KIF18A inhibitor

Abstract

The amide compounds of formula (I) as defined herein: and compositions containing these compounds, as well as methods for preparing such compounds. Also provided herein are methods of treating disorders or diseases treatable by inhibiting the kinesin motor protein KIF18A, such as cancer, psoriasis, atopic dermatitis, autoimmune diseases or inflammatory bowel disease, etc. #imgabs0#

Description

[0001] The present invention relates to the field of pharmaceutical reagents, and more particularly, to compounds and compositions for modulating KIF18A and uses and methods for managing cell proliferation and treating cancer. Background Art

[0002] Cancer is one of the most prevalent diseases afflicting humans and is a leading cause of death worldwide. In the quest for effective treatment or cure for one or more of the many different cancers, many groups have invested a great deal of time, effort, and financial resources over the past few decades. However, to date, among the available cancer treatments and therapies, only a few offer a reasonable degree of success.

[0003] Cancer is typically characterized by unregulated cell proliferation. Damage to one or more genes responsible for cellular pathways (which control the progression of proliferation through the cell cycle and centrosome cycle) can cause loss of normal regulation of cell proliferation. These dysregulated genes can encode various tumor suppressors or oncogene proteins, which are involved in a series of events leading to unchecked cell cycle progression and cell proliferation. Various kinases and kinesins have been identified as playing key roles in the regulation and progression of the cell cycle and mitosis in both normal 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 separation, and dynamics (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, and the ATPase activity within this domain drives unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are responsible for cargo attachment; the "cargo" can include any of a variety of different membranous organelles, signal transduction scaffold systems, and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Thus, kinesins are commonly referred to as "plus-end" or "minus-end" directed motors.

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end directed motor. KIF18A is thought to affect the dynamics of the plus ends of kinetochore microtubules to control proper chromosome positioning and spindle tension. Depletion of human KIF18A results in longer spindles, increased chromosome oscillation at metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology 17, 488-98, 2007). KIF18A appears to be a viable target for cancer therapy. KIF18A is overexpressed in multiple types of cancer, including but not limited to colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, uterine cervical cancer, and ovarian cancer. Additionally, 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 cell arrest, a known vulnerability that can promote mitotic cell death through apoptosis, mitotic catastrophe, or polyploidy-driven lethality or death following mitotic slippage during interphase. Accordingly, there is strong interest in finding inhibitors of the KIF18A protein.

[0006] Accordingly, 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 class of novel compounds that, individually or in combination with microtubules, form binding complexes to modulate the KIF18A protein for treating KIF18A-mediated disorders and / or diseases, including cancer, inflammation, or ciliopathologies.

[0008] The compounds provided by the present invention have MT-based KIF18A regulatory activity, and in particular, KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds and their pharmaceutically acceptable salts in the preparation and manufacture of pharmaceutical compositions or drugs for the therapeutic, prophylactic, acute, or chronic treatment of KIF18A-mediated diseases and disorders, including but not limited to cancer. Accordingly, the compounds of the present invention can be used to manufacture anticancer drugs. The present invention also provides methods for preparing compounds of formula I, as well as intermediates useful in such methods.

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

[0010] or any of its pharmaceutically acceptable salts, wherein:

[0011] R X is selected from H,

[0012] R Xa 、R Xb 、R Xc 、R Xd 、R Xe 、R Xf 、R Xg 、R Xh 、R Xi 、R Xj 、R Xk and R Xl each of which is H, a halogen group, R Xm 、or R Xn ;

[0013] Alternatively, R Xa and R Xb pair, R Xc and R Xd pair, R Xe and R Xf pair, R Xg and R Xh pair, R Xi and R Xj pair, and R Xk and R Xl pair can each independently combine with their respective attached carbon atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro-fused to an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepanyl 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: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OR a 、-OC 1-4 haloalkyl, CN, -NR a R a 、or oxo;

[0014] Alternatively again, R Xa and R Xb pair, R Xc and R Xd pair, R Xe and R Xf pair, R Xg and R Xh pair, R Xi and R Xj pair, and R Xk and R Xl pair can each independently combine to form a double bond;

[0015] R 1 is the group -Z-R 12 ; where Z is absent, is -C 0-4 alkyl-S-C 0-4 alkyl-, C 0-4 alkyl-S(=O)-C 0-4 alkyl-, -C 0-4 alkyl-SO2-C 0-4 alkyl-, -C 0-4 alkyl-NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 SO2-C 0-4 alkyl-, -C 0-4 alkyl-SO2NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 SO2NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-O-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-O-C 0-4 alkyl-, -C 0-4 alkyl-(C=O)NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 (C=O)-C 0-4 alkyl-, -C 0-4 alkyl-S(=O)(=NH)-, -N=S(=O)<, -(C=O)-, or -C(=N-OH)-;

[0016] R 2 is the group -Y-R 13 , where Y is -C 0-4 alkyl-S-C 0-4 alkyl-, C 0-4 alkyl-S(=O)-C 0-4 alkyl-, -C 0-4 alkyl-SO2-C 0-4 alkyl-, -C 0-4 alkyl-NR 13c -C 0-4 alkyl-, -C 0-4 alkyl-SO2NR 13c -C 0-4 alkyl-, -C0-4 alkyl-NR 13c SO2-C 0-4 alkyl-, -C 0-4 alkyl-S(=O)(=NH)-, -C 0-4 alkyl-O-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-O-C 0-4 alkyl-, -C 0-4 alkyl-(C=O)NR 13c -C 0-4 alkyl-, -C 0-4 alkyl-NR 13c (C=O)-C 0-4 alkyl-, - or -N=S(=O)<;

[0017] R 3 is H, halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0018] R 4 is H, halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0019] R 5 is H, halo, C 1-8 alkyl, or C 1-4 haloalkyl;

[0020] R 6 is H, halo, C 1-8 alkyl, or C 1-4 haloalkyl;

[0021] R 7 is H, halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0022] R 8 is H, halo, C 1-8 alkyl, or C 1-4 haloalkyl;

[0023] Or alternatively, R 2 and R 8may combine with the respective carbon atoms to which they are attached to form a saturated or partially saturated 5- or 6-membered monocyclic ring fused to a benzene ring; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein the 5- or 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OR a 、-OC 1-4 haloalkyl, CN, -NR a R a 、or oxo;

[0024] R 9 is H, halo, C 1-4 alkyl, or C 1-4 haloalkyl;

[0025] L is -(C=O)-NR 10 - or -NR 10 -(C=O)-;

[0026] R 10 is H or C 1-4 alkyl;

[0027] R 11 is H or C 1-4 alkyl;

[0028] R 12 is H, halo, OH, CN, R 12a 、or R 12b ;

[0029] R 13 is halo, R 13a or R 13b ;

[0030] R 13c is H or C 1-4 alkyl;

[0031] R 12a and R 13a in each case independently are selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 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, which are substituted with 0, 1, 2 or 3 groups selected from the group consisting of: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OR a 、-OC 1-4 haloalkyl, CN, -C(=O)Rb 、 -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 Ra , -C 1-6 alkyl C(=O)OR a , saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic, and oxo;

[0032] R 12b and R 13b are each independently selected from the group consisting of C 1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)OR a , -OR a , -OC 1-4 haloalkyl, CN, NH2, NH(CH3), N(CH3)2, and saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic;

[0033] R a is each independently H or R b ; and

[0034] R b is each independently C 1-6 alkyl, phenyl or benzyl, wherein C 1-6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from: halogen, -OH, -OC 1-4 alkyl, -NH2, -NHC 1-4 alkyl, -OC(=O)C 1-4 alkyl, or -N(C 1-4 alkyl)C 1-4 alkyl; and said phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from: halogen, C 1-4 alkyl, C 1-3 haloalkyl, -OH, -OC 1-4 alkyl, -NH2, -NHC 1-4 alkyl, -OC(=O)C 1-4 alkyl, or -N(C 1-4 alkyl)C 1-4 alkyl.

[0035] In Example 2, the present invention provides a compound wherein R X is selected from H,

[0036]

[0037] wherein R Xa , R Xb , R Xc , and R XdEach of them is H, a halogen group, R Xm , or R Xn ;

[0038] Alternatively, R Xa and R Xb pair, and R Xc and R Xd pair can each independently combine with their respective attached carbon atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro-fused 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: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OR a , -OC 1-4 haloalkyl, CN, -NR a R a , or oxo;

[0039] Alternatively again, R Xa and R Xb pair or R Xc and R Xd pair can each independently combine to form a double bond.

[0040] In sub-example 2a, the present invention provides a compound wherein R X is

[0041] In sub-example 2b, the present invention provides a compound wherein R X is

[0042] In sub-example 2c, the present invention provides a compound wherein R X is

[0043] In Example 3, the present invention provides a compound wherein R Xa , R Xb , R Xc , and R Xd each is selected from

[0044] a) H, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2F, -CHF2, -CF3, or cyclopropyl; or

[0045] b) Alternatively, R Xa and R Xb pair, and R Xc and RXd Each of the pairs may independently combine with their respective attached carbon atoms to form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring, where each ring is spiro-fused to a pyrrolidinyl, piperidinyl, or morpholinyl ring; and where each of said rings is substituted with 0, 1, 2, or 3 groups selected from: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, or methoxy; or

[0046] c) Alternatively, R Xa and R Xb pair or R Xc and R Xd each of the pairs may independently combine to form >C=CH or >C=CH-CH3; and

[0047] wherein R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk and R Xl each is H, F, or methyl.

