TOR inhibitors include, but are not limited to, AP-23573, CCI-779, everolimus, RAD-001, rapamycin, tesiromolimus, ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and Torin 1. Other TOR inhibitors include FKBP12 enhancers; rapamycin and its derivatives, including: CCI-779 (tesirobolimus), RAD001 (everolimus; WO 9409010) and AP23573; rapamycin analogues, such as those disclosed in WO98 / 02441 and WO 01 / 14387, such as AP23573, AP23464 or AP23841; 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropionate]-rapamycin (also known as CC1779), 40-epi-(tetrazole)-rapamycin (also known as ABT578), 32-deoxyrapamycin, 16-pentyneoxy-32(S)-dihydrorapamycin and other derivatives disclosed in WO05005434; derivatives disclosed in the following patents: US Patent No. 5,258,389, WO 94 / 090101, WO 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, WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and U.S. Patent No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Application No. 60 / 528,340).

[0256] Immunotherapy includes, but is 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 the following literature: 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 / JP 2006 / 309606 (Publication No. WO 2006 / 121168A1), each of which is expressly incorporated herein by reference. Including: Yervoy TMIpilimumab or Tremelimumab (for CTLA-4), galiximab (for B7.1), BMS-936558 (for PD-1), MK-3475 (for PD-1), AMP224 (for B7DC), BMS-936559 (for B7-H1), MPDL3280A (for B7-H1), MEDI-570 (for ICOS), AMG557 (for B7H2), MGA271 (for B7H3), IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Health) Services), huMAbOX40L (for OX40L), Atacicept (for TACI), CP-870893 (for CD40), Lucatumumab (for CD40), Dacetuzumab (for CD40), Muromonab-CD3 (for CD3), Ipilimumab (for CTLA-4). Immunotherapy also includes genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

[0257] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Patent No. 6,111,090box.c, European Patent No. 090505B1, U.S. Patent No. 8,586,023, PCT Publication Nos. WO 2010 / 003118 and 2011 / 090754, or anti-GITR antibodies described, for example, in U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. EP 1866339, PCT Publication No. WO 2011 / 028683, PCT Publication No. WO 2013 / 039954, PCT Publication No.: WO2005 / 007190, PCT Publication No.: WO 2007 / 133822, PCT Publication No.: WO 2005 / 055808, PCT Publication No.: WO 99 / 40196, PCT Publication No.: WO 2001 / 03720, PCT Publication No.: WO 99 / 20758, PCT Publication No.: WO 2006 / 083289, PCT Publication No.: WO 2005 / 115451, US Patent No. 7,618,632 and PCT Publication No.: WO 2011 / 051726.

[0258] The compounds described herein may be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more of the compounds disclosed herein will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein may be administered simultaneously or separately from a second agent. Such combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration of individual dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the agents described above may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, any of the agents described above may be administered immediately after administration of the compounds disclosed herein, or vice versa. In some embodiments of the single-administration regimen, the administration of the compounds disclosed herein and any of the agents described above may be spaced several minutes, several hours, or several days apart.

[0259] Since one aspect of the invention contemplates the treatment of diseases / conditions with combinations of pharmaceutically active compounds that can be administered separately, the invention further relates to the combination of individual pharmaceutical compositions in the form of a kit. The kit contains two separate pharmaceutical compositions: the compound of the invention and a second pharmaceutical compound. The kit includes containers for containing the individual compositions, such as separate bottles or separate foil pouches. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when the prescribing healthcare professional requires titration of individual components in the combination.

[0260] experiment

[0261] Abbreviations: The following abbreviations may be used in this article:

[0262]

[0263]

[0264] Unless otherwise stated, all materials were obtained from commercial suppliers and used directly without further purification. Unless otherwise specified, all parts are by weight and temperatures are expressed in °C. All microwave-assisted reactions were performed using Biotage. TM Smith Synthesizer TM The reactions were performed. All compounds showed NMR spectra consistent with their specified structures. Melting points were determined on a Buchi apparatus and were uncorrected. Mass spectrometry data were determined by electrospray ionization. All examples were purified to >90% purity, as determined by high-performance liquid chromatography. Unless otherwise stated, the reactions were performed at room temperature.

[0265] In synthesizing the compounds of the present invention, certain leaving groups may be desired. The term "leaving group" ("LG") generally refers to a group that can be replaced by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates / esters such as methanesulfonates / esters, toluenesulfonates / esters), sulfides (e.g., SCH3), N-hydroxysuccinimide, N-hydroxybenzotriazole, etc. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), etc.

[0266] The examples presented below illustrate specific embodiments of the invention. These examples are representative and are not intended to limit the scope of the claims in any way.

[0267] It should be noted that when referring to percentages (%) used in liquids, this is a volume percentage relative to the solution. When used with solids, this is a percentage relative to the solid composition. Materials obtained from commercial suppliers are generally ready for use without further purification. Reactions involving air- or moisture-sensitive reagents are generally carried out under a nitrogen or argon atmosphere. Purity was measured using a high-performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6 x 150 mm, 5 μm, 5% to 100% CH3CN (in H2O containing 0.1% TFA), 15 min, 1.5 mL / min; System B: Zorbax SB-C8, 4.6 x 5 mm, 10% to 90% CH3CN (in H2O containing 0.1% formic acid), 12 min, 1.0 mL / min) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography is typically performed using pre-loaded silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, Nebraska). 1 ¹H NMR spectra were recorded at ambient temperature on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. All observed protons were reported in parts per million (ppm) at low magnetic fields in a suitable solvent with tetramethylsilane (TMS) or other internal references. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiply), coupling constant, and proton number. Low-resolution mass spectrometry (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS using UV detection at 254 nm and 215 nm and low resonance electrospray (ESI) mode.

[0268] General synthesis scheme

[0269] Unless otherwise stated, the starting materials and reagents used to prepare these compounds may be obtained from commercial suppliers (e.g., Aldrich Chemical Co., Milwaukee, Wisconsin), Bachem, Torrance, California, or Sigma, St. Louis, Missouri, or prepared by methods known to those skilled in the art following procedures as set forth in the following references: 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 Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes illustrate only some methods for synthesizing the compounds of the present invention, and various modifications can be made to these schemes, which will be advised to those skilled in the art upon reference to this disclosure. The starting materials, intermediates, and end products of the reactions can be separated 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 methods, including physical constants and spectroscopic data.

[0270] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure and at temperatures 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 temperature (or ambient temperature) (e.g., about 20°C).

[0271] In this general synthesis section, for clarity, compounds of formula (I) defined in the summary of the invention can be schematically drawn to contain Ar. 1 Ring and Ar 2 The ring is as follows:

[0272]

[0273] Where the group L is -NR 10 -(C=O)- or -(C=O)-NR 10 -, X 1 For N or -CR 3 X 2 For N or -CR 4 And X 3 For N or -CR 1 ; Ring Ar 1 Located on the left side of the connector, and ring Ar 2 Located on the right side of the connector

[0274] Typically, compounds of formula (I) can be synthesized through the following three general steps:

[0275] Step 1: Loop Ar 1 Preparation of compounds.

[0276] Step 2: Ring Ar 2 Preparation of compounds.

[0277] Step 3: Reconstitute the cyclic Ar1 compound with the cyclic Ar 2 Compound Coupling

[0278] The general approach (AD) described below is intended to provide guidance to ordinary synthetic chemists who will find it easy to understand. They can modify the solvent, concentration, reagents, protecting groups, order of synthesis steps, time, temperature, etc., as needed, which are entirely within the technical and judgment range of ordinary technicians.

[0279] In one embodiment, scheme AC below provides a general preparation of compounds of formula (I), where L is -NR 10 -(C=O); X 1 For -CR 4 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For -CR 1 It has the following formula (Ia):

[0280] Preferably, R 5 For H.

[0281] Examples of compounds of formula (Ia) include, but are not limited to:

[0282] Preferably, R 5 For H.

[0283] In another embodiment, scheme AC below provides a general preparation of compounds of formula (I), where L is -NR 10 -(C=O); X 1 -N; X 2 For -CR 3 And X 3 For -CR 1 ; with formula (Ic):

[0284]

[0285] Examples of compounds of formula (Ic) include, but are not limited to, those of other formulas.

[0286]

[0287] Scheme A: Preparation of compound (Ia) or (Ic):

[0288] According to scheme A, in one embodiment, the compound of formula (I) as disclosed herein can be synthesized as follows:

[0289] Step 1a: Ring Ar 1 Preparation of compounds:

[0290]

[0291] Step A-1: ​​Loop Ar 1 Preparation of compounds:

[0292] Compound A-1, in which W 1 It is H, which can be converted to sulfonyl chloride by treatment with chlorosulfonic acid. In the presence of a suitable base and in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., it reacts with R-containing compounds. 13 The amine group further reacts to give 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.

[0293] Alternatively, compound A-1, wherein W 1 F can be converted to sulfonyl chloride via a two-step procedure: treatment with benzyl thiol followed by oxidative chlorination with 1,3-dichloro-5,5-dimethylhydantoin. Compound A-1 is commercially available or can be synthesized by those skilled in the art using known methods.

[0294] 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.

[0295] Compound A-2 can then be reacted with a suitable reducing agent, such as a palladium catalyst, and a hydrogen source, such as Pd / C, in the presence of hydrogen to form compound A-3.

[0296] Step A-1-a: Ring Ar 1 Preparation of compounds:

[0297]

[0298] Alternatively, compound A-4 can be combined with R 13 The reaction is carried out with an amine reagent, followed by metal-catalyzed amination, using a suitable palladium or copper catalyst and a base, to form compound A-3, as defined in step A-1. Examples of commercially available compounds A-4 include 3-bromo-2-fluorobenzenesulfonyl chloride.

[0299] Step A-1-b: Loop Ar 1 Preparation of compounds:

[0300]

[0301] Alternatively, thiol compound A-5 can react with R 13 The reagent is reacted with a thiol alkylation reaction followed by an oxidation reaction to form compound A-3, wherein R 2 =SO2R 13 R can be used in this way. 13 Examples of reagents include, but are not limited to, methylenecyclobutane, 2,2,2-trifluoroethyl 4-methylbenzenesulfonate, or cyclopent-2-enone.

[0302] Step A-1-c: Ring Ar 1 Preparation of compounds:

[0303]

[0304] Alternatively, compound A-1, wherein W 1 It is a halogen group (e.g., fluorine, chlorine, or bromine), which can react with a suitable R in the presence of a suitable base and in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, etc. 2 The reagent reacts, and then reacts with a suitable reducing agent, such as a palladium catalyst, and a hydrogen source, such as Pd / C, in the presence of hydrogen to form compound A-3.

[0305] Compound A-1 is commercially available or can be synthesized by those skilled in the art using known methods.

[0306] 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.

[0307] R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazacyclobutane hydrochloride, (4) 3,3,3-trifluoroprop-1-ol, (5) 2-aminoethyl-1-ol, or (6) 2-amino-3-methylprop-1-ol.

[0308] Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0309] Step A-1-d: Ring Ar 1 Preparation of compounds:

[0310]

[0311] Alternatively, compound A-1 as defined in step A-1c may be reacted with a suitable R in the presence of a metal catalyst such as palladium or copper catalyst and a base such as cesium carbonate, potassium carbonate or potassium phosphate in an amination reaction. 2 The reagent reacts, and then reacts with a suitable reducing agent, such as a palladium catalyst, and a hydrogen source, such as Pd / C, in the presence of hydrogen to form compound A-3.

[0312] Step A-2: Loop Ar 2 Preparation of compounds:

[0313]

[0314] In step A-2, compound A-6 (wherein W) can be placed in a suitable organic solvent (e.g., NMP, acetonitrile, dioxane, DMF, DMSO, etc.) 2 and W 3 Each of them is independently a halogen, such as fluorine, chlorine, bromine or iodine) and R X The reagents (e.g., (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) are reacted to form compound A-7.

[0315] Step A-3: Place ring Ar 1 Compounds and cyclic Ar 2 Compound coupling, followed by the introduction of R 1 :

[0316]

[0317]

[0318] In step A-3, the compound A-7 obtained in step A-2 can be reacted with an activator (e.g., acyl chloride (COCl)2 or SOCl2) in a suitable organic solvent (e.g., tetrahydrofuran, dichloromethane, etc.) to form an acyl chloride derivative, which can then be reacted with compound A-3 to form compound A-8.

[0319] Alternatively, compound A-3 can be directly coupled to compound A-7 obtained from step A-2 in the presence of a coupling agent (e.g., N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxotripyrrolidinylphosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, thionyl chloride, carbonyl diimidazole, and polyphosphonic anhydrides) in a suitable organic solvent (e.g., acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.).

[0320] Those who are merely familiar with synthetic chemists will readily understand that other coupling agents can be used. This can be achieved by using a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) with a metal catalyst and R... 1 Transformation reactions in the presence of reagents (e.g., metal-catalyzed sulfonation, sulfidation, or sulfonylation) further treat the halogen group W3 to form compounds (Ia) or (Ic), where R... 1 Reagents such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane-3-amine, (3) tert-butyl-3-mercaptoazacyclobutane-1-carboxylate, (4) ethyl 2-aminosulfonylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethane-1-ol, or (11) cyclopropanethiol. Those skilled in the art will readily understand that coupling reactions (e.g., as shown in step A-3) can be carried out under up to a number of known conditions.

[0321] Option B: Alternative preparation of compounds (Ia) or (Ic):

[0322] Step B-1: Loop Ar 1 Preparation of the compound: Refer to steps A-1 to A-1-d of scheme A above.

[0323] Step B-2: Loop Ar 2 Preparation of compounds:

[0324]

[0325] 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 as described in Scheme A, R can alternatively be... 1 The group is introduced into the ring Ar in step B-22 Instead of introducing it in step B-3 of scheme A, it can be introduced in the presence of a base (e.g., potassium carbonate) according to step 2b. 4 and W 5 Each of the elements (individually a halogen, such as fluorine, chlorine, bromine, or iodine) reacts with a suitable carboxylic acid protecting group (PG1 reagent, such as iodomethane) to form a methyl ester or reacts with other suitable protecting groups in a suitable organic solvent (such as NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) to form other esters (such as benzyl esters) to form compound B-2, wherein W 4 and W 5 Each of these is as defined in compound B-1. In the presence of a base such as potassium tert-butoxide, compound B-2 can react with a suitable protected amine (PG). 2 Reagents, such as 4,4-dimethyloxazolidin-2-one, react to form compound B-3. It can react with R... X Reagents (e.g., (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) react in suitable organic solvents (e.g., NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, DMSO, etc.) to form compound B-4, which can then be further reacted with a suitable 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 discussed in Greene protecting groups in organic synthesis.

[0326] Step B-3: Place ring Ar 1 Compounds and cyclic Ar 2 Compound coupling and removal of protecting groups

[0327]

[0328] Step B-3 can be carried out under conditions similar to the coupling reaction described in step A-3 above.

[0329] Option C

[0330] Step C-1: Loop Ar 1 Preparation of the compound: Refer to steps A-1 to A-1d of scheme A above.

[0331] Step C-2: Loop Ar 2 Preparation of compounds: Compound C-1 is commercially available or can be prepared according to methods known to those skilled in the art.

[0332] Step C-3: Place ring Ar 1 Compounds and cyclic Ar 2 Compound coupling and introduction of R X

[0333]

[0334] A commercially available compound C-1 (e.g., 2-fluoro-3-pyridinecarboxylic acid or 3-fluoroisonicotinic acid) can be reacted with an activator (e.g., acyl chloride (COCl)2 or SOCl2) in a suitable organic solvent (e.g., tetrahydrofuran, dichloromethane, etc.) to form an acyl chloride derivative, which can then be reacted with compound A-3 to form compound C-2.

[0335] Alternatively, compound C-1 can be directly coupled to compound A-3 obtained from step A-2 in a suitable organic solvent (e.g., acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) in the presence of a coupling agent (e.g., N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxotripyrrolidinylphosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, thionyl chloride, carbonyl diimidazole, and polyphosphonic anhydrides). Compound C-2 can be coupled to R in a suitable organic solvent (e.g., NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, DMSO, etc.). X The reagents (e.g., (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) react to form compound (Ia).

[0336] Option D

[0337] In another embodiment, the compound of formula (I) has the following formula:

[0338] Where L is -(C=O)-NH-; as shown in compounds of formulas (Ib), (Id), and (If):

[0339] as well as

[0340] As defined above, it can be synthesized according to scheme D.

[0341] Step D-1: Loop Ar 1 Preparation of compounds: Ring Ar 1 One embodiment of the compound includes compound D-1, having the following formula:

[0342]

[0343] In step D-1, compound D-1 (wherein W) can be placed in a suitable organic solvent, such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., in the presence of a suitable base. 5 (e.g., halogenated, such as fluorine or chlorine) with R2 The reagents react 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. R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazacyclobutane hydrochloride. Examples of bases include, but are not limited to, diisopropylethylamine and potassium carbonate.

[0344] Compound D-1 is commercially available or can be prepared using methods and reagents known to those skilled in the art.

[0345] Step D-2: Loop Ar 2 Preparation of compounds:

[0346]

[0347] In step D-2, compound D-3 (where W) can be placed in a suitable organic solvent (e.g., NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) 6 (e.g., halogenated, chlorine, bromine, or iodine) with R X The reagents (e.g., (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) react to form compound D-4. Examples of compound D-3 include, but are not limited to, 2-fluoropyridine-3-amine, 2-fluoro-6-methylpyridine-3-amine, 2-fluoro-5-methylpyridine-3-amine, 4-fluoropyridine-3-amine, or 6-bromo-2-fluoropyridine-3-amine.

[0348] Step D-3: Place ring Ar 1 Compounds and cyclic Ar 2 Compound coupling.

[0349]

[0350] In step D-3, compound D-4, wherein X 1 For N; X 2 For -CR 4 And X 3 For W 6 It is a halogen group (e.g., fluorine, chlorine, bromine, or iodine), which can react with compound D-2 in the presence of an activator such as T3P, HATU, or TATU, and in the presence of DIPEA, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., to form compound (D-5), wherein X 1 For N; X 2 For -CR 4 And X 3 For W 6 .

[0351] Then, it can be achieved by using a metal catalyst and R in a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, etc.). 1 Transformation reactions in the presence of reagents (e.g., SNAr, metal-catalyzed sulfonamide, sulfidation, or sulfonylation) further treat the halogen group W. 6 To form compound (Id), the R 1 Reagents such as (1) oxetane-3-amine, (2) 2-amino-2-methylpropane-1-ol, (3) (3-aminooxetane-3-yl)methanol, (4) ethyl 2-aminosulfonylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropane-1-ol, (8) 2-mercapto-2-methylpropane-1-ol, (9) 2-aminoethane-1-ol or (10) cyclopropanethiol, wherein X 1 For N; X 2 For -CR 4 And X 3 For R 1 .

[0352]

[0353] Alternatively, compound D-4, in which X 1 For -CR 3 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For W 7 It is a halogen group (e.g., fluorine, chlorine, bromine, or iodine), which can react with compound D-2 in the presence of an activator such as T3P, HATU, or TATU, and in the presence of DIPEA, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., to form compound (D-5), wherein X 1 For -CR 3 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For W 7 .

[0354] Then, it can be achieved by using a metal catalyst and R in a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, etc.). 1 Transformation reactions in the presence of reagents (e.g., SNAr, metal-catalyzed sulfonamide, sulfidation, or sulfonylation) further treat the halogen group W. 7 To form compound (Id), the R 1Reagents such as (1) oxetane-3-amine, (2) 2-amino-2-methylpropane-1-ol, (3) (3-aminooxetane-3-yl)methanol, (4) ethyl 2-aminosulfonylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropane-1-ol, (8) 2-mercapto-2-methylpropane-1-ol, (9) 2-aminoethane-1-ol or (10) cyclopropanethiol, wherein X 1 For -CR 3 ;X 2 Let N be the number of elements; and X be the number of elements. 3 For R 1 .

[0355]

[0356] Alternatively, compound D-4, in which X 1 For -CR 3 ;X 2 For CR 4 And X 3 N can react with compound D-2 in the presence of an activator such as T3P, HATU, or TATU, and in the presence of DIPEA, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., to form compound (If), wherein X 1 For -CR 3 ;X 2 For CR 4 And X 3 Let N be the number of elements in the array.

[0357] Those skilled in the art will readily understand that coupling reactions (e.g., as shown in step D-3) can be carried out under up to a number of known conditions.

[0358] Ring Ar 1 Preparation of intermediates

[0359] Intermediate 1: 3-amino-N-(tert-butyl)-5-methylbenzenesulfonamide.

[0360]

[0361] Step 1: Chlorosulfonic acid (14.57 mL, 219 mmol) was slowly added to ice-cold 1-methyl-3-nitrobenzene (2.0 g, 14.58 mmol) over 15 min. The resulting mixture was heated at 80 °C for 3 h. The reaction mixture was quenched with crushed ice and extracted with EtOAc (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-methyl-5-nitrobenzenesulfonyl chloride as a brown liquid. The crude sample was used immediately for the next step. 1¹H 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).

[0362] Step 2 A solution of 3-methyl-5-nitrobenzene-1-sulfonyl chloride (crude) (3.2 g, 13.58 mmol) in dichloromethane (50 mL) was slowly added to an ice-cold solution of 2-methylprop-2-amine (1.09 g, 14.94 mmol) and DIPEA (3.56 mL, 20.37 mmol) in DCM (50 mL). After the addition, the reaction mixture was slowly heated to ambient temperature and stirred for 2 h. Then, water (100 mL) was added and stirred for 10 min. 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 adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with a gradient of 0% to 10% EtOAc in petroleum ether) to provide N-(tert-butyl)-3-methyl-5-nitrobenzenesulfonamide (1.9 g, 6.98 mmol, 51% yield) as a pale yellow solid. 1 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 ions) m / z: 271.2 (M⁻¹).