[0048] In Example 4, the present invention provides a compound wherein L is -NR 10 -(C=O)-.

[0049] In Example 5, the present invention provides a compound wherein L is -(C=O)-NR 10 -.

[0050] In Example 6, the present invention provides a compound wherein L is -NR 10 -(C=O); having formula (Ia): wherein R X is preferably

[0051] In Example 7, the present invention provides a compound wherein L is -(C=O)-NR 10 -; having formula (Ib): wherein R X is preferably

[0052] In Example 8, the present invention provides a compound wherein R X is

[0053] In Example 9, the present invention provides a compound wherein R 10 is H or methyl.

[0054] In Example 10, the present invention provides a compound, wherein Z is absent, -SO2-, -CH2-SO2, -NH-, -NHSO2-, -SO2NH-, -SO2N(CH3)-, -O-, -(C=O)O-, -(C=O)NH-, -(C=O)N(CH3)-, -S(=O)(=NH)-, -CH2-N(CH3)-, or -C(=N-OH)-.

[0055] In Example 11, the present invention provides a compound, wherein R 12 is selected from:

[0056] a) H, F, Br, OH, or CN;

[0057] b) R 12a is selected from saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocycles containing 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which are substituted with 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, methyl, ethyl, -CF3, -CH2OH, -OH, -OCH3, -NH2, or oxo; or

[0058] c) R 12b is selected from C 1-6 alkyl substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, -CF3 or -OH.

[0059] In Example 12, the present invention provides a compound, wherein R 12 is: R 12a is selected from cyclopropyl, oxetanyl, imidazolyl, isothiazolidinyl, azetidinyl, oxazolyl, pyrazolyl or diaziridinyl; each of which is independently substituted with 0, 1, 2 or 3 groups selected from the following: methyl, ethyl, -CF3, or oxo; or R 12b is selected from methyl, ethyl, isopropyl, tert-butyl, -vinyl, which is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, -CF3 or -OH.

[0060] In Example 13, the present invention provides a compound, wherein R 1 is the group -Z-R 12 , wherein Z is absent, -SO2-, -CH2SO2-, -(C=O)NH-, -NH-, -NHSO2- or -SO2NH-; and R 12 is cyclopropyl, oxetanyl, azetidinyl or imidazolyl ring, each of which is independently substituted with 0, 1 or 2 groups selected from the following: methyl, -CF3, or oxo; or R 12is methyl, ethyl, isopropyl or tert-butyl, each independently substituted with 0, 1, 2 or 3 F, -CF3 or OH groups.

[0061] In Example 14, the present invention provides a compound, wherein R 1 is the group -Z-R 12 , wherein Z is -NHSO2- and R 12 is -CH2-CH2-OH or -CH(CH3)CH2OH.

[0062] In Example 15, the present invention provides a compound, wherein Y is absent, is -SO2NH-, -NH-, -SO2-, -S(=O)(=NH)-, or -O-.

[0063] In Example 16, the present invention provides a compound, wherein R 13 is H or F; R 13a is selected from morpholinyl, piperidinyl, cyclopentyl, cyclopropyl, azetidinyl or oxetanyl; wherein each said ring is substituted with 0, 1, 2 or 3 OH groups selected from methyl or -OH; or R 13b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl or isopentyl; each independently substituted with 0, 1, 2 or 3 OH groups.

[0064] In Example 17, the present invention provides a compound, wherein R 2 and R 8 may combine with the carbon atoms to which they are attached to form a saturated or partially saturated 6-membered monocyclic ring fused to the benzene ring; wherein said 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and further, wherein said 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, or oxo.

[0065] In Example 18, the present invention provides a compound, wherein R 4 is H.

[0066] In Example 19, the present invention provides a compound, wherein R 5 is H.

[0067] In Example 20, the present invention provides a compound, wherein R 6 is H or F.

[0068] In Example 21, the present invention provides a compound, wherein R 7 is H or F.

[0069] In Example 22, the present invention provides a compound, wherein R 8 is H, F or methyl; or alternatively, R 2 and R 8 may combine with the carbon atoms to which they are attached to form a saturated 6-membered monocyclic ring fused to the benzene ring; selected from the group consisting of:

[0070]

[0071] In Example 23, the present invention provides a compound, wherein R 2 is:

[0072] a) the group -Y-R 13a , where Y is absent or is -S(=O)(=NH)-; and R 13 is piperidinyl or azetidinyl; where each said ring is independently substituted with 0, 1, 2 or 3 F groups;

[0073] b) the group -Y-R 13b , where Y is -SO2NH-, -O-, NH-; and where R 13b is tert-butyl substituted with 0, 1, 2 or 3 OH groups; or

[0074] c) alternatively, combines with the carbon atoms to which R 2 and R 8 are attached to form a saturated 6-membered monocyclic ring fused to the benzene ring; which is wherein the 6-membered monocyclic ring is unsubstituted.

[0075] In Example 24, the present invention provides a compound, wherein R 2 is a -SO2NH-tert-butyl group or a -NH-tert-butyl-OH group.

[0076] In Example 25, the present invention provides a compound, wherein R 8 is H.

[0077] In Example 26, the present invention provides a compound, wherein R 9 is H.

[0078] In Example 27, the present invention provides a compound, wherein R 10 is H.

[0079] In Example 28, the present invention provides a compound or a pharmaceutically acceptable salt thereof, selected from:

[0080] In Example 29, the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound being selected from the group consisting of:

[0081] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0082] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0083] N-(3-Isopropylphenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0084] N-(3-Cyclopropylphenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0085] N-(3-(tert-Butyl)phenyl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0086] 4-(Methylsulfonyl)-N-(quinolin-8-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0087] N-(4-Methylquinolin-8-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0088] N-(Chroman-8-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0089] N-(Benzofuran-7-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0090] N-(Benzo[b]thiophen-7-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0091] 4-(Methylsulfonyl)-N-(3-morpholinophenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0092] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0093] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0094] 4-(N-(tert-Butyl)sulfamoyl)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0095] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0096] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(3-hydroxyoxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0097] N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0098] N-(2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0099] N-(2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0100] N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0101] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0102] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0103] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0104] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0105] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(cyclopropanesulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0106] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1,1-dimethylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0107] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,1-dioxoisothiazolidin-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0108] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0109] (R)-4-((2-Hydroxyethyl)sulfamoyl)-N-(3-(2-methylmorpholino)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0110] (R)-N-(2-Fluoro-3-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0111] (R)-N-(3-Fluoro-5-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0112] (R)-N-(4-Fluoro-3-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0113] N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0114] N-(3-(4,4-Difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0115] N-(3-(4,4-Difluoropiperidin-1-yl)-2-fluorophenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0116] (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0117] (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0118] N-(3-(2-Hydroxy-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0119] 4-(Azetidin-1-ylsulfonyl)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0120] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0121] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0122] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N,N-Dimethylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0123] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-Methylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0124] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(Oxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0125] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-Cyclopropylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0126] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(1-methylcyclopropyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0127] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-4-sulfamoylbenzamide;

[0128] (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0129] (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0130] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-imidazol-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0131] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0132] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0133] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(oxazol-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0134] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0135] N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)benzamide;

[0136] N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(2-hydroxyethyl)-2-(6-azaspiro[2.5]oct-6-yl)terephthalamide;

[0137] N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -methyl-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide;

[0138] N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(2-hydroxyethyl)-N 4 -methyl-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide;

[0139] N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(1-hydroxy-2-methylpropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide;

[0140] N 1 -(3-(cyclopentanesulfonyl)phenyl)-N 4 -(2-hydroxyethyl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide;

[0141] (R)-N-(3-(azetidine-1-sulfinyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide;

[0142] (S)-N-(3-(azetidine-1-sulfinyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide;

[0143] (R)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(S-methylsulfinyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide;

[0144] (S)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(S-methylsulfinyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide;

[0145] (R)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(2-methylpropan-2-ylsulfinyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide;

[0146] (S)-4-((2-Hydroxyethyl)sulfonamido)-N-(3-(2-methylpropan-2-ylsulfinyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; or

[0147] N-(4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-3-(piperidin-1-yl)benzamide.

[0148] In Example 30, the present invention provides a compound or a pharmaceutically acceptable salt thereof, said compound being selected from the group consisting of:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] or any pharmaceutically acceptable salt thereof.

[0155] Another aspect of the present invention is a pharmaceutical composition, which comprises a novel class of compounds or pharmaceutically acceptable salts thereof, which can be used to regulate the KIF18A protein alone or in combination with microtubules to form a complex.

[0156] In Example 31, the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising a compound according to any one of Examples 1-30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0157] Yet another aspect of the present invention is a method for treating a disorder treatable with a KIF18a inhibitor, said method comprising administering to a patient in need thereof a therapeutically effective amount of a novel class of compounds or pharmaceutically acceptable salts thereof, which can be used to regulate the KIF18A protein alone or in combination with microtubules to form a complex.