[0363] 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 for 3 h under a hydrogen atmosphere (approximately 14.5 psi-bladder pressure) and then... Filter the mixture through a filtration pad. Rinse the pad with methanol (150 mL). Concentrate the filtrate under reduced pressure to provide a white residue. Adsorb the crude material onto a silica gel stopper and purify by chromatography (eluting with a 15%–20% EtOAc gradient in petroleum ether) to provide 3-amino-N-(tert-butyl)-5-methylbenzenesulfonamide (1.2 g, 4.95 mmol, 71% yield) as an off-white solid. 1¹H 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).

[0364] Table 1: The preparation of intermediates 1-1 to 1-3 is similar to steps 2-3 of intermediate 1:

[0365]

[0366] Intermediate 2: 3-Amino-N-(tert-butyl)-5-fluorobenzenesulfonamide

[0367]

[0368] Step 1 At 0 °C, benzyl mercaptan (1.1 mL, 9.24 mmol) was added to a mixture of 3,5-difluoronitrobenzene (1 mL, 8.80 mmol), potassium carbonate (0.59 mL, 9.68 mmol), and DMF (10 mL). The reaction mixture was stirred at RT for 2 h, and water (10 mL) was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over anhydrous Na₂SO₄ and concentrated under vacuum to provide a crude product, which was ready for use without further purification.

[0369] Step 2 Add benzyl(3-fluoro-5-nitrophenyl)thione (1.63 g, 6.19 mmol), acetonitrile (12 mL), water (0.3 mL), and acetic acid (0.45 mL) to a 100 mL round-bottom flask. Cool the reaction mixture to 0 °C and add 1,3-dichloro-5,5-dimethylhydantoin (1.14 mL, 8.67 mmol) in portions. After the addition is complete, stir the reaction mixture at 0 °C for 20 min, then dilute with saturated NaHCO3 and extract with EtOAc. Wash the organic extract with water and dry it with Na2SO4. Filter the solution and concentrate it under vacuum to give crude 3-fluoro-5-nitrobenzene-1-sulfonyl chloride (1.48 g, 6.19 mmol, 100% yield) as a white solid, which can be used without further purification. m / z (ESI): 240.2 (M+1).

[0370] Step 3:3-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) were added to a 100-mL round-bottom flask. The mixture was stirred at RT for 3 h, 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 vacuum to give a crude substance as a white oil. The crude substance was adsorbed onto a silica gel stopper and purified by chromatography via a silica gel column (eluting with a gradient of 0% to 25% EtOAc in heptane) to provide 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).

[0371] Step 4: Add 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) to a 25 mL glass vial, then add 0.5 mL of water. Stir the reaction mixture at 80 °C for 1 h, cool to rt, and then... The mixture was filtered and the solvent removed under vacuum. The reaction mixture was diluted with saturated NH4Cl (10 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (10 mL) and dried over Na2SO4. The solution was filtered and concentrated under vacuum to give a crude substance as a white oil. The crude substance was adsorbed onto a silica gel stopper 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 provide 3-amino-N-(tert-butyl)-5-fluorobenzenesulfonamide (334 mg, 1.35 mmol, 75% yield) as a white solid. 1 ¹H NMR (400MHz, chloroform-d) δ 6.99 (t, J = 1.76 Hz, 1H), 6.93 (td, J = 1.91, 8.12 Hz, 1H), 6.51 (td, J = 2.35, 10.17 Hz, 1H), 4.52 (s, 1H), 1.26 (s, 9H). m / z (ESI): 247.1 (M+1).

[0372] Intermediate 3: 3-amino-N-(tert-butyl)-2-fluorobenzenesulfonamide.

[0373]

[0374] Step 1:Under a nitrogen atmosphere, triethylamine (6.12 mL, 43.9 mmol) and tert-butylamine (2.33 mL, 21.94 mmol) were added to a solution of 3-bromo-2-fluorobenzenesulfonyl chloride (4.0 g, 14.62 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (30 mL), and the biphasic mixture was extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with 5% to 8% EtOAc in hexane) to give 3-bromo-N-(tert-butyl)-2-fluorobenzenesulfonamide (3.5 g, 77% yield) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ8.01-7.95(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].

[0375] Step 2: 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 oxide (I) (0.074 g, 0.516 mmol), and ammonia (7.5 mL) were added to a solution of 3-bromo-N-(tert-butyl)-2-fluorobenzenesulfonamide (3.2 g, 10.32 mmol) in ethylene glycol (5 mL). 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 x 50 mL). The combined organic extracts were washed with a brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper (60-120 mesh) and purified by silica gel chromatography (eluting with 25% to 35% EtOAc in hexane) to provide 3-amino-N-(tert-butyl)-2-fluorobenzenesulfonamide (0.90 g, 3.65 mmol, 35% yield) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6): δ7.56(s,1H),6.98-6.88(m,3H),5.50(s,2H),1.12(s,9H). m / z(ESI):247.2[M+1].

[0376] Intermediate 4: 3-((1-methylcyclobutyl)sulfonyl)aniline

[0377]

[0378] Step 1 Concentrated H₂SO₄ (3.83 mL, 71.9 mmol) was carefully added 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), and the mixture was stirred at room temperature for 45 min. The reaction mixture was quenched by pouring into a cold, saturated aqueous solution of NaHCO₃ (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with cold water (5 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper and purified by rapid chromatography via a Redi-Sep pre-packed silica gel column (eluting with a gradient of 1% to 15% EtOAc in hexane) to provide 3-((1-methylcyclobutyl)thio)aniline (3.2 g, 69% yield) as a colorless oil. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 7.02–6.95 (m, 1H), 6.63 (s, 1H), 6.55–6.45 (m, 2H), 2.27–2.14 (m, 2H), 2.08–1.84 (m, 4H), 1.45 (m, 3H), NH₂ protons not visible. m / z (ESI): 194.2 [M+1].

[0379] Step 2 At room temperature, a solution of 3-((1-methylcyclobutyl)thio)aniline (3.0 g, 15.52 mmol) in tetrahydrofuran (30 mL) was added to Boc anhydride (7.21 mL, 31.0 mmol) and triethylamine (3.24 mL, 23.28 mmol) and stirred for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper (60-120 mesh) and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (40 g) (eluted with a 5% to 8% EtOAc gradient in hexane) to provide tert-butyl(3-((1-methylcyclobutyl)thio)phenyl)carbamate (3.2 g, 70% yield) as a white solid. 1 ¹H NMR (300MHz, chloroform-d): δ 7.44–7.33 (m, 2H), 7.30–7.20 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 2.42–2.26 (m, 2H), 2.16–1.93 (m, 4H), 1.57 (s, 9H), 1.54 (s, 3H). m / z (ESI): 294.2 [M+1].

[0380] Step 3 oxone (9.22 g, 15.00 mmol) was added 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) and stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, adjusted to pH 7 with 10% NaHCO3 aqueous solution (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (eluting with a gradient of 1% to 40% EtOAc in hexane) to provide tert-butyl(3-((1-methylcyclobutyl)sulfonyl)phenyl)carbamate (1.8 g, 81% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.78(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].

[0381] Step 4 HCl (4M in 1,4-dioxane, 6.91 mL, 27.7 mmol) was added to a solution of tert-butyl(3-((1-methylcyclobutyl)sulfonyl)phenyl)carbamate (1.8 g, 5.53 mmol) in 1,4-dioxane (20 mL) 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 using a 10% aqueous solution of 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 (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was ground with diethyl ether (100 mL) to give 3-((1-methylcyclobutyl)sulfonyl)aniline (1.05 g, 84% yield) as a grayish-white solid. 1HNMR(400MHz,DMSO-d6)δ7.34-7.21(m,1H),7.00(s,1H),6.93-6.79(m,2H),5.6 6(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].

[0382] Intermediate 5: 3-((1,1,1-trifluoro-2-methylpropane-2-yl)sulfonyl)aniline.

[0383]

[0384] Step 1 Triethylamine (4.64 mL, 33.3 mmol) and p-toluenesulfonyl chloride (6.35 g, 33.3 mmol) were added to a solution of 2,2,2-trifluoroethyl-1-ol (5.0 g, 50.0 mmol) in dichloromethane (300 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (200 mL) and extracted in dichloromethane (2 x 500 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2,2,2-trifluoroethyl-4-methylbenzenesulfonate (5 g, 59% yield) as a grayish-white solid. 1 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].

[0385] Step 2 Sodium hydride (1.77 g, 44.3 mmol) was added to a solution of 3-aminobenzenethiol (4.43 g, 35.4 mmol) in THF (225 mL) at 0 °C and stirred for 30 min. Then, 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 x 50 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by rapid chromatography through a Redi-Sep pre-packed silica column (eluting with a 5% to 10% EtOAc gradient in hexane) to provide 3-((2,2,2-trifluoroethyl)thio)aniline (5 g, 68% yield) as a light brown oil. 1H NMR (300MHz, DMSO-d6): δ6.99 (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].

[0386] Step 3 Triethylamine (6.73 mL, 48.3 mmol) and Boc₂O (8.40 mL, 36.2 mmol) were added to a solution of 3-((2,2,2-trifluoroethyl)thio)aniline (5.0 g, 24.13 mmol) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a silica gel stopper (60–120 mesh) and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (eluting with a 5%–8% EtOAc gradient in hexane) to provide tert-butyl(3-((2,2,2-trifluoroethyl)thio)phenyl)carbamate (4.2 g, 57% yield) as a white solid. 1 HNMR (400MHz, DMSO-d6): δ9.43 (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].

[0387] Step 4 oxone (9.24 g, 30.1 mmol) was added 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), and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was neutralized with 10% NaHCO3 aqueous solution and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with water (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl(3-((2,2,2-trifluoroethyl)sulfonyl)phenyl)carbamate (3.2 g, 69% yield) as a white solid. 1H NMR (300MHz, DMSO-d6): δ9.86 (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]

[0388] Step 5: At 0 °C, methyl iodine (15.66 mL, 250 mmol) and HMPA (43.6 mL, 250 mmol) were added to a solution of tert-butyl(3-((2,2,2-trifluoroethyl)sulfonyl)phenyl)carbamate (8.5 g, 25.05 mmol) in anhydrous tetrahydrofuran (50 mL). 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 then warmed to room temperature. The reaction mixture was diluted with saturated aqueous NH4Cl solution (100 mL) and extracted with diethyl ether (3 x 250 mL). The combined organic extracts were washed with brine (250 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with 5% to 7% EtOAc in hexane) to provide tert-butyl(3-((1,1,1-trifluoro-2-methylpropane-2-yl)sulfonyl)phenyl)carbamate (1.9 g, 21% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.86 (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]

[0389] Step 6:Hydrochloric acid (12.3 mL, 49.0 mmol) was added to a solution of tert-butyl(3-((1,1,1-trifluoro-2-methylpropane-2-yl)sulfonyl)phenyl)carbamate (1.8 g, 4.90 mmol) in 1,4-dioxane (20 mL) at 0 °C, and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and adjusted to pH 7–8 using a 10% aqueous solution of 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 a brine solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper (60-120 mesh) and purified by Isolera-Biotage (eluting with 17% to 19% EtOAc in hexane) to provide 3-((1,1,1-trifluoro-2-methylpropane-2-yl)sulfonyl)aniline (0.9 g, 69% yield) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ7.30 (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].