[0158] In Example 32, the present invention provides a method for treating a disorder treatable with a KIF18a inhibitor, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Examples 1-30 or a composition according to Example 31.

[0159] In Example 33, the present invention provides the method according to Example 32, wherein the disorder is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenous tumor selected from the following cancers: bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid system selected from the following: leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma; (c) a hematopoietic tumor of the myeloid system selected from the following: acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, or Kaposi's sarcoma.

[0160] In sub - embodiment 33a, the present invention provides the method according to embodiment 32, wherein the disease is cancer selected from the group consisting of melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma or leukemia. See: Zhang C. et al., “Kif18A is involved in human breast carcinogenesis”, Carcinogenesis, 2010.09; 31(9):1676 - 84. doi:10.1093 / carcin / bgq134. Epub 2010 Jul 1. Also see: (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.

[0161] In embodiment 34, the present invention provides a method for reducing the size of a solid tumor in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to embodiments 1 - 30 or a composition according to embodiment 31.

[0162] In embodiment 35, the present invention provides a method for treating a cell proliferation disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to embodiments 1 - 30 or a composition according to embodiment 31.

[0163] In Example 36, the present invention provides a method for inhibiting KIF18A in cells, the method comprising contacting the cells with a compound according to Examples 1-30 or a pharmaceutically acceptable salt thereof or a composition according to Example 31.

[0164] Another aspect of the present 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 form a complex to regulate KIF18A protein.

[0165] In Example 37, the present invention provides a method for preparing a compound of formula (I) as described herein.

[0166] In Example 38, the present invention provides an intermediate compound used in the method for preparing a compound of formula (I) as described herein. Detailed Description

[0167] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.

[0168] Examples of isotopes suitable for inclusion in the compounds of the present 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, such as 38 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 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 P and isotopes of sulfur, such as 35 S.

[0169] Certain isotopically labeled compounds of the present invention, such as compounds incorporating radioactive isotopes, can be used in drug and / or substrate tissue distribution studies. Given the ease of incorporation and ready means of detection, the radioactive isotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose.

[0170] With heavier isotopes (such as deuterium, i.e., 2H) Substitution can provide certain therapeutic advantages arising from higher metabolic stability (e.g., extended in vivo half-life or reduced dose requirements), and is thus preferred in some cases.

[0171] Substitution with a positron-emitting isotope, such as 11 C, 18 F, 15 O and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0172] The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the appended examples and preparations, using appropriately isotopically labeled reagents in place of the previously employed unlabeled reagents.

[0173] Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0174] Particular embodiments of the present invention include the compounds exemplified in the following examples and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof.

[0175] Unless otherwise specified, the following definitions apply to the terms used in this specification and claims:

[0176] “C α-β alkyl” means an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship or any combination of the three, where α and β represent integers. The alkyl groups described in this section may also contain one or two double or triple bonds. The name C0 alkyl indicates a direct bond. C 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0177]

[0178] “Benzo group” alone or in combination means a divalent group C4H4=, where one representation is -CH=CH-CH=CH-, which forms a benzene-like ring when attached ortho to another ring - for example, tetralin, indole, etc.

[0179] The terms “oxo” and “thio” represent =O (such as a carbonyl group) and =S (such as a thiocarbonyl group), respectively.

[0180] “Halogenated” or “halogen” means a halogen atom selected from F, Cl, Br, and I.

[0181] “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.

[0182] N(R a )R a Groups such as include substituents in which two R a groups together form a ring (optionally containing N, O, or S atoms), and include the following groups, for example:

[0183]

[0184] The group N(C α-β alkyl)C α-β alkyl (where α and β are as defined above) includes substituents in which two C α-β alkyl groups together form a ring (optionally containing N, O, or S atoms), and include the following groups, for example:

[0185]

[0186] "Bicyclic" means a group having two connected rings. The bicyclic can be carbocyclic (all ring atoms are carbon atoms) or heterocyclic (in addition to carbon atoms, the ring atoms include, for example, 1, 2, or 3 heteroatoms such as N, O, or S). The two rings can both be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene).

[0187] Bicyclics include:

[0188] (a) Spiro compounds, in which the two rings share only a single atom (the spiro atom, which is usually a quaternary carbon). Examples of spiro compounds include, but are not limited to:

[0189]

[0190] (b) Fused bicyclic compounds, in which the two rings share two adjacent atoms. In other words, the rings share a covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclics include, but are not limited to:

[0191]

[0192] And

[0193] (c) Bridged bicyclic compounds, in which two rings share three or more atoms and the two bridgehead atoms are separated by a bridge containing at least one atom. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be considered as a pair of cyclopentane rings, each sharing three of their five carbon atoms. Examples of bridged bicyclics include, but are not limited to:

[0194]

[0195] Unless otherwise indicated, "carbocyclic" or "carbocyclic ring" means a ring, alone or in combination with other terms, representing the cyclic form of "C α-β alkyl". Examples of carbocycles include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylidene, cyclohexylidene, etc.

[0196] "Heterocyclic" or "heterocyclic ring" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may appear in the claims include, but are not limited to, the following:

[0197]

[0198] "Pharmaceutically acceptable salts" means salts prepared by conventional methods and well known to those skilled in the art. "Pharmaceutically acceptable salts" include basic salts of inorganic and organic acids, said 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 acidic functional groups such as carboxyl groups, then suitable pharmaceutically acceptable cation pairs for the carboxyl groups are well known to those skilled in the art and include alkali metals, alkaline earth metals, ammonium, quaternary ammonium cations, etc. For additional examples of "pharmaceutically acceptable salts", see below and Berge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66:1 (1977).

[0199] "Saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen, and substituents partially saturated with hydrogen.

[0200] "Leaving group" generally refers to a group that is easily displaced 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, tosylates, etc. Preferred leaving groups are indicated herein where appropriate.

[0201] "Protecting group" generally refers to a group well-known in the art, which is used to prevent undesired reactions of selected reactive groups such as carboxyl, amino, hydroxyl, mercapto groups, etc., such as nucleophilic, electrophilic, oxidation, reduction, etc. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, etc. Examples of aralkyl include, but are not limited to, benzyl, o-methylbenzyl, trityl and diphenylmethyl, which may optionally be substituted by halogen, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, etc., as well as salts (such as phosphonium salts and ammonium salts). Examples of aryl include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthryl, durenyl, etc. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl groups preferably have 6 to 10 carbon atoms and include, but are not limited to, cyclohexenylmethyl, etc. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl include benzyloxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, etc. A mixture of protecting groups can be used to protect the same amino group, e.g., a primary amino group can be protected by both aralkyl and aralkoxycarbonyl. Amino protecting groups can also form heterocycles with the nitrogen to which they are attached, e.g., 1,2-bis(methylene)benzene, phthalimido, succinimido, maleimido, etc., and these heterocyclic groups can further contain adjacent aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitro-phthalimido. Amino groups can also be protected from undesired reactions, such as oxidation, by forming addition salts (such as hydrochloride, p-toluenesulfonic acid, trifluoroacetic acid, etc.). Many amino protecting groups are also suitable for protecting carboxyl, hydroxyl and mercapto groups. For example, aralkyl. Alkyl is also a group suitable for protecting hydroxyl and mercapto groups, such as tert-butyl.

[0202] A silyl protecting group is a silicon atom optionally substituted with one or more alkyl, aryl, and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane, and diphenylmethylsilyl. Silylation of an amino group provides a mono- or di-silylamino group. Silylation of an amino alcohol compound can result in an N,N,O-trimethylsilyl derivative. Removal of the silyl functionality from a silyl ether functionality is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a separate reaction step or in situ during reaction with an alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or a combined product thereof with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods for preparing 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.

[0203] Protecting groups are removed under conditions that do not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, etc. Preferred methods involve removal of a protecting group, for example, removal of a benzyloxycarbonyl group by palladium-catalyzed hydrogenolysis in a suitable solvent system such as an alcohol, acetic acid, etc., or a mixture thereof. A tert-butoxycarbonyl protecting group can be removed using an inorganic or organic acid (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 obtain the free amine. Carboxyl protecting groups (such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, etc.) can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0204] It should be noted that the compounds of the present invention can contain groups that can exist in tautomeric forms, such as cyclic and acyclic amidines and guanidino groups, heteroaryl groups substituted with heteroatoms (Y' = O, S, NR), etc., which are illustrated in the following examples:

[0205]

[0206] Although one form is named, described, shown, and / or claimed herein, all tautomeric forms are intended to be inherently included in such name, description, showing, and / or claim.

[0207] The present invention also contemplates prodrugs of the compounds of the present invention. A prodrug is an active or inactive compound that is chemically modified in vivo, such as by hydrolysis, metabolism, etc., to the compound of the present invention after administration of the prodrug to a patient. The applicability and techniques related 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 a variety of esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkoxycarbonyloxyalkyl (e.g., pivaloyloxymethyl). Amines have been masked as derivatives substituted with arylcarbonyloxymethyl, which are cleaved by esterases in vivo to release 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 (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 Mannich base hydroxamic acid prodrugs, their preparation, and uses.