[0390] Intermediate 6: 3-((3,3-difluorocyclopentyl)sulfonyl)aniline.

[0391]

[0392] Step 1 To a solution of 3-aminobenzylthiol (10.0 g, 80 mmol) in acetone (160 mL), Boc anhydride (37.1 mL, 160 mmol) and 10% Na₂CO₃ aqueous solution (20 mL, 160 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, quenched with water (250 mL), and extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a silica gel stopper and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (eluting with a gradient of 1% to 15% EtOAc in hexane) to provide tert-butyl (3-mercaptophenyl) carbamate (11 g, 61% yield) as a white solid. 1¹H NMR (400MHz, chloroform-d) δ 13.1 (s, 1H), 7.56 (s, 1H), 7.42 (d, J = 7.2Hz, 1H), 7.31 (dd, J = 7.6, 7.2Hz, 1H), 7.19 (d, J = 7.6Hz, 1H), 6.54 (s, 1H), 1.52 (s, 9H).

[0393] 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 at 120 °C for 24 h. The reaction mixture was directly adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with 9% to 12% EtOAc in hexane) to provide tert-butyl (3-((3-oxocyclopentyl)thio)phenyl)carbamate (10.0 g, 73% yield) as a colorless, viscous oil. 1 H NMR (300MHz, chloroform-d) δ7.54 (s, 1H), 7.28-7.17 (m, 2H), 7.07 (d, J = 8.8Hz, 1H), 6.55 (s, 1H), 3. 94(t,J=8.0Hz,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]:

[0394] Step 3: A solution of oxone (22 g, 35.8 mmol) in water (50 mL) was added to a solution of tert-butyl(3-((3-oxocyclopentyl)thio)phenyl)carbamate (5.0 g, 16.27 mmol) in MeOH (100 mL), and the mixture was 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 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide tert-butyl(3-((3-oxocyclopentyl)sulfonyl)phenyl)carbamate (4.5 g, crude) as a pale yellow oil, which was used as is in the next step. 1 H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 8.14 (s, 1H), 7.71 (d, J = 7.92Hz, 1H), 7.60-7.53 (m, 1H), 7.48 (d, J = 7.7Hz, 1H), 4.08 (t, J = 7.4Hz, 1H), 2.45-2.16 (m, 6H), 1.50 (s, 9H).

[0395] Step 4: DAST (1.606 mL, 12.15 mmol) was added to a solution of tert-butyl(3-((3-oxocyclopentyl)sulfonyl)phenyl)carbamate (1.65 g, 4.86 mmol) in DCM (20 mL) at -78 °C under a nitrogen atmosphere, and the mixture was stirred at -78 °C for 30 min. The reaction mixture was then slowly heated to room temperature and stirred for 18 h. The reaction mixture was quenched with 1N NaOH aqueous solution (10 mL), diluted with water (25 mL), and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with 6% to 8% EtOAc in hexane) to provide tert-butyl (3-((3,3-difluorocyclopentyl)sulfonyl)phenyl)carbamate (0.95 g, 54% yield) as a colorless, viscous oil. 1 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, negative ions) m / z: 360.2 [M⁻¹].

[0396] Step 5: HCl (4M solution in dioxane, 10 mL, 40.0 mmol) was added 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) at 0 °C and stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in water (15 mL) and adjusted to pH 7 with 10% NaHCO3 aqueous solution, diluted with H2O (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was adsorbed onto a silica gel stopper and purified by silica gel chromatography (eluting with 20% to 25% EtOAc in hexane) to provide 3-((3,3-difluorocyclopentyl)sulfonyl)aniline (250 mg, 35% yield) as a viscous oil. 1¹H NMR (400MHz, 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), NH₂ protons are not visible. MS (ESI, cation) m / z: 262.1 [M+1].

[0397] Intermediate 7: (R)-3-fluoro-5-(2-methylmorpholino)aniline.

[0398]

[0399] 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 oven at 100 °C for 2 h. The reaction mixture was concentrated and purified by rapid column chromatography (eluting with a gradient of 0% to 40% EtOAc in petroleum ether) to give (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): δppm 7.54(d,J=2.3Hz,1H),7.38(dt,J=8.4,2.1Hz,1H),7.27(dt,J=12.3,2.3Hz,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) + .

[0400] Step 2Palladium on carbon (0.5 g, 4.70 mmol, Hindustanplatinum) was added to a solution of (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.8 g, 7.49 mmol) in MeOH (10 mL) and THF (10 mL) and stirred for 16 h under H2 pressure (14 psi). The reaction mixture was then passed through... The mixture was filtered through a bed, washed with MeOH, and the combined filtrates were concentrated to give (R)-3-fluoro-5-(2-methylmorpholino)aniline as a beige solid (1.1 g, 5.23 mmol, 70% yield). 1 H NMR (400MHz, DMSO-d6): δppm 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) + .

[0401] Intermediate 8: (R)-4-fluoro-3-(2-methylmorpholino)aniline.

[0402]

[0403] Step 1 A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Technologies), (R)-2-methylmorpholine (1.94 g, 19.23 mmol, Abbott Chemicals), Pd(OAc)₂ (0.36 g, 1.63 mmol), Cs₂CO₃ (8.89 g, 27.3 mmol), and Xantphos (0.87 g, 1.50 mmol) in 1,4-dioxane (15 mL) was heated at 100 °C for 16 h. The reaction mixture was then passed through... The mixture was filtered through a bed and washed with EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (eluting with 0% to 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. 1HNMR (400MHz, DMSO-d6): δppm 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,1 H),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) + .

[0404] Step 2 Palladium on carbon (0.35 g, 3.29 mmol, Hindustan Platinum) was added 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), and the reaction mixture was stirred at H2 pressure (14 psi) for 16 h. The reaction mixture was then passed through... The mixture was filtered through a bed, washed with MeOH, and 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): δppm 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) + .

[0405] Ring Ar 2 Preparation of intermediates:

[0406] Intermediate 9: 6-Fluoro-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid

[0407]

[0408] 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) were placed in a 250 mL round-bottom flask. DIPEA (6.6 mL, 37.9 mmol) was added, and the light brown solution was stirred at RT for 18 h. The mixture was concentrated, and the residue was diluted with EtOAc (80 mL), followed by washing with water (2 x 10 mL) and brine (10 mL) sequentially. The organic phase was reduced to about 50 mL, and some solids began to precipitate. The suspension was allowed to stand for 18 h. The solids were collected to provide 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 residues. The volume was reduced to about 20 mL, and a second batch of product was collected to provide the title compound (2.23 g) as a yellow solid. The procedure was repeated to provide the third batch of the title compound (1.10 g). All three batches were combined to obtain 6-fluoro-2-(6-azaspiro[2.5]oct-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) + .

[0409] Table 1: Intermediates 9-1 and 9-2 were prepared in a manner similar to that used for intermediate 9:

[0410]

[0411] Intermediate 10: 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid.

[0412]

[0413] Step 1 AIBN (0.442 g, 2.69 mmol) and N-bromosuccinimide (4.79 g, 26.9 mmol) were added to a stirred solution of methyl 2-chloro-6-methylnicotinate (5.0 g, 26.9 mmol) in carbon tetrachloride (50 mL) 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 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to provide methyl 6-(bromomethyl)-2-chloronicotinate (5 g, crude) as a pale yellow oil. The crude product was used without purification. MS (ESI, cation) m / z: 264 [M+1].

[0414] Step 2 Sodium methanesulfinate (2.73 g, 26.8 mmol) was added to a solution of methyl 6-(bromomethyl)-2-chloronicotinate (5.9 g, 22.31 mmol) in DMF (50 mL) and stirred at room temperature for 1 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with a saline solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica gel stopper (60-120 mesh) and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (120 g) (eluting with a 1% to 50% EtOAc gradient in hexane) to provide methyl 2-chloro-6-((methanesulfonyl)methyl)nicotinate (4.0 g, 68% yield) as an off-white solid. 1 ¹H 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].

[0415] Step 3 In a microwave reaction vessel (20 mL), a solution of methyl 2-chloro-6-((methanesulfonyl)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 in a microwave reactor (Biotage microwave initiator+) at 140 °C for 1 h. The reaction mixture was adsorbed onto a silica gel stopper (60-120 mesh) and purified by rapid chromatography through a Redi-Sep pre-packed silica gel column (80 g) (eluted with a gradient of 1% to 40% EtOAc in hexane) to provide methyl 6-((methanesulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinate (1.4 g, 45% yield) as an off-white solid. 1 ¹H 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].

[0416] Step 4Sodium hydroxide (0.496 g, 12.41 mmol) was added to a solution of methyl 6-((methanesulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinate (1.4 g, 4.14 mmol) in ethanol (10 mL) and water (10 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to remove ethanol. The aqueous layer was neutralized to pH approximately 7 using 1.5 N HCl solution and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with a saline solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was adsorbed onto a silica stopper (60-120 mesh) and purified by rapid chromatography through a Redi-Sep pre-packed silica column (40 g) (eluting with a gradient of 1% to 6% MeOH in DCM) to provide 6-((methanesulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (680 mg, 51% yield) as an off-white solid. 1 ¹H 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, negative ions) m / z: 323.2 [M⁻¹].

[0417] Intermediate 11: 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid acid.

[0418]

[0419] 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 slight reflux for 2 h. The solution was concentrated to dryness under reduced pressure. Toluene (100 mL) was added to the crude product and evaporated to dryness again. The crude acyl 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 min, and the mixture was stirred at rt for 30 min. Then, 0.1 N HCl (100 mL) was 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 provide benzyl 2,6-difluoronicotinic acid ester, which was used without purification. m / z (ESI): 250.0 (M+H) + .

[0420] Step 2 Under nitrogen atmosphere, 4,4-dimethyloxazolidin-2-one (0.80 g, 6.95 mmol) was dissolved in THF (15 mL). Potassium tert-butoxide (0.75 g, 6.68 mmol) was added, and the suspension was stirred at RT for 5 min. A solution of benzyl 2,6-difluoronicotinic acid ester (1.60 g, 6.42 mmol) in N,N-dimethylacetamide (40 mL) was added, and the mixture was stirred at RT for 10 min. 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. Benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-fluoronicotinic acid ester (1.82 g, 5.29 mmol, 82% yield) was purified as a white solid by silica gel chromatography (heptane to EtOAc gradient).

[0421] Step 3 Benzyl 6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-fluoronicotinic acid ester (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 RT for 18 h. 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) yielded benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinate as a milky white oil (1.77 g, 4.06 mmol, 78% yield). m / z (ESI): 436.1 (M+H) + .

[0422] Step 4: Benzyl 6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid ester (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 at 40 psi for 15 min. The mixture was then passed through... The mixture was filtered through a pad 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]oct-6-yl)nicotinic acid (1.15 g, 3.33 mmol, 82% yield) as a white solid. m / z (ESI): 346.0 (M+H) + .

[0423] Table 2: Preparation of intermediates 11-1 and 11-2 according to a similar method to that used for intermediate 11:

[0424]

[0425] Intermediate 12: 2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinic acid

[0426]

[0427] 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 RT for 24 h. 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]oct-6-yl)nicotinate (4.34 g, 15.46 mmol, 64% yield). m / z (ESI): 281.0 (M+H) + .