[0208] This specification and the claims contain species listings (sometimes referred to as Markush groups) using the language "selected from... and..." and "being... or...". When this language is used in the present application, unless otherwise indicated, it is meant to include the group as a whole, or any single member thereof, or any subgroup thereof. The use of this language is for shorthand purposes only and is not meant to limit in any way the removal of individual elements or subgroups as needed.

[0209] Drug Compositions, Routes of Administration and Administration

[0210] Also provided herein are pharmaceutical compositions that comprise a compound as disclosed herein and a pharmaceutically acceptable excipient, such as a diluent or a carrier. The compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an effective amount to achieve its intended purpose. The administration of the compound will be described in more detail below.

[0211] Suitable pharmaceutical formulations can be determined by one of ordinary skill in the art based on the route of administration and the desired dosage. See, e.g., Remington’s Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co., Easton, Pa., 1990). The formulation can affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agent. Depending on the route of administration, the appropriate dosage can be calculated based on body weight, body surface area, or organ size. One of ordinary skill in the art can make further refinements to the calculations required to determine the appropriate therapeutic dose in a conventional manner, particularly based on the dosage information and assays disclosed herein and pharmacokinetic data obtainable from animal or human clinical trials.

[0212] The phrases “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse reactions, allergic reactions, or other untoward reactions when administered to an animal or a human. As used herein, “pharmaceutically acceptable” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such excipients in connection with a pharmaceutically active substance is well known in the art. Unless any conventional medium or agent is incompatible with the therapeutic composition, it is contemplated for use in the therapeutic composition. Supplementary active ingredients can also be incorporated into the compositions. In an exemplary embodiment, the formulation can include 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-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, cupric sulfate, thiamine hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenite, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0213] A compound can exist in a pharmaceutical composition as a pharmaceutically acceptable salt. As used herein, “pharmaceutically acceptable salt” includes, for example, base addition salts and acid addition salts.

[0214] Pharmaceutically acceptable base addition salts can be formed with metals or amines (such as alkali metals, alkaline earth metals or organic amines). Pharmaceutically acceptable salts of the compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali 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 trivalent, etc. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

[0215] Pharmaceutically acceptable acid addition salts include inorganic acid salts or organic acid salts. Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, phosphate. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include salts of, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; salts with organic formic acids, sulfonic acids, thioacids or phosphonic acids or N-substituted aminosulfonic acids, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, pamoic acid, nicotinic acid or isonicotinic acid; and salts with amino acids, such as the 20 α-amino acids involved in protein synthesis in nature, such as glutamic acid or aspartic acid, and salts with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2-phosphoglyceric acid or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylaminosulfonic acid (for the formation of cyclohexylaminosulfonates), or salts with other acidic organic compounds, such as ascorbic acid.

[0216] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulating, sugar coating, milling, emulsifying, encapsulating, entrapping or lyophilization methods. Suitable formulations depend on the chosen route of administration.

[0217] 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 compounds of the invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding solid excipients to the compounds disclosed herein, optionally grinding the resulting mixture, and processing the granule mixture, if necessary after adding suitable auxiliaries, to obtain tablet or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can 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, auxiliaries, antimicrobial agents, antioxidants, and carriers for various types of formulations.

[0218] When orally administering a therapeutically effective amount of the compounds disclosed herein, the composition is generally in the form of a solid (e.g., tablets, capsules, pills, powders, or lozenges) or a liquid formulation (e.g., an aqueous suspension, solution, elixir, or syrup).

[0219] When administered in tablet form, the composition can additionally contain functional solids and / or solid carriers, such as gelatin or auxiliaries. Tablets, capsules, and powders can contain from about 1% to about 95% of the compound, and preferably from about 15% to about 90% of the compound.

[0220] When administered in liquid or suspension form, functional liquids and / or liquid carriers, such as water, petroleum, or oils of animal or vegetable origin, can be added. The liquid form of the composition can further contain saline solutions, sugar alcohol solutions, dextrose or other sugar solutions, or diols. When administered in liquid or suspension form, the composition can contain from about 0.5% to about 90% by weight of the compounds disclosed herein, and preferably from about 1% to about 50% of the compounds disclosed herein. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition can be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0221] When administering a therapeutically effective amount of a compound disclosed herein by 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 full account of pH, isotonicity, stability, etc. and is within the scope of those skilled in the art. In addition to the compounds disclosed herein, preferred compositions for intravenous, transdermal or subcutaneous injection generally contain an isotonic vehicle. Such compositions can be prepared for administration as a solution in water of the free base or a pharmaceutically acceptable salt, appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures, and in oils. Under ordinary storage and use conditions, these preparations can optionally contain preservatives to prevent the growth of microorganisms.

[0222] Injectable compositions can include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy injectability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi, optionally including a preservative. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one embodiment contemplated, the carrier is non-aqueous or substantially non-aqueous. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin; by maintaining the required particle size of the compounds in the case of dispersions; and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, the inclusion of isotonic agents such as sugars or sodium chloride will be preferred. Prolonged absorption of injectable compositions can be achieved by the use of absorption delaying agents such as aluminum monostearate and gelatin in the compositions.

[0223] Sterile injectable solutions are prepared by incorporating the active compound in the required amount into a suitable solvent, optionally containing various other ingredients enumerated above, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients and other required ingredients from those enumerated above into a sterile vehicle containing a base dispersion medium. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any other required ingredients from its previously sterile-filtered solution.

[0224] It is also possible to prepare slow-release or sustained-release formulations to achieve controlled release of the active compound in contact with body fluids in the gastrointestinal tract and to provide a substantially constant and effective level of the active compound in the plasma. For example, the release can be controlled by one or more of dissolution, diffusion, and ion exchange. Additionally, the slow-release method can facilitate absorption through saturable or restricted pathways within the gastrointestinal tract. For example, for this purpose, the compound can be encapsulated in a polymeric 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 polymeric matrix. Controlled-release formulations are also obtained by encapsulating the dispersed microparticles or emulsified droplets via known dispersion or emulsion coating techniques.

[0225] For administration by inhalation, the compounds of the present invention are conveniently delivered from a pressurized package or nebulizer in the form of an aerosol spray using a suitable propellant. In the case of a pressurized aerosol, the dose unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, such as gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder matrix, such as lactose or starch.

[0226] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations can be presented in unit dosage forms (e.g., in ampoules or in multi-dose containers) and are added with preservatives. The compositions can take forms such as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents.

[0227] Pharmaceutical formulations for parenteral administration include aqueous solutions of the compounds in water-soluble form. Additionally, suspensions of the compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0228] The compounds disclosed herein may also be formulated in rectal compositions, such as suppositories or retention enemas (e.g., containing conventional suppository bases). In addition to the formulations previously described, the compounds may be formulated as long-acting preparations. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or ion exchange resins, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

[0229] In particular, 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, either alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid formulations may be prepared with pharmaceutically acceptable additives (e.g., suspending agents). The compounds may also be injected parenterally, e.g., intravenously, intramuscularly, subcutaneously or intracoronarily. 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 render the solution isotonic with blood.

[0230] For veterinary use, the compounds disclosed herein are administered as suitably acceptable formulations according to normal veterinary practice. A veterinarian can readily determine the most suitable dosing regimen and route of administration for a particular animal.

[0231] In some embodiments, all the necessary components for using the compounds disclosed herein, either alone or in combination with another agent or intervention conventionally used to treat the disease, for treating KIF18A-related disorders may be packaged into a kit. Specifically, the present invention provides a kit for therapeutic intervention of a disease, the kit comprising a packaged set of medicaments, including the compounds disclosed herein and buffers and other components for preparing the deliverable form of the medicaments; and / or a device for delivering such medicaments; and / or any agent for combination therapy with the compounds disclosed herein; and / or instructions for treating the disease packaged together with the medicaments. The instructions may be fixed in any tangible medium, such as printed paper, or computer-readable magnetic or optical medium, or instructions referring to a remote computer data source (e.g., a World Wide Web page accessible via the Internet).

[0232] "Therapeutically effective amount" means an amount effective to treat or prevent the development of an existing condition or to alleviate an existing condition in a subject being treated. In particular, based on the detailed disclosure provided herein, determination of an effective amount is well within the ability of those skilled in the art. Generally, a "therapeutically effective dose" refers to the amount of a compound that results in the achievement of the desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KIF18A activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90% compared to a control group.

[0233] The amount of the 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 mode and frequency of treatment, and the judgment of the prescribing physician. The dosing frequency can also depend on the pharmacodynamic effect on arterial oxygen partial pressure. Although individual requirements vary, determination of the optimal range of an effective amount of the compound is within the skill of the art. Such doses can be administered in a single dose, or they can be divided into multiple doses.

[0234] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers 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, as used herein, the term "cancer" is not limited to any particular form of the disease, it is believed that the methods of the present invention are particularly effective for detecting cancers associated with unregulated KIF18A levels or dependent on KIF18A, which is required for proper chromosome segregation and survival in mammals.

[0235] As used herein, the terms "treat", "treating" and "treatment" refer to therapy, including but not limited to curative therapy, prophylactic therapy, and preventive therapy. Prophylactic treatment generally includes completely preventing the onset of an individual's disease or delaying the onset of the clinically apparent stage of an individual's disorder.

[0236] 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.

[0237] The term "comprising / including" means open-ended, including the one or more components indicated, but not excluding other elements.

[0238] The term "Formula I" includes any sub-formula.

[0239] Methods of using KIF18A inhibitors

[0240] The present disclosure provides compounds that generally have MT-based KIF18A modulating activity, particularly inhibitory activity. In one embodiment of the invention, a method for modulating KIF18A protein in a subject is provided, the method comprising administering to the subject an effective dose of a compound of Formula I. Thus, the compounds of the present invention can be used to treat cell proliferation disorders, including uncontrolled cell growth, abnormal cell cycle regulation, centrosome abnormalities (structural and / or numerical, fragmentation). Other diseases or disorders associated with the accumulation of extra centrosomes (>2) include human papillomavirus (HPV) infections, including HPV-related tumors. The compounds can also be used for cilia-related diseases and ablation of haploid germ cell populations that can be used as male contraceptives.

[0241] In addition, the compounds of the present invention can be used for, but are not limited to, preventing or treating 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 hematogenous tumors, such as carcinomas, including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including squamous cell carcinoma and small cell lung cancer), esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma); hematopoietic tumors of the myeloid lineage (including acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma and other sarcomas, such as soft tissue and bone); central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular carcinoma, or Kaposi's sarcoma).

[0242] The compounds of the present invention can also be used to treat cancer-related indications, such as solid tumors, sarcomas (particularly Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, hematopoietic malignancies (including leukemia and lymphoma), pleural or pericardial effusions caused by tumors, and malignant ascites.

[0243] Based on the ability to modulate kinesin and affect angiogenesis, the compounds of the present 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 for the treatment of motor performance, such as various inflammatory rheumatoid diseases, especially chronic polyarthritis, including rheumatoid arthritis, juvenile arthritis or psoriatic arthritis; tumor-associated syndromes or tumor-induced inflammatory diseases, turbid effusions, collagen diseases, such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma or mixed collagen diseases; post-infectious arthritis (where no live pathogenic organisms are found at or in the affected area of the body), seronegative spondyloarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis or arthropathy; or any further combination thereof.

[0244] The compounds of the present invention can also be used as active agents against such conditions as arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collateralization, colloid local ischemic angiogenesis, wound healing, peptic ulcer, Helicobacter pylori-related diseases, fracture, cat-scratch fever, flushing, neovascular glaucoma and retinopathy (such as retinopathy associated with diabetic retinopathy or macular degeneration). In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperplastic disorders (such as thyroid hyperplasia (especially Graves' disease)) and cysts (such as ovarian stromal vascular hyperplasia, a characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)), since such diseases require vascular cell proliferation for growth and / or metastasis.

[0245] In addition to being used for human treatment, these compounds can also be used for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs and cats can be treated with the compounds provided by the present invention.

[0246] Combination

[0247] Although the compounds of the present invention can be administered or applied as the sole active pharmaceutical reagent, they can also be used in combination with one or more compounds of the present invention or in combination with other reagents. When administered in combination, the therapeutic agents can be formulated into separate compositions, which are administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.

[0248] In the definition of the use of the compounds of the present invention and another pharmaceutical agent, the phrase "combination therapy" (or "combined therapy") is intended to include administering each agent in a sequential manner in a regimen that provides a beneficial combined effect of the drugs, and is also intended to include co-administering these agents in a substantially simultaneous manner, such as in a single capsule with the active agents in a fixed ratio or in multiple separate capsules of each agent.

[0249] Specifically, the administration of the compounds of the present invention can be combined with other therapies for the prevention or treatment of cancer known to those skilled in the art, such as radiotherapy, small molecule targeting agents (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies with tumor or cytotoxic agents (e.g., naked and drug-conjugated), immunotherapy antibodies (checkpoint inhibitors, bispecific T cell engagers).

[0250] If formulated as a fixed dose, such combination products employ the compounds of the present invention within an acceptable dose range. When a combination formulation is not appropriate, the compounds of formula I can also be administered sequentially with known anti-cancer agents or cytotoxic agents. The present invention is not limited to the order of administration; the compounds of the present invention can be administered before, simultaneously with, or after the administration of known anti-cancer agents or cytotoxic agents.

[0251] There are a large number of anti-cancer agents that are commercially available, in clinical evaluation, and available for pre-clinical development, and they can be selected for the treatment of tumors by combination chemotherapy. Such agents are divided into several major categories, such as antibiotic agents, alkylating and alkylating-like agents, anti-mitotic agents, small molecule targeting agents, anti-metabolites, hormonal agents, immunological agents, anti-angiogenic agents, interferon agents, and miscellaneous agent classes.

[0252] The present disclosure also provides methods for combination therapy, wherein agents that are known to modulate other pathways or the same pathway, or even an overlapping set of target enzymes, are used in combination with the compounds of the present disclosure or their pharmaceutically acceptable salts. In one aspect, such therapy includes, but is not limited to, the combination of one or more of the compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, small molecule targeting agents, and radiation therapy to provide a synergistic or additive therapeutic effect.

[0253] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of: anti-mitotic agents, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormonal agents, angiogenesis inhibitors, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules, such as (Imatinib mesylate), (carfilzomib), (bortezomib), Casodex (bicalutamide), (Gefitinib) and doxorubicin (Adriamycin), as well as a variety of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, CasodexTM, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, elsamitrucin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptozocin, streptozotocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thioguanine, tioguanine;Pyrimidine analogs such as azacitidine, aza-cytidine, 6-azauridine, carmofur, cytarabine, didoxuridine, doxifluridine, enocitabine, floxuridine; androgens such as caproterone, dromostanolone propionate, thiotroterone, methandriol, testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; glucuronolactone; aldophosphamide glycoside; aminolevulinic acid; aclarubicin; bestrabucil; bisantrene; edatraxate; defofamine; colchicine amide; diaziquone; eflornithine; elisidepsin; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichloroethylamine; urethan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes such as paclitaxel and docetaxel, nab-paclitaxel; retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.

[0254] Suitable chemotherapeutic cell conditioners also include antihormonal agents for modulating or inhibiting the action of hormones on tumors, such as antiestrogens, including, for example, tamoxifen (NolvadexTM), raloxifene, aromatase inhibitory 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin, oxaliplatin, and carboplatin; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vinblastine, vincristine; vinorelbine; Navelbine; novantrone; teniposide; daunomycin; aminopterin; capecitabine (xeloda); ibandronate; topotecan; irinotecan (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO),

[0255] If desired, the compounds or pharmaceutical compositions of the present disclosure can be used in combination with commonly prescribed anticancer drugs, such as Abraxane, ABVD, Avicine, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, Antitumor drug, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximinesulfoximine), CBV (chemotherapy), Calyculin, cell cycle non-specific anti-tumor agents, dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, 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), tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar, CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, Kisqali; abemaciclib, Verzenio).

[0256] This disclosure further relates to methods of inhibiting abnormal cell growth or treating hyperproliferative disorders in a mammal using a combination of a compound or pharmaceutical composition provided herein and 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 of this disclosure in such combination therapies can be determined as described herein.

[0257] Radiotherapy can be administered by one or a combination of several methods, including but not limited to external beam therapy, brachytherapy, implant radiation, stereotactic radiosurgery, total body radiotherapy, radiotherapy and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiotherapy delivered by spatially confined radioactive material that is inserted into the body at or near the site of a tumor or other hyperplastic tissue lesion. The term is intended to include, without limitation, exposure to radioactive isotopes (e.g., radioactive isotopes of At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and Lu). Suitable radiation sources for use as cell conditioners in this disclosure include solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, 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 slurry of a suitable fluid containing small particles of a solid radionuclide (e.g., Au-198, Y-90). In addition, one or more radionuclides can be encapsulated in a gel or radioactive microspheres.

[0258] The compounds or pharmaceutical compositions of this disclosure can be used in combination with an amount of one or more substances selected from the group consisting of anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors or autophagy inhibitors.

[0259] Angiogenesis inhibitors can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. These angiogenesis inhibitors are, for example, MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors. Angiogenesis inhibitors include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in the following patents: WO 96 / 33172, WO 96 / 27583, 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 931 788, WO 90 / 05719, WO 99 / 52910, WO99 / 52889, WO 99 / 29667, WO 1999007675, European Patent Publication EP 1786785, European Patent Publication No. EP 1181017, US Publication No. US 20090012085, US Patent US 5863 949, US Patent US 5861510, and European Patent Publication EP 0780386, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those having minimal or no activity against MMP-1. More preferred are those that selectively inhibit MMP-2 and / or AMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO 32-3555, and RS13-0830.