[0428] Step 2 A mixture of methyl 6-chloro-2-(6-azaspiro[2.5]oct-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)palladium(II) dichloride (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 RT and treated with HCl (4 M in dioxane, 18.25 mL, 73.00 mmol) and stirred for 2 h. The reaction mixture was then passed through The sample was filtered through a pad and washed with EtOAc. The filtrate was washed with a saturated aqueous solution of 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]oct-6-yl)nicotinic acid ester (2.75 g, 9.54 mmol, 65% yield). 1 H NMR(400MHz,DMSO-d6)δppm 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).

[0429] Step 3: At 0 °C, (trifluoromethyl)trimethylsilane (1.54 mL, 10.40 mmol, Aldrich) was added to a stirred solution of methyl 6-acetyl-2-(6-azaspiro[2.5]oct-6-yl)nicotinate (2.50 g, 8.67 mmol) in tetrahydrofuran (1 mL). After addition, the mixture was stirred for 2 h. The solid was filtered off, washed with EtOAc and concentrated. Purification was performed by silica gel chromatography (eluting with 0% to 30% EtOAc in heptane) to provide methyl 2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinate (2.87 g, 8.01 mmol, 92% yield). 1 H NMR (400MHz, chloroform-d) δppm 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) + .

[0430] Step 4:Under RT, an aqueous solution of NaOH (8.0 mL of 5M solution, 40.0 mmol) was added to a stirred solution of methyl 2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinic acid (2.87 g, 8.01 mmol) in MeOH (20 mL). After addition, the reaction mixture was stirred for 3 days. The reaction mixture was concentrated, diluted with H2O, and acidified with 5N HCl aqueous solution (to pH about 4). The precipitated solid was collected, washed with H2O, and dried to give 2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinic acid (2.70 g, 98% yield). 1 H NMR(400MHz,DMSO-d6)δppm 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) + .

[0431] AR 1 and AR 2 Intermediate coupling

[0432] Intermediate 13: N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-6-yl) Niacinamide .

[0433]

[0434] 6-Fluoro-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (2.0 g, 8.00 mmol, intermediate 9) and DCM (30 mL) were placed in a 250 mL round-bottom flask. Oxaloyl dichloride (6.00 mL, 11.99 mmol) was added to the reaction mixture at RT, followed by two drops of DMF. The mixture was stirred at RT for 30 min and the solvent was removed under vacuum. 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 treatment with DIPEA (6.98 mL, 40.0 mmol). The reaction mixture was stirred at RT for 1 h, then 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 rapid column chromatography (eluting with 5% to 50% EtOAc in heptane) to give N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-fluoro-2-(spiro[2.5]oct-6-yl)nicotinamide (3.02 g, 82% yield) as a grayish-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) + .

[0435] Table 3: Preparation of intermediates 13-1 to 13-5 according to a method similar to that used for intermediate 13:

[0436]

[0437]

[0438] Intermediate 14: 2-Fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide

[0439]

[0440] Oxaloyl dichloro(0.80 mL, 9.01 mmol) and catalytic DMF were added to a solution of 2-fluoro-3-pyridinecarboxylic acid (1.0 g, 7.09 mmol) in DCM (9 mL). The reaction mixture was stirred at RT for 1 h and the solvent was removed under vacuum. The residue was redissolved in DCM (10 mL) and treated with 3-(piperidin-1-sulfonyl)-aniline (0.78 mL, 4.16 mmol), followed by treatment with sodium bicarbonate (0.405 mL, 10.40 mmol). The reaction mixture was stirred at RT for 16 h, then 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 rapid column chromatography (eluting with 0% to 50% EtOAc in hexane) to provide 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (1.16 g, 77 g) as a white solid.

[0441] % yield). 1H 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),7.5 2-7.65(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) + .

[0442] Table 4: Preparation of intermediates 14-1 to 14-8 according to a similar method to that used for intermediate 14:

[0443]

[0444]

[0445] Intermediate 15: 3-(2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)benzenesulfonyl chloride

[0446]

[0447] N-(3-(benzylthio)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (3.01 g, 7.01 mmol, intermediate 14-14), ACN (28 mL), water (0.7 mL), and acetic acid (1.4 mL) were placed in a 150 mL round-bottom flask. 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 mixture was stirred at 0 °C for 3 h, heated to RT, and partitioned between saturated NaHCO3 (approximately 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: EtOAc in heptane 5%-40%) to provide 3-(2-(6-azaspiro[2.5]oct-6-yl)nicotinamide)benzenesulfonyl chloride (2.01 g, 71% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 12.51 (br s, 1H), 8.66 (s, 1H), 8.59–8.47 (m, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.70–7.61 (m, 1H), 7.29 (s, 1H), 3.29 (t, J = 5.4 Hz, 4H), 1.66 (br s, 4H), 0.45 (s, 4H). MS (ESI, cation) m / z: 406.1 [M+1].

[0448] Example

[0449] Example 100: 2-(4,4-dimethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide.

[0450]

[0451] To a solution of 2-fluoro-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide (44 mg, 0.12 mmol, intermediate 14) in ACN (1 mL), 4,4-dimethylpiperidine hydrochloride (33 mg, 0.22 mmol) and DIPEA (50 μL, 0.29 mmol) were added. The reaction mixture was stirred at 85 °C for 4 h, and then cooled to RT. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were concentrated under vacuum and adsorbed onto a silica gel stopper and separated by silica gel column chromatography (eluting with 0%–60% EtOAc in heptane) to provide 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(brs,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 s,4H),3.06(br s,4H),1.65(br s,8H),1.26(br s,2H),1.08(br s,6H). m / z(ESI):457.2(M+H) + .

[0452] Table 5: Examples 100-1 to 100-24 were prepared according to a similar preparation method to Example 100:

[0453]

[0454]

[0455]

[0456]

[0457]

[0458] Example 101: N-(3-(N-cyclopropylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]octyl-6-yl)nicotinamide.

[0459]

[0460] 3-(2-(6-azaspiro[2.5]oct-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) were placed in glass vials. DIPEA (0.065 mL, 0.37 mmol) was added to the reaction mixture, and the mixture was stirred at rt for 2 h. The mixture was concentrated, and the crude product was purified by silica gel chromatography (EtOAc in heptane 10%-70%) to give N-(3-(N-cyclopropylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (43 mg, 84% yield) as a white solid. 1 ¹H 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].

[0461] Table 6: Examples 101-1 to 101-10 were prepared in a manner similar to that of Example 101:

[0462]

[0463]

[0464] Example 102: (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxypyrrolidone-1-yl)-2- (6-azaspiro[2.5]oct-6-yl)nicotinamide

[0465]

[0466] N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (0.080 g, 0.17 mmol, intermediate 13), DMSO (2 mL), (R)-3-pyrrolidone (0.028 g, 0.33 mmol), and DIPEA (0.091 mL, 0.52 mmol) were placed in glass vials. The mixture was stirred at 110 °C for 5 h and cooled to rt. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (using a 30%–100% EtOAc gradient in heptane) to provide (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxypyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (71 mg, 77% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.14(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].

[0467] Table 7: Examples 102-1 to 102-31 were prepared according to a similar preparation method to Example 102:

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476] Example 103: N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)-2-(6-nitrogen Spiro[2.5]oct-6-yl)nicotinamide

[0477]

[0478] N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (95 mg, 0.21 mmol, intermediate 13-1), 1-amino-2-methyl-prop-2-ol (0.037 mL, 0.41 mmol), DIPEA (0.036 mL, 0.21 mmol), and DMSO (3 mL) were placed in glass vials. The mixture was stirred at 85 °C for 24 h and cooled to rt. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (using a 0%-100% EtOAc:EtOH (3:1) gradient in heptane) to provide N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)-2-(6-azaspiro[2.5]oct-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].

[0479] Table 8: Examples 103-1 to 103-28 were prepared according to a similar preparation method to Example 103:

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487] Example 104: N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxacyclobutane-3-yloxy)-2-(6-azaspiro) [2.5] Oct-6-yl)nicotinamide

[0488]

[0489] A mixture of N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-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. H2O was added, the solid was collected, dried, and purified by silica gel column chromatography (0-50% EtOAc / heptane) to give N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxetane-3-yloxy)-2-(6-azaspiro[2.5]oct-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].

[0490] Table 9: Preparation of Example 104-1 according to a similar preparation method to Example 104:

[0491]

[0492] Example 105: N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-hydroxy-2-methylpropyl-2-yl)amino (2,5)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide.

[0493]

[0494] Step 1 6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (549 mg, 1.59 mmol, intermediate 11) and DCM (8 mL) were charged into a 100 mL round-bottom flask. Oxaloyl dichloride (1.43 mL, 2.86 mmol, 2 M in DCM) was added to the reaction mixture at RT, followed by two drops of DMF. The mixture was stirred at RT for 1 h and the solvent was removed under vacuum. 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 RT for 18 h, then 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 rapid column chromatography (eluting with 0% to 60% EtOAc in heptane) to N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (703 mg, 1.26 mmol, 80% yield) as a pale yellow solid. MS (ESI, cation) m / z: 556.1 [M+1].

[0495] Step 2 N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (703 mg, 1.26 mmol), MeOH (2 mL), and sodium hydroxide (1.26 mL, 6.33 mmol, 5 N) were added to a glass vial. The vial was stirred at 70 °C for 1 h, cooled to RT, and the solvent was removed under reduced pressure. The residue was partitioned between semi-saturated NH4Cl (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (20 mL) and dried over Na2SO4. The crude material was adsorbed onto a silica gel stopper and purified by chromatography via a Redi-Sep pre-packed silica gel column (eluted with a gradient of 0% to 60% EtOAc in heptane) to provide N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-hydroxy-2-methylpropyl-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (485 mg, 0.92 mmol, 72% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (singlet, 1H), 8.32 (triplet, J = 1.45 Hz, 1H), 7.84 (doublet of triplets, J = 7.88, 1.45 Hz, 1H), 7.71 (doublet, J = 8.71 Hz, 1H), 7.50 - 7.57 (multiplet, 2H), 7.49 (doublet of triplets, J = 7.88, 1.45 Hz, 1H), 6.60 (singlet, 1H), 6.28 (doublet, J = 8.50 Hz, 1H), 4.81 (triplet, J = 5.70 Hz, 1H), 3.59 (doublet, J = 5.81 Hz, 2H), 3.11 - 3.17 (multiplet, 4H), 1.44 - 1.51 (multiplet, 4H), 1.36 (singlet, 6H), 1.12 (singlet, 9H), 0.31 (singlet, 4H). MS (ESI, cation) m / z: 530.2 [M+1].

[0496] Table 10: Examples 105-1 to 105-32 were prepared according to a similar preparation method to Example 105:

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504] Example 106: N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxypropane-2-yl)amino)-2-(6- Azaspiro[2.5]oct-6-yl)nicotinamide

[0505]

[0506] A mixture of N-(3-(cyclopentylsulfonyl)phenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-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 cooled to RT, H2O was added, and the precipitated solid was collected by filtration. The crude solid was purified by silica gel chromatography (0-50% EtOAc:EtOH (3:1) in heptane) to give N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxypropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (48 mg, 0.09 mmol, 41% yield). 1 H 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].

[0507] Table 11: The following examples were prepared according to a procedure similar to that described in Example 106:

[0508]

[0509]

[0510] Examples 107-1 and 107-2: (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]) Oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide and (S)-N-(3-(N-(tert-butyl)aminosulfonyl) phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide

[0511]

[0512] 2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinic acid (0.87 g, 2.52 mmol, intermediate 12) and DCM (8 mL) were placed in a 100 mL round-bottom flask. Oxaloyl dichloride (2.52 mL, 5.05 mmol, 2 M in DCM) was added to the reaction mixture at RT, followed by two drops of DMF. The mixture was stirred at RT for 1 h and the solvent was removed under vacuum. 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 RT for 18 h, then 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 rapid column chromatography (eluting with 10% to 60% EtOAc in heptane) to give racemic N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide. 1 ¹H NMR (400MHz, 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, cation) m / z: 555.2 [M+1]. The substance was separated by preparative SFC using an ADH column (250x21mm, 5mic) with a mobile phase of 80% liquid CO2 and 20% MeOH at a flow rate of 75 mL / min to obtain:

[0513] Example 107-1: (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]octyl-6- 6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide. First elution peak; ee > 99.5%. 1¹H NMR (400MHz, 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 = 5.28 Hz, 4H), 1.28 (s, 9H), 0.43 (s, 4H). MS (ESI, cation) m / z: 555.2 [M+1].

[0514] Example 107-2: (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]octyl-6- 6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide. Second elution peak; ee > 99.5%. 1 ¹H NMR (400MHz, chloroform-d) δ 11.23 (s, 1H), 8.54 (d, J = 8.02 Hz, 1H), 8.28 (t, J = 1.76 Hz, 1H), 7.93 (dd, J = 1.17, 8.22 Hz, 1H), 7.69 (d, J = 7.82 Hz, 1H), 7.49–7.56 (m, 1H), 7.38 (d, J = 7.83 Hz, 1H), 5.85 (s, 1H), 4.61 (s, 1H), 3.31–3.39 (m, 4H), 1.77 (s, 3H), 1.60–1.66 (m, 4H), 1.29 (s, 9H), 0.43 (s, 4H). MS (ESI, cation) m / z: 555.2 [M+1].

[0515] Stereochemistry is arbitrarily determined.

[0516] Table 12: The following examples were prepared according to a procedure similar to that described in Examples 107-1 and 107-2:

[0517]

[0518] Examples 109-1 and 109-2: (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropyl) Alkyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide and (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)- 6-(1,2-dihydroxypropane-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide.

[0519]

[0520] Step 1N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-chloro-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (1.00 g, 2.09 mmol, intermediate 13-2), AmPhos (0.151 g, 0.21 mmol), tributyl(1-ethoxyvinyl)stanane (0.85 mL, 2.51 mmol), and toluene (10 mL) were loaded into a 100-mL round-bottom flask. The reaction mixture was stirred at 90 °C for 30 min. The mixture was cooled to rt, treated with HCl / dioxane (2 mL, 4 M), and stirred at rt for 30 min. The reaction mixture was partitioned between saturated sodium bicarbonate aqueous solution (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were dried using a Chem Elut extraction column eluted with EtOAc (2 x 10 mL). The organic phase was concentrated and the crude product was purified by Biotage (SNAP25, Ultra, eluent: EtOAc in heptane 0%-50%) to provide 6-acetyl-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (0.85 g, 84% yield). 1 H 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).

[0521] Step 2:Trimethyl sulfoxide (0.201 g, 0.914 mmol) and DMSO (1.5 mL) were placed in a 20 mL scintillation vial. Potassium tert-butoxide (0.093 g, 0.83 mmol) was added to the mixture, and the mixture was stirred at rt for 30 min. Then, 6-acetyl-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (0.399 g, 0.82 mmol) was added to 1.0 mL of DMSO, and the yellow solution was stirred at rt for 3 h. The reaction mixture was partitioned between water (15 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (30 mL) and dried using a Chem Elut extraction column eluted with EtOAc (2 x 5 mL). The organic phase was concentrated, and the crude product was reused. MS (ESI, cation) m / z: 499.2 [M+1].

[0522] Step 3 N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(2-methylethyleneoxy-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (2.19 g, 3.95 mmol), dioxane (12 mL), and water (12 mL) were charged into a 150 mL round-bottom flask. Hydrochloric acid (2.0 mL, 8.00 mmol) was then added, and the reaction mixture was stirred at RT for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with water and dried using a Chem Elut extraction column eluted with EtOAc (2 x 10 mL). The combined organic extracts were concentrated and purified by Biotage (SNAP100, Ultra, eluent: EtOAc in heptane 40%-100%) to provide N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropane-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (1.14 g, 56% yield). 1H NMR (400MHz, chloroform-d) δ11.52(s,1H),8.50(d,J=8.02Hz,1H),8.27(t,J=1.66Hz,1H),7.94(dd,J=1.08,8.12Hz,1H),7.67(d,J=8.02Hz,1H) ,7.49-7.54(m,1H),7.33(d,J=7.82Hz,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 s, 1H), 1.60–1.66 (m, 4H), 1.53 (s, 3H), 1.29 (s, 9H), 0.43 (s, 4H). MS (ESI, cation) m / z: 517.2 [M+1]. The substance was separated by preparative SFC using an OX-H column (250 x 21 mm, 5 mic) with a mobile phase of 40% liquid CO2 and 60% MeOH (20 mM NH3) at a flow rate of 50 mL / min to obtain:

[0523] Example 109-1: (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropane-2-yl)- 2-(6-azaspiro[2.5]oct-6-yl)nicotinamide First elution peak; ee > 99.5%. 1 H NMR (400MHz, chloroform-d) δ = 11.49 (s, 1H), 8.46 (d, J = 8.0Hz, 1H), 8.25 (s, 1H), 7. 95(dd,J=1.1,8.1Hz,1H),7.67(d,J=7.8Hz,1H),7.55-7.47(m,1H),7.33( d,J=8.0Hz,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].

[0524] Example 109-2: (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropane-2-yl)- 2-(6-azaspiro[2.5]oct-6-yl)nicotinamide The second elution peak; ee > 99.5%. 1¹H NMR (400MHz, chloroform-d) δ=11.50(s, 1H), 8.46(d, J=7.8Hz, 1H), 8.25(s, 1H), 7.95(dd, J=1.1, 8.1Hz, 1H), 7.67(d, J=7.8Hz, 1H), 7.54-7.47(m, 1H), 7.33(d, J=8.0Hz, 1H), 4.81( s, 1H), 4.69 (dt, J = 2.0, 4.1 Hz, 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].

[0525] Stereochemistry is arbitrarily determined.

[0526] Example 110: N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(methylsulfonamido)-2-(6-azaspiro) [2.5] Oct-6-yl)nicotinamide .

[0527]

[0528] Add 6-bromo-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-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) to a glass vial. Vacuum the vial and backfill with N2. Repeat this process four more times, adding DMF (1 mL) followed by (1r,2r)-(-)-N,N″-dimethylcyclohexane-1,2-diamine (0.017 mL, 0.11 mmol). Seal the vial and stir the reaction mixture at 100 °C for 4 h. Dilute the mixture with EtOAc (4 mL) and pass through... Filter the solution through a pad. Wash the filtrate with water (2 x 5 mL) and concentrate. Purify the crude product by Biotage (SNAP10, Ultra, eluent: EtOAc in heptane 40%–90%) to provide N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (41 mg, 42% yield) as a white solid. 1¹H 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].

[0529] Example 111: 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(oxazol-2-yl)benzene) 2-(6-azaspiro[2.5]oct-6-yl)nicotinamide

[0530]

[0531] Step 1 A mixture of N-(3-bromo-4-methylphenyl)-6-fluoro-2-(6-azaspiro[2.5]oct-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 RT and partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4, 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-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (0.26 g, 0.53 mmol, 45% yield). MS (ESI, cation) m / z: 487.1 / 489.1 [M+1].

[0532] Step 2:N-(3-bromo-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (0.050 g, 0.10 mmol), tetrapalladium (0.024 g, 0.021 mmol), and 2-(tri-n-butylmethylstannyl)oxazole (0.028 mL, 0.13 mmol) were placed in a pressure vial. The vial was purged with N2 for a few minutes, and then 1,4-dioxane (1 mL) was added. The vial was sealed 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-methylpropane-2-yl)amino)-N-(4-methyl-3-(oxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (15 mg, 0.032 mmol, 31% yield) as a grayish-white solid. 1 ¹H NMR (400MHz, chloroform-d) δppm 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].

[0533] Table 13: Examples 111-1 to 111-13 below were prepared according to a similar procedure as described with respect to Example 111. :

[0534]

[0535]

[0536]

[0537] Example 112: N-(3-(N-(tert-butyl)aminosulfonyl)-5-(furan-2-yl)phenyl)-6-((1-hydroxy-2-methyl) 2-(6-azaspiro[2.5]oct-6-yl)nicotinamide

[0538]

[0539] Step 1:A solution of N-(3-bromo-5-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-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) was added to a 5 mL microwave reaction tube. The mixture was degassed by bubbling Ar through the reaction mixture for 5 min. The tube was then microwaved at 120 °C for 30 min. The mixture was cooled to rt and partitioned between water (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with EtOAc (2 x 5 mL). The combined organic phases were washed with water (15 mL) and saturated sodium chloride aqueous solution (15 mL). The organic phases were dried using a Chem Elut extraction column eluted with EtOAc (2 x 5 mL). The organics were concentrated and purified by Biotage (Ultra, eluent: acetone in heptane 20%–70%) to provide N-(3-(N-(tert-butyl)aminosulfonyl)-5-(furan-2-yl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (34 mg, 41% yield). 1 H NMR (400MHz, chloroform-d) δ11.95(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=1.3 7Hz,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].

[0540] Step 2:N-(3-(N-(tert-butyl)aminosulfonyl)-5-(furan-2-yl)phenyl)-6-(4,4-dimethyl-2-oxooxazolidine-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (34 mg, 0.054 mmol), MeOH (2 mL), and NaOH (0.1 mL, 0.5 mmol, 5 M) were added to a glass vial. The reaction mixture was stirred at 70 °C for 1 h. The mixture was cooled to rt and concentrated. The residue was partitioned between semi-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: EtOAc in heptane 30%-100%) to provide N-(3-(N-(tert-butyl)aminosulfonyl)-5-(furan-2-yl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide (27 mg, 84% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.24(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].

[0541] Table 14: Examples 112-1 to 112-3 were prepared according to a similar preparation method to Example 112:

[0542]

[0543]

[0544] Example 113: N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((methylsulfonyl)methyl)-2-(6-aza Spiro[2.5]oct-6-yl)nicotinamide

[0545]

[0546] At 0 °C, HATU (0.176 g, 0.462 mmol) and diisopropylethylamine (0.135 mL, 0.771 mmol) were added to a solution of 6-((methanesulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinic acid (0.1 g, 0.308 mmol, intermediate 10) in DMF (2 mL) 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 x 15 mL). The organic layer was washed with a brine solution (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (using a 50% EtOAc gradient in hexane) to give the title compound (68 mg, 28% yield) as a pale yellow solid. 1 ¹H 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].