[0260] The compounds of the present invention can also be used in combination therapies with other anti-tumor agents, such as acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, amifostine, aminolevulinic acid, amrubicin, aclarubicin, anagrelide, anastrozole, ANCER, ancesim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cimicifugae racemosae rhizoma, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon-α, daunomycin, doxorubicin, tretinoin, edelfosine, eculizumab, eflornithine, emitefur, epirubicin, erythropoietin-β, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, 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, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte α-interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, milgramostim, mismatched double-stranded RNA, mitoguazone, dibromodulcitol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon-α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, peginterferon-α-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium (Re 186) etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachloro-decaoxide, thalidomide, thymalfasin, thyrotropin α, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, tretosuran, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor α, natural bestatin, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimalamer or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin-17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rupatadine, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurinetiopurpurin), tirapazamine, cancer vaccines (Bavarian Nordic), melanoma vaccines (New York University), melanoma vaccines (Sloan Kettering Institute), melanoma tumor lysate vaccines (New York Medical College), viral melanoma cell lysate vaccines (Royal Newcastle Hospital), or valspodar.

[0261] The compounds of the invention can be further used in combination with VEGFR inhibitors. The following other compounds described in the following patents and patent applications can 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.

[0262] In some embodiments, the combination comprises a combination of a composition of the invention with at least one anti-angiogenic agent. Agents include, but are not limited to, chemical compositions prepared synthetically in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof. The agent can be an agonist, antagonist, allosteric modulator, toxin, or more generally, can be used to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or prevent cell growth.

[0263] Exemplary anti-angiogenic agents include ERBITUX TM (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen-binding regions that specifically bind VEGF, or soluble VEGF receptors or their ligand-binding regions) (e.g., AVASTIN TM or VEGF-TRAP TM) and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto) (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 thereto or to its receptor (e.g., Tie2 / Tek)), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the present invention may also comprise one or more agents that specifically bind to growth factors 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 scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor "c-met".

[0264] Other anti-angiogenic agents include alemtuzumab (Campath), IL-8, B-FGF, Tek antagonists (Ceretti et al., US Publication No. 2003 / 0162712; US Patent No. 6,413,932), anti-TWEAK agents (e.g., specific binding antibodies or antigen-binding regions, or soluble TWEAK receptor antagonists; see, Wiley, US Patent No. 6,727,225), ADAM disintegrin domain antagonists that inhibit the binding of integrin to its ligand (Fanslow et al., US Publication No. 2002 / 0042368), specific binding anti-eph receptor and / or anti-ephrin antibodies or antigen-binding regions (US Patent Nos. 5,981,245, 5,728,813 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of its patent family), anti-PDGF-BB antagonists (e.g., specific binding antibodies or antigen-binding regions), and antibodies or antigen-binding regions that specifically bind to the PDGF-BB ligand and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto).

[0265] Other anti-angiogenesis / 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, US 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-angiogenesis agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA);SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Angiostatin (EntreMed, USA); Angiogenesis inhibitor (Tripep, Sweden); Serine protease inhibitor (maspin) (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Flumetralin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); Platelet factor 4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, α5β3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); Gene therapy, retinopathy (Oxford BioMedica, UK); Zeranol hydrochloride (USAN) (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); Angiogenesis inhibitor (Alchemia, Australia); VEGF antagonist (Regeneron, USA); rBPI 21 and BPI-derived anti-angiogenic agent (XOMA, USA);PI 88 (Progen, Australia); cilengitide (pINN) (Merck KGaA, Germany; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); cetuximab (INN) (Aventis, France); AVE 8062 (Ajinomoto, Japan); 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); vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); Wogongteng alcohol (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); metastatin (EntreMed, USA); troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-guanidino promoter (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E 7820 (Eisai, Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); vaccines, angiogenesis inhibitors (EntreMed, USA); urokinase-type plasminogen activator inhibitor (Dendreon, USA); oglufanide (pINN) (Melmotte, USA); HIF-1α inhibitor (Xenova, UK); CEP 5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea);GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan); within drug delivery system, intraocular, 2-methoxyestradiol (EntreMed, USA); pircarzate (anginex) (Maastricht University, Netherlands and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-α inhibitor (National Institute on Aging, USA); SU 11248 (Pfizer, USA and SUGEN, USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson&Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan);Comstatine A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); MAb, Vascular Endothelial Growth Factor (Xenova, UK); Irsogladine (INN) (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (pINN) (Genaera, USA); RPI 4610 (Sirna, USA); Cancer Therapy (Marinova, Australia); Heparanase Inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan);VEGF receptor modulators (Pharmacopeia, USA); VE-cadherin-2 antagonists (ImClone Systems, USA); angiostatin (National Institutes of Health, USA); vaccines, Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); tumstatin (Beth Israel Hospital, USA); short soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin-1 inhibitors (Allegheny Health, Education and Research Foundation, USA).;

[0266] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil TM ) bafilomycin A1, 5-amino-4-imidazolecarboxamide ribonucleoside (AICAR), okadaic acid, autophagy-inhibiting marine toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine ribonucleoside, and vinblastine. Additionally, antisense or siRNA that inhibits protein expression can be used, and these proteins include, but are not limited to, ATG5 (which is involved in autophagy).

[0267] Other pharmaceutically active compounds / agents 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; ansermin; AMG 102; AMG 386; AMG 479; AMG 655; AMG 745; AMG 951; and AMG 706 or a pharmaceutically acceptable salt thereof.

[0268] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents can include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), taxol, epidipodophyllotoxin (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunomycin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and deprives cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, antiproliferative / antimitotic alkylating agents (e.g., nitrogen mustards such as mechlorethamine, e.g., dichloromethyldiethylamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozocin), triazenes-dacarbazinine (DTIC), antiproliferative / antimitotic antimetabolites such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, hydroxamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (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 hormonal agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF-neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., 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., enzastaurin), FTI (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 targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib, Talazoparib, Niraparib, and veliparib (ABT-888)), BCL-2 antagonists. Other chemotherapeutic agents can include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derivative variant of the foregoing.

[0269] The compounds of the invention can also be used in combination with radiotherapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0270] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids can include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoxymethasone, dexamethasone, diflorasone, diflucortolone, difuprednate, glycyrrhetinic acid, flucortolone, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetonide acetate, fluocortin butyl, flucortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, maprednilone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednisolone valerate, prednylidene, rimcazole, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In a particular embodiment, the compounds of the invention can also be used in combination with other pharmaceutically active agents for treating nausea.Examples of agents useful for treating nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0271] The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more substances selected from: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and immunotherapies, including anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

[0272] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNA. Useful EGFR antibody inhibitors include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently lapatinib (TykerB). See, e.g., Yan L et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005; 39(4):565-8 and Paez J G et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304(5676):1497-500.

[0273] Non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitors described in the following patent publications, as well as all pharmaceutically acceptable salts and solvates of said EGFR inhibitors: European Patent Application EP520722, published December 30, 1992; European Patent Application EP 566226, published October 20, 1993; PCT International Publication WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, issued 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 WO97 / 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 WO95 / 19774, published July 27, 1995; PCT International Publication WO 95 / 19970, published July 27, 1995; PCT International Publication WO 97 / 13771, published April 17, 1997; PCT International Publication WO 98 / 02437, published January 22, 1998; PCT International Publication WO 98 / 02438, published January 22, 1998; PCT International Publication WO 97 / 32881, published September 12, 1997; German Application DE 19629652, published 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 WO97 / 02266, published January 23, 1997; PCT International Publication WO 97 / 27199, published July 31, 1997; PCT International Publication WO 98 / 07726, published February 26, 1998; PCT International Publication WO 97 / 34895, published September 25, 1997;PCT International Publication WO 96 / 31510, published 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 97 / 19065, published on May 29, 1997; PCT International Publication WO98 / 17662, published on April 30, 1998; U.S. Patent No. 5,789,427, authorized on August 4, 1998; U.S. Patent No. 5,650,415, authorized on July 22, 1997; U.S. Patent No. 5,656,643, authorized on August 12, 1997; PCT International Publication WO99 / 35146, published on July 15, 1999; PCT International Publication WO 99 / 35132, published on July 15, 1999; PCT International Publication WO 99 / 07701, published on February 18, 1999; and PCT International Publication WO 92 / 20642, published on 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 8(12):1599-1625.;

[0274] 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, S.M. et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X. et al., 1999, Cancer Res. 59:1236-1243. Thus, an EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, ibid.), or Mab C225 (ATCC accession number HB-8508), or an antibody or antibody fragment having its binding specificity.

[0275] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0276] PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxy wortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propanenitrile (also known as BEZ 235 or NVP-BEZ 235 and described in PCT Publication No. WO 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in PCT Publication No. WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI103 hydrochloride (3-[4-(4-morpholinopyrido-[3′,2′:4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (N′-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfonyl-hydrazine hydrochloride, available from Axon Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Axon Medchem), GDC-0941 dimethanesulfonate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine dimethanesulfonate, available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolidine-2,4-dione, available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one, available from Axon Medchem), XL-765, and XL-147.Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0277] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05011700); indole-3-methanol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) JNutr., 134 (12 Suppl.), 3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al., (2004) Clin. Cancer Res., 10 (15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs, 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC154020; Yang et al., (2004), Cancer Res., 64, 4394-9).