[0547] Example 114: N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide amine

[0548]

[0549] To a solution of N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-3-fluoroisonicotinamide (1.43 g, 4.07 mmol, intermediates 14-16) in DMSO (1 mL), 6-azaspiro[2.5]octane (0.68 g, 6.10 mmol) and Cs₂CO₃ (4.64 g, 14.24 mmol) were added. The reaction mixture was stirred at 100 °C for 18 h, and then cooled to RT. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were concentrated in vacuum and adsorbed onto a silica gel stopper and separated by chromatography using a silica gel column (eluting with 0%-60% EtOAc in heptane) to provide N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide (0.28 g, 0.64 mmol, 16% yield). 1H 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) + .

[0550] Table 15: Examples 114-1 to 114-2 were prepared according to a similar preparation method to Example 114:

[0551]

[0552] Example 115: N-(3-(3,3-difluoropiperidin-1-carbonyl)-4-methylphenyl)-3-(6-azaspiro[2.5]octyl-6- (Base) isonicotinamide

[0553]

[0554] Step 1 6-azaspiro[2.5]octyl-2-methylbenzoate (0.82 g, 2.84 mmol, intermediate 14-8) was added to a solution of methyl 5-(3-fluoroisonicotinamide)-2-methylbenzoate (0.82 g, 2.84 mmol, intermediate 14-8) in dioxane-CH3CN (2:1, 5 mL) with 0.38 g, 3.41 mmol, and 0.55 g, 4.27 mmol. The reaction mixture was stirred at 170 °C for 1 h under microwave. The mixture was adsorbed onto a silica gel stopper and subjected to silica gel column chromatography (eluting with 25-45% EtOAc in heptane) to provide methyl 5-(3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide)-2-methylbenzoate (0.80 g, 2.11 mmol, 74% yield) as a grayish-white solid. m / z (ESI): 380.1 (M+H) + .

[0555] Step 2A mixture of methyl 5-(3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide)-2-methylbenzoate (0.80 g, 2.11 mmol) and lithium hydroxide hydrate (0.22 g, 5.27 mmol) in THF (3 mL), H₂O (3 mL), and MeOH (1 mL) was heated at 50 °C for 3 h. The reaction mixture was cooled to rt and concentrated under vacuum. The residue was treated with 1N HCl (10 mL), a yellow precipitate was filtered off, washed with water, and dried. 5-(3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide)-2-methylbenzoate dihydrochloride (0.72 g, 1.64 mmol, 78% yield) was given as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.99(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) + .

[0556] Step 3 A mixture of 5-(3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide)-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 stirred at 45 °C for 2 h. The mixture was diluted with EtOAc and washed successively with 1 N NaOH and brine. The organic layer was concentrated and the residue purified by reversed-phase HPLC (10–90% [0.1% TFA] in CH3CN in a 0.1% TFA aqueous solution) to give the title compound as a yellow, fluffy powder (45 mg, 0.06 mmol, 57% yield). 1H NMR (400MHz, DMSO-d6) δ10.97(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) + .

[0557] Table 16: Examples 115-1 to 115-5 were prepared according to a similar preparation method to Example 115:

[0558]

[0559]

[0560] Additional Examples

[0561] The examples 116-128 below can be prepared using commercially available raw materials according to a procedure similar to that of the examples above, or according to a procedure familiar to those skilled in the art.

[0562]

[0563]

[0564]

[0565] Biological examples

[0566] The following assays were used to test exemplary compounds of the present invention. Data from those examples tested according to the following procedures are shown in Table A below.

[0567] KIF18A enzyme assay: KIF18A enzyme activity after compound treatment was measured using a microtubule-stimulated ATPase activity assay. The compound was serially diluted 2-fold in DMSO (Sigma Inc.) within a 22-point range. Recombinant human KIF18A (1-467His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography (Amgen Inc.). ADP-Globe assay was used to measure KIF18A activity. TMThe kinase / ATPase assay kit (Promega Inc.) optimizes the concentrations of KIF18A protein, microtubules (MT), and ATP in the reaction for a standardized homozyme assay. This assay measures ADP formed by the ATPase reaction. The reaction buffer was 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 paclitaxel (Cytoskeleton Inc.), and 30 μg / mL porcine microtubules (Cytoskeleton Inc.))]. The compound and KIF18A protein (30 nM) were added to the prepared reaction buffer and incubated at room temperature for 15 min. Next, ATP (K... m Incubate at room temperature for 15 min (75 μM). Add 5 μl of ADP-Glo TM Mix the reagent with 2.5 μl of the reaction mixture and incubate at room temperature for 40 min. Add 10 μl of ADP-Glo TM The assay reagent was prepared and incubated at room temperature for 40 min. The luminescence was read using an EnVision microplate reader equipped with a superluminescence module (Perkin Elmer Inc). Concentration-response curve fitting and IC50 analysis were performed using Genedata Screener software (version 15.0.1, Genedata Inc.) with a four-parameter logistic regression fitting model. 50 Sure.

[0568] Table A provides data for compounds exemplified in this application and its priority documents, which are representative compounds of the present invention, as follows: chemical name (named by ACD software or ChemDraw (Professional 15.0)) and biological data (IC). 50 (in μM). Ex. # refers to the instance number.

[0569] Table A: Biological Data

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585] For purposes of clarity and understanding, the foregoing invention has been described in detail by way of illustration and example. Those skilled in the art will understand that changes and modifications can be made within the scope of the appended claims. Therefore, it should be understood that the above description is intended to be illustrative rather than restrictive. Consequently, the scope of the invention should not be determined by reference to the foregoing description, but rather by reference to the following appended claims and the full scope of their equivalents.

[0586] For all purposes, all patents, patent applications and publications cited herein are incorporated herein by reference in their entirety as if each individual patent, patent application or publication were so individually represented.

Claims

1. A compound of formula I: Or any pharmaceutically acceptable salt thereof, wherein: X 1 For -CR 3 ; X 2 Let N be the number of people in the group. X 3 For -CR 1 ; R 1 -ZR group 12 Where Z does not exist and is -C 0-4 Alkyl-NR 11 -C 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-, -C 0-4 Alkyl-(C=O)NR 11 -、-C-((C=O)-OR 11 )2-、-C 0-4 Alkyl-(C=O)-O-, -C 0-4 Alkyl-O-, -C 0-4 Alkyl-NR 11 (C=O)-、-C 0-4 Alkyl-NR 11 SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-SO2-, -NR 11 -C 0-4 Alkyl-O-, -C 0-4 Alkyl-S(=O)(=N) + (CH3)2)-, -C=N(OH)-, or -N=S(=O)<, R 2 The group is -YR 13 Where Y does not exist and is -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-S=OC 0-4 Alkyl-, -C 0-4 Alkyl-SO2-C 0-4 Alkyl, -SO2NR 13c -C 0-4 Alkyl-, -SO2N(C 1-4 alkyl)-, -SO2N(C 1-4 Alkyl-OC 1-4 alkyl)-, -C 0-4 Alkyl-S(=O)(=NH)-, -C 0-4 Alkyl-(C=O)-, -C 0-4 Alkyl-(C=O)-O-, -C 0-4 Alkyl-(C=O)NR 13c -、-NR 13c -、-OC 0-4 Alkyl group -, -N=S (=O)<, or -NR 13c -SO2-C 0-4 alkyl-; R 3 For H; R 5 For H; R 6 H, halogen, C 1-8 Alkyl, -OC 1-8 Alkyl, furanyl, cyclopropyl, or pyridyl; R 7 H, halogen, C 1-8 Alkyl, or -OC 1-8 alkyl; R 8 It is H or a halogen group; L is -NR 10 -(C=O)-; R 9 For H; R 10 For H; R X yes R 11 and R 13c Each independently is H or C 1-8 alkyl; R 12 H, halogen, CN, -OH, R 12a 、or R 12b ; R 13 H, halogen, CN, R 13a Or R 13b ; R 12a and R 13a Each of these is independently selected, in each case, from the group consisting of: saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings or 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2, 3, or 4 groups selected from: F, Cl, Br, C 1-6 Alkyl, C 1-4 Halogenated alkyl groups, -OR a -OC 1-4 Haloalkyl, 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 Alkyl NR a R a -OC 2-6 Alkyl OR 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 Alkyl NR a R a -NR a C 2-6 Alkyl OR a -C 1-6 Alkyl NR a R a -C 1-6 Alkyl OR a -C 1-6 Alkyl N(R) a )C(=O)R b -C 1-6 Alkyl OC(=O)R b -C 1-6 Alkyl C(=O)NR a R a -C 1-6 Alkyl C(=O)OR a Oxygenated, or saturated, partially saturated or unsaturated 3-, 4-, or 5-membered monocyclic rings; R 12b and R 13b Each of these groups is independently selected from the group consisting of the following in each case: selected from F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)OR a -C 0-6 Alkyl OR a -OC 1-4 Haloalkyl, CN, NH2, NH(CH3), N(CH3)2, -(C=O)NR a -NR a (C=O)C 0-4 Alkyl group, -S(=O)2R a C-shaped monocyclic rings with 0, 1, 2, 3, 4, or 5 substituents, whether saturated, partially saturated, or unsaturated. 1-6 alkyl; R a H or R independently in each case b ;and R b C is independent in each case. 1-6 alkyl, phenyl, or benzyl, wherein the C 1-6 The alkyl group is substituted by 0, 1, 2, or 3 of the following substituents: halogen, -OH, -OC. 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl group, -OC (=O)C 1-4 Alkyl, or -N(C) 1-4 Alkyl)C 1-4 Alkyl; and the phenyl or benzyl group is substituted with 0, 1, 2 or 3 of the following substituents: halogen, C 1-4 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-4 Alkyl, -NH2, -NHC 1-4 Alkyl group, -OC (=O)C 1-4 Alkyl, or -N(C) 1-4 Alkyl)C 1-4 alkyl.

2. The compound of claim 1, having formula (Ia):

3. The compound of claim 1 or 2, wherein R X Selected from 4. The compound of claim 1 or 2, wherein R X for 5. The compound of claim 1 or 2, wherein Z is absent or is -NH-, -(C=O)-, -CH(CH3)-(C=O)NH-, -C-((C=O)-O-(CH3))2, -C-((C=O)-O-(CH3)3)2, -CH(CH3)-(C=O)-O-, -C(CH3)2-(C=O)-O-, -(C=O)-O-, -N(CH3)-, -O-, -NH(C=O)-, -(C=O)NH, -CH2-(C=O)-O-, -CH2NCH3-, -NCH3-, -CH2-(C=O)-NH-, -NHSO2-, -CH2SO2-, -NHCH2-, or -NHCH2CH2-O-.

6. The compound of claim 1 or 2, wherein R 12 Selected from: a)H, F, Cl, Br, OH, or CN; b) Selected from F, Cl, Br, -CF3, -CH2OH, -OH, -OCH3, -C(=O)OH, C with 0, 1, 2 or 3 substituents of -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 Alkyl; or c) A saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 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, wherein the ring is 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.

7. The compound of claim 1 or 2, wherein R 12 Selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridine, oxadiazolyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolyl, dioxopentyl, morpholinyl, phenyl, Each R 12 It is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, methyl, ethyl, CN, -CF3, -CH2OH, -CH2CH2OH, -OH, -OCH3, -COOH, -CONH2, COOCH3, -CONH(CH3), -NH2, -SO2CH3, or oxo.

8. The compound of claim 1 or 2, wherein R 1 -ZR group 12 Where Z is absent, is -NH-, -O-, -NHSO2-, or -CH2SO2-; and R 12 It is H, pyrrolidinyl, oxetyl, cyclopropyl, or cyclobutyl, or R 12 C is a carbon atom substituted with 0, 1, 2 or 3 OH, CF3 or -CH2OH groups. 1-6 alkyl.

9. The compound of claim 1 or 2, wherein Y is absent, or is -S-, -SO2-, -SO2CH2-, -SO2CH(CH3)-, -SO2NH-, -SO2NHCH2-, -SO2N(CH2CH3)-, -SO2N(CH3)-, -SO2N(CH2C≡CH)-, SO2N(CH2CH2OCH3)-, -S(=O)(=NH)-, -C=O-, -CH2-(C=O)-, -(C=O)-O-, -CH2(C=O)-O-, -(C=O)NH-, -(C=O)-N(CH3)-, -CH2-(C=O)-NH-, -NH-, -O-, -N=S(=O)<, or -NHSO2-.

10. The compound of claim 1 or 2, wherein R 13 Selected from: a) H, halogen, or CN; b)R 13a Selected from saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, wherein the ring is substituted with 0, 1, 2, or 3 groups selected from: F, Cl, Br, methyl, ethyl, isopropyl, CHF2, CF3, CH2OH, -OH, -OCH3, -NH2, -NH(CH3), oxo, cyclopropyl, or cyclobutyl; or c)R 13b C substituted with 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, -OH, -CF3, cyclopropyl or cyclobutyl 1-6 alkyl.

11. The compound of claim 1 or 2, wherein R 13a Selected from: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, imidazoalkyl, oxazolyl, phenyl, pyrrolyl, pyrazolyl, morpholinyl, thiomorpholinyl, piperidinyl, azacyclobutane, furanyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, oxadiazolyl, tetrazolyl, pyridinyl Each of them is independently substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, methyl, ethyl, isopropyl, CHF2, CF3, CH2CF3, -OCH3, -CH2CH2OCH3, or oxo.

12. The compound of claim 1 or 2, wherein R 13b Selected from: methyl, ethyl, isopropyl, isobutyl, tert-butyl or neopentyl, each of which is independently substituted by 0, 1, 2 or 3 groups selected from: F, CF3, OH or cyclopropyl.

13. The compound of claim 1 or 2, wherein R 2 The group is -YR 13 Where Y is nonexistent, is -SO2-, or -SO2NH-; and R 13 For tert-butyl, or R 13a Selected from cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, or piperidinyl, wherein each of the R... 13a It is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, methyl, or CF3.

14. The compound of claim 1 or 2, wherein R 2 The group is -YR 13 Where Y is -SO2- and R 13 It is cyclopropyl, cyclobutyl, cyclopentyl, morpholino, or piperidinyl, each of which is substituted by 0, 1, 2, or 3 methyl groups.

15. The compound of claim 1 or 2, wherein R 3 It can be H, F, or methyl.

16. The compound of claim 2, wherein R 4 For H.

17. The compound of claim 1 or 2, wherein R 6 It can be H, F, Br, methyl, methoxy, cyclopropyl, furanyl, or pyridyl.

18. The compound of claim 1 or 2, wherein R 6 It can be H or F.

19. The compound of claim 1 or 2, wherein R 7 It can be H, F, Br, Cl, methyl, or methoxy.

20. The compound of claim 1 or 2, wherein R 7 It can be H, F, or methyl.

21. The compound of claim 1 or 2, wherein R 8 It can be H or F.

22. The compound of claim 1 or 2, wherein R 8 For H.

23. A compound, or a pharmaceutically acceptable salt thereof, said compound being selected from the group consisting of: 2-(4,4-dimethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide; N-(3-(piperidin-1-ylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 2-(4-ethylpiperidin-1-yl)-N-(3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide; N-(3-(piperidin-1-ylsulfonyl)phenyl)-2-(4-propylpiperidin-1-yl)nicotinamide; N-(3-(piperidin-1-ylsulfonyl)phenyl)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-((4-fluoropiperidin-1-yl)sulfonyl)phenyl)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-((4-fluoropiperidin-1-yl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 2-(4,4-dimethylpiperidin-1-yl)-N-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)nicotinamide; N-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-isopropylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)-4-methylphenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(4-ethylpiperidin-1-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(4-ethyl-4-methylpiperidin-1-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(4-propylpiperidin-1-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(2,2-difluoro-7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-4-methylphenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-2-fluorophenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-((cyclopropylmethyl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclohexylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclobutylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclobutylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclobutyl-N-methylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(1-methylcyclobutyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclohexylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-((3,3-difluoroazacyclobutane-1-yl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-((3,3-difluoropyrrolidone-1-yl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(1-methylcyclopropyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(1-fluoro-2-methylpropane-2-yl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(3,3-difluorocyclobutyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(4-fluorophenyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxypyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3,3-dimethylpyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3,3-difluoropyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(2,2-dimethylpyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxypyrrolidone-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1R,5S)-3-azabicyclo[3.1.0]hex-3-yl)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1S,5R)-2-azabicyclo[3.1.0]hex-2-yl)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-morpholino-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1S,5R)-8-oxa-2-azabicyclo[3.2.1]oct-2-yl)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-(azacyclobutane-1-yl)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-cyanoazacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-methoxyazacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxy-3-methylazacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-hydroxy-3-(trifluoromethyl)azacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(3-(methylsulfonyl)azacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(cyclobutylamino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((3,3-difluorocyclobutyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((1R,2R)-2-hydroxycyclopentyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((1S,2R)-2-hydroxycyclopentyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((3S,4R)-4-hydroxytetrahydrofuran-3-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-((tetrahydrofuran-3-yl)amino)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((1R,3S)-3-hydroxycyclopentyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((1S,3S)-3-hydroxycyclopentyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(oxecyclobutane-3-ylamino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((3-methyloxetane-3-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((3-(hydroxymethyl)oxecyclobutane-3-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(((1S,3S)-3-hydroxycyclobutyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((3-hydroxypropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-(benzylamino)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxy-2-methylpropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-methoxyethyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((3-hydroxypropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-(tert-butylamino)-N-(3-(cyclopentylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclopropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclobutyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((3-(hydroxymethyl)oxecyclobutane-3-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((4-hydroxy-2-methylbut-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(((1-hydroxycyclopropyl)methyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (S)-N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-hydroxypropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-hydroxypropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxypropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (S)-N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxypropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxetane-3-ylamino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(((1R,2R)-2-hydroxycyclobutyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(cyclopentylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-((tetrahydrofuran-3-yl)amino)nicotinamide; (S)-N-(3-(cyclopentylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-((tetrahydrofuran-3-yl)amino)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(((1-hydroxycyclobutyl)methyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((3-hydroxy-2,3-dimethylbut-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-(2-hydroxyethyl)cyclopropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(3-(hydroxymethyl)azacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(3-hydroxyazacyclobutane-1-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-(dimethylamino)ethyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(ethylamino)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((2-hydroxyethyl)amino)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclopropyl)amino)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; 6-(azacyclobutane-1-yl)-N-(3-(cyclopentylsulfonyl)phenyl)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-morpholino-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((4-hydroxy-2-methylbut-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-(oxacyclobutane-3-yloxy)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-methoxy-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-((1-methylcyclobutyl)sulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(tert-butylsulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)-N-(3-((1,1,1-trifluoro-2-methylpropane-2-yl)sulfonyl)phenyl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(isobutylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)-N-(3-((trifluoromethyl)sulfonyl)phenyl)nicotinamide; N-(3-(cyclobutylsulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(7-azaspiro[3.5]non-7-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-4-methylphenyl)-6-((1-(hydroxymethyl)cyclopropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclopropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-(hydroxymethyl)cyclopropyl)amino)-N-(3-(N-(1-methylcyclobutyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(N-(1-methylcyclobutyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)phenyl)-6-((1-(hydroxymethyl)cyclopropyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-4-fluorophenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-4-chlorophenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-4-methoxyphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-fluorophenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-methoxyphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-2-fluorophenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-bromo-5-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(tert-butylcarbamoyl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(pyrrolidine-1-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-morpholinophenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(1,1-thiomorpholino)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(2-oxopyrrolidone-1-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-morpholinophenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(4-fluoro-3-(2-methylmorpholino)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-fluoro-5-(2-methylmorpholino)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxypropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1,3-dihydroxypropane-2-yl)amino)-N-(3-(N-(1-methylcyclobutyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1,3-dihydroxypropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-6-((1,3-dihydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)-4-methylphenyl)-6-((1,3-dihydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((1,3-dihydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)phenyl)-6-((1,3-dihydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide; (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide; N-(3-(N-cyclopropylaminosulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropane-2-yl)nicotinamide; (S)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropane-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; (R)-N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(1,2-dihydroxypropane-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(oxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(furan-3-yl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(furan-2-yl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(1H-pyrazol-3-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(thiazolyl-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(4-methyloxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(5-methyloxazol-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(1-methyl-1H-pyrazol-5-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(3-(1-methyl-1H-imidazol-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(pyridin-3-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(pyridin-4-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; 6-((1-hydroxy-2-methylpropane-2-yl)amino)-N-(4-methyl-3-(5-methylpyridin-3-yl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-(furan-2-yl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(furan-3-yl)-4-methylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-cyclopropylphenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)-5-(pyridin-3-yl)phenyl)-6-((1-hydroxy-2-methylpropane-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)nicotinamide; N-(3-(N-(tert-butyl)aminosulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(3-(cyclopentylsulfonyl)phenyl)-3-(1,1-difluoro-6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(3-(3,3-difluoropiperidin-1-carbonyl)-4-methylphenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(4-bromo-3-(3,3-difluoropiperidine- 1-Carbonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(4-chloro-3-(3,3-difluoropiperidin-1-carbonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(3-(3,3-difluoropiperidin-1-carbonyl)-4-fluorophenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; N-(3-(4,4-difluoropiperidin-1-carbonyl)-4-methylphenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide; or N-(3-(3,3-difluoropiperidin-1-carbonyl)phenyl)-3-(6-azaspiro[2.5]oct-6-yl)isonicotinamide.

24. A compound selected from the group consisting of: Or any pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound as described in any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

26. The method of using the compound of any one of claims 1 to 24 or the composition of claim 25 in the preparation of a medicament for treating a condition treatable with a KIF18a inhibitor in patients in need.

27. An in vitro method for inhibiting KIF18A in cells, the method comprising contacting the cells with a compound as described in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or a composition as described in claim 25.

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