[0278] TOR inhibitors include, but are not limited to, inhibitors including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors including PI-103, PP242, PP30 and Torin 1. Other TOR inhibitors include FKBP12 enhancers; rapamycin and its derivatives including: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010) and AP23573; rapalogs 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)methyl propionate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxyrapamycin, 16-pentyloxy-32(S)-dihydrorapamycin and other derivatives disclosed in WO05005434; derivatives disclosed in the following patents: U.S. 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; phosphorous-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Application No. 60 / 528,340).

[0279] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents and anti-OX40 agents. Exemplary anti-PD-1 antibodies and methods of use thereof are described in the following: 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 hereby expressly incorporated by reference. Including: Yervoy TMIpilimumab or tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3475 (against PD-1), AMP224 (against B7DC), BMS-936559 (against B7-H1), MPDL3280A (against B7-H1), MEDI-570 (against ICOS), AMG557 (against B7H2), MGA271 (against B7H3), IMP321 (against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (against OX40L), atacicept (against TACI), CP-870893 (against CD40), lucatumumab (against CD40), dacetuzumab (against CD40), muromonab-CD3 (against CD3), ipilimumab (against CTLA-4). Immunotherapy also includes genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

[0280] 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. 6,111,090 box.c, European Patent No.: 090505B1, U.S. Patent No. 8,586,023, PCT Publication No.: WO 2010 / 003118 and 2011 / 090754, or anti-GITR antibodies described, for example, in the following: 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.: WO 2005 / 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, U.S. Patent No. 7,618,632 and PCT Publication No.: WO 2011 / 051726.

[0281] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Thus, 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 are administered simultaneously or separately from a second agent. Such combination administration can include administering both agents in the same dosage form simultaneously, administering separate dosage forms simultaneously, and administering separately. That is, the compounds described herein and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds disclosed herein and any of the above agents can be administered simultaneously, where the two agents are present in separate formulations. In another alternative, any of the above agents can be administered immediately after administering the compounds disclosed herein, or vice versa. In some embodiments of the separate administration regimen, the compounds disclosed herein and any of the above agents are administered separated by minutes, or by hours, or by days.

[0282] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining individual pharmaceutical compositions in the form of a kit. The kit comprises two individual pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit comprises containers for holding the individual compositions, such as separate bottles or separate foil pouches. Other examples of containers include syringes, cartridges, and bags. In some embodiments, the kit comprises instructions for use of the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosage intervals, or when titration of the individual components in the combination is required by the prescribing healthcare professional.

[0283] Experiment

[0284] Abbreviations: The following abbreviations may be used herein:

[0285]

[0286]

[0287]

[0288] Unless otherwise stated, all materials were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all parts are by weight and temperatures are in °C. All microwave-assisted reactions were carried out using Biotage TM Smith Synthesizer TM and were performed. All compounds showed NMR spectra consistent with their assigned structures. Melting points were determined on a Buchi apparatus and were not corrected. Mass spectral data were determined by electrospray ionization techniques. All examples were purified to >90% purity as determined by high-performance liquid chromatography. Unless otherwise stated, reactions were carried out at room temperature.

[0289] In synthesizing the compounds of the present invention, it may be desirable to use certain leaving groups. The term "leaving group" ("LG") generally refers to a group that can be displaced by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates / esters such as mesylates / tosylates, sulfides (e.g., SCH3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), and the like.

[0290] The examples presented below illustrate specific embodiments of the present invention. These examples are representative and are not intended to limit the scope of the claims in any way.

[0291] It should be noted that when using percentages (%) with respect to liquids, this is the volume percentage relative to the solution. When used with solids, this is the percentage relative to the solid composition. Materials obtained from market suppliers are generally used without further purification. Reactions involving air- or moisture-sensitive reagents are typically carried out under a nitrogen or argon atmosphere. Purity is 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 75 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 generally carried out using pre-packed silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, NE). 1 1H NMR spectra were recorded at ambient temperature on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian 400 MHz spectrometer (Agilent Technologies, Santa Clara, CA). All observed protons were reported in parts per million (ppm) at low field relative to tetramethylsilane (TMS) or other internal references in the appropriate solvent specified. The data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad peak, m = multiplet), coupling constant, and number of protons. Low-resolution mass spectrometry (MS) data were determined on an Agilent 1100 series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm and in low-resolution electrospray ionization (ESI) mode.

[0292] General synthetic scheme

[0293] Unless otherwise indicated, starting materials and reagents used to prepare these compounds are available from commercial suppliers (such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St Louis, Mo.)) or can be prepared by methods known to those skilled in the art following procedures set forth, for example, 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 of the ways in which the compounds of the present invention can be synthesized, and various modifications to these schemes can be made and will be suggested to those skilled in the art referring to this disclosure. Starting materials, intermediates, and final 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 means, including physical constants and spectral data.

[0294] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure and within the following temperature ranges: 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).

[0295] For clarity purposes in this general synthesis section, the compound of formula (I) can be schematically drawn to include ring Ar 1 and ring Ar 2 , as follows:

[0296] wherein the group L is a linker as defined in the Summary of the Invention, i.e., -NR 3 -(C=O)- or -NR 3 -(C=O)-; ring Ar 1 is located on the left side of the linker, and ring Ar 2 is located on the right side of the linker.

[0297] Generally, the compound of formula (I) can be synthesized as follows through the following three general steps:

[0298] Step 1: Preparation of the compound of ring Ar 1 .

[0299] Step 2: Preparation of the compound of ring Ar 2 .

[0300] Step 3: Coupling of the compound of ring Ar 1 with the compound of ring Ar 2 .

[0301] The general schemes below are intended to provide guidance to the average synthetic chemist, who will readily understand that the solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, etc. can be modified as needed, which are entirely within the skill and judgment of the person of ordinary skill in the art.

[0302] In one embodiment, the compound of formula (I) has the following formula (Ia):

[0303] It can be synthesized according to Schemes A and B.

[0304] Examples of the compound of formula (Ia) include but are not limited to:

[0305]

[0306] Scheme A: Preparation of Compound (Ia):

[0307] Step A-1: Ring Ar 1 Preparation of the compound:

[0308] According to Scheme A, in one embodiment, the compound of ring Ar 1 can be prepared as follows:

[0309]

[0310] Compound A-1 (where the group W 1is a leaving group, such as a halogen group, such as fluorine, chlorine, bromine or iodine; commercially available or can be prepared according to methods and reagents known to those skilled in the art), can, in the presence of a base (such as diisopropylethylamine, potassium carbonate or sodium hydride), in a suitable organic solvent (such as NMP, acetonitrile, tetrahydrofuran, DMF, dioxane, etc.) react with a suitable R 2 reagent (such as (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethan-1-ol, or (6) 2-amino-3-methylpropan-1-ol) to form compound A-2. Examples of compound A-1 include but are not limited to 1-fluoro-3-nitrobenzene, 1,3-difluoro-5-nitrobenzene, 1-fluoro-3-methylbenzene or 2-bromo-1-fluoro-4-nitrobenzene. Examples of compound A-2 include (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine, 4-(3-fluoro-5-nitrophenyl)morpholine, (R)-2-methyl-4-(3-methyl-5-nitrophenyl)morpholine, or 4,4-difluoro-1-(3-fluoro-5-nitrophenyl)piperidine. Then compound A-2 can react with a reducing agent such as hydrogen in the presence of a suitable catalyst such as Pd / C in a suitable organic solvent such as MeOH, EtOH, THF, etc. to form compound A-3. Examples of compound A-3 include (R)-3-fluoro-5-(2-methylmorpholino)aniline, (R)-3-methyl-5-(2-methylmorpholino)aniline, or 3-(4,4-difluoropiperidin-1-yl)-5-fluoroaniline.

[0311] Alternatively, compound A-1 can be converted to compound A-3 in a one-pot synthesis as described in step 1a above without further purifying compound A-2.

[0312]

[0313] Alternatively, compound A-1 can be converted to compound A-2 as defined in step 1a above by metal-catalyzed amination, where a suitable palladium or copper catalyst and a base are used. After this step, reduction can be carried out in the presence of hydrogen with a suitable palladium catalyst and a hydrogen source (such as Pd / C) to form compound A-2.

[0314] Alternatively, compound A-2 is commercially available. An example of a commercially available compound A-2 is 3-amino-N-(tert-butyl)benzenesulfonamide.

[0315] Step A-2: Ring Ar 2 Preparation of the compound:

[0316]

[0317] In step A-2, compound A-4 (wherein each of W 2 and W 3 is independently a halogen, such as fluorine, chlorine, bromine or iodine) can be reacted with an R X reagent (such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride or (5) 7-azaspiro[3.5]nonane hydrochloride) in a suitable organic solvent (such as NMP, acetonitrile, tetrahydrofuran, DMF, DMSO, etc.) to form compound A-5. Examples of compound A-4 that can be reacted in this way include 4,6-dichloronicotinic acid, 2-fluoro-4-iodobenzoic acid or 4,6-difluoro-nicotinic acid.

[0318]

[0319] Alternatively, compound A-4 as defined above can be reacted with a suitable carboxylic acid protecting group (PG 1 reagent, such as PG 1 OH in the presence of SOCl2, or benzyl bromide in the presence of sodium carbonate) to form a methyl ester or a benzyl ester, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc., and then reacted with an R X reagent such as (1) 6-azaspiro[2.5]octane, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, etc. to form compound A-4A, wherein W 3 is as defined in compound A-4. Then compound A-4A can be reacted with a deprotecting agent, which can be a base such as lithium hydroxide, and then neutralized with HCl to form compound A-5, wherein W 3 is as defined in compound A-4.

[0320] Step A-3: Couple the ring Ar 1 compound with the ring Ar 2 compound, and then introduce R 1 :

[0321]

[0322] In step A-3, the compound A-5 obtained from step A-2 can be reacted with an activator (such as acyl chloride (COCl)2 or SOCl2) in a suitable organic solvent (such as tetrahydrofuran, dichloromethane, etc.) to form an acyl chloride derivative, which is then reacted with compound A-2 to form compound A-6.

[0323] Alternatively, compound A-2 can be directly reacted with compound A-5 obtained from step A-2 in the presence of a coupling reagent (such as N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, thionyl chloride, carbonyldiimidazole, and polyphosphoric anhydride) in a suitable organic solvent (such as acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.). Those of ordinary synthetic chemists will readily understand that other known coupling agents can be used.

[0324] Compound A-6 can then be converted to compound (Ia) by a transformation reaction (such as metal-catalyzed sulfonamidation, sulfidation, or sulfonylation) in a suitable organic solvent (such as DMSO, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) in the presence of a metal catalyst and an R 1 reagent. Such R 1 reagents are, for example, (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethan-1-ol, or (11) cyclopropanethiol. Those of ordinary skill in the art will readily understand that the coupling reaction (such as as shown in step A-3a) can be carried out under up to known conditions.

[0325] Scheme B: Alternative Preparation of Compound (Ia):

[0326] According to Scheme B, in another embodiment of the present invention, the preparation of the cyclic Ar 1 compound can be carried out as described in step A-1 of Scheme A above.

[0327] Step B-2: Ring Ar 2 Preparation of the compound:

[0328]

[0329] Scheme B provides an alternative method for forming the compounds of formula (I) disclosed herein. After step A-1 as described in Scheme A, the R 1 group can alternatively be introduced into the cyclic Ar 2 in step B-2, rather than in step A-3 of Scheme A. According to step B-2, compound B-1 (where W 4 and W 5Each independently is a halogen, such as fluorine, chlorine, bromine or iodine) reacts with a suitable carboxylic acid protecting group (PG1 reagent, such as methyl iodide) 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, where W 4 and W 5 are each as defined in compound B-1. Then, compound B-2 can be reacted with R x reagent (such as 6-azaspiro[2.5]octane) in a suitable organic solvent (such as NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, DMSO, etc.) to form compound B-3, where W 5 is as defined in compound B-1. Then, compound B-3 can be reacted with R 1 reagent in the presence of a metal catalyst (such as copper iodide, Pd2(dba)3) in a suitable organic solvent (such as DMSO, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) through a transformation reaction (such as metal-catalyzed sulfonamidation, sulfidation or sulfonylation) 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, such as those discussed in Greene's Protecting Groups in Organic Synthesis, for example.

[0330] Step B-3: Couple the ring Ar 1 compound with the ring Ar 2 compound :

[0331]

[0332] In step B-3, compound B-5 obtained from step B-2 can be reacted with an activator (such as acyl chloride (COCl)2 or SOCl2) in a suitable organic solvent (such as tetrahydrofuran, dichloromethane, etc.) to form an acyl chloride derivative, which can then be reacted with compound A-2 to form compound (Ia).

[0333] Scheme C

[0334] In another embodiment, the compound of formula (I) has the general formula (Ib):

[0335] As defined herein, it can be synthesized according to Scheme C.

[0336] Examples of the compound of formula (Ib) include but are not limited to

[0337]

[0338] Step C-1: Ring Ar 1 Preparation of the compound:

[0339]

[0340] In step C-1, compound C-1 (where W 4 is a halogen, such as fluorine or chlorine) can be reacted with an R 2 reagent in the presence of a suitable base in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc. to form compound C-2. Examples of compound C-1 include but are not limited to 3-fluorobenzoic acid or 3-fluoro-3-methylbenzoic acid. Examples of the R 2 reagent include but are not limited to (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazetidine hydrochloride. Examples of the base include but are not limited to diisopropylethylamine, potassium carbonate.

[0341] Step C-2: Ring Ar 2 Preparation of the compound:

[0342]

[0343] In step C-2, compound C-3 (where each of W 5 and W 6 is independently a halogen, such as fluorine, chlorine, bromine or iodine) can be reacted with an R X reagent (such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride or (5) 7-azaspiro[3.5]nonane hydrochloride) in a suitable organic solvent (such as NMP, acetonitrile, tetrahydrofuran, DMF, dichloromethane, DMSO, etc.) to form compound C-4. Examples of compound C-3 include but are not limited to (1) 4-bromo-2-fluoro-1-nitrobenzene, (2) 4-iodo-2-fluoro-1-nitrobenzene or (3) 6-bromo-2-fluoro-3-nitropyridine. Then the nitro group on compound C-4 can be converted to an amino group by reacting with a reducing agent (including but not limited to palladium on carbon) and a hydrogen source (such as hydrogen) to form compound C-5.

[0344] Step C-3: Couple the ring Ar 1 compound with the ring Ar 2 compound :

[0345]

[0346] In step C-3, the compound C-2 obtained from step C-1 can be reacted with the compound C-5 obtained from step C-2 in the presence of a coupling reagent (such as N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyldiimidazole or polyphosphoric anhydride) in a suitable organic solvent (such as acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) to form compound C-6. Those skilled in the art will readily understand that other coupling agents can be used. Then, the halogen group W can be further processed by a transformation reaction (such as SNAr, metal-catalyzed sulfonamidation, sulfidation or sulfonylation) in a suitable organic solvent (such as DMSO, acetonitrile, tetrahydrofuran, DMF, etc.) in the presence of a metal catalyst and an R 1 reagent. 6 to form compound (Ib), and the R 1 reagent is, for example, (1) oxetan-3-amine, (2) 2-amino-2-methylpropan-1-ol, (3) (3-aminooxetan-3-yl)methanol, (4) ethyl 2-sulfamoylpropionate, (5) 2-hydroxypropan-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropan-1-ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethan-1-ol or (10) cyclopropanethiol. Those skilled in the art will readily understand that the coupling reaction (such as as shown in step C-3) can be carried out under conditions known up to.

[0347] Those skilled in the art should be aware that, depending on the feasibility of the transformation, the above transformation can also be carried out at an earlier stage of the synthesis process.

[0348] Preparation of Synthetic Intermediates

[0349] Ring Ar 1 Intermediate:

[0350] Intermediate 1: (R)-3-Fluoro-5-(2-methylmorpholino)aniline.

[0351]

[0352] Step 1:A mixture of 1,3-difluoro-5-nitrobenzene (3.0 g, 18.86 mmol, Apollo Scientific), (R)-2-methylmorpholine (2.29 g, 22.63 mmol, Arbor Chemicals), and DIPEA (6.59 mL, 37.7 mmol) in 1,4-dioxane (30 mL) was stirred under microwave at 100 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (eluting with a gradient of 0%-40% EtOAc in petroleum ether) to afford (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine as a yellow solid (1.5 g, 6.24 mmol, 33% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 7.54 (d, J = 2.3 Hz, 1H), 7.38 (dt, J = 8.4, 2.1 Hz, 1H), 7.27 (dt, J = 12.3, 2.3 Hz, 1H), 3.92 (ddd, J = 11.5, 3.7, 1.4 Hz, 1H), 3.80 (dt, J = 12.2, 2.2 Hz, 1H), 3.68 (ddt, J = 12.2, 3.1, 1.6 Hz, 1H), 3.53 - 3.67 (m, 2H), 2.79 (td, J = 11.9, 3.6 Hz, 1H), 2.41 - 2.49 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H). m / z (ESI): 241.1 (M+H) + 。

[0353] Step 2 :To a solution of (R)-4-(3-fluoro-5-nitrophenyl)-2-methylmorpholine (1.8 g, 7.49 mmol) in MeOH (10 mL) and THF (10 mL) was added palladium on carbon (0.5 g, 4.70 mmol, Hindustan platinum) and the mixture was stirred under H2 pressure (14 psi) for 16 h. The reaction mixture was filtered through a bed, washed with MeOH, and the filtrate was concentrated to give (R)-3-fluoro-5-(2-methylmorpholino)aniline as a beige solid (1.1 g, 5.23 mmol, 70% yield). 11H NMR (400 MHz, DMSO-d6): δ ppm 5.90 (d, J = 12.5 Hz, 2H), 5.78 (d, J = 11.0 Hz, 1H), 5.19 (d, J = 7.9 Hz, 2H), 3.86 (dd, J = 11.2, 3.4 Hz, 1H), 3.57 (dtd, J = 14.7, 11.5, 10.0, 4.3 Hz, 2H), 3.43 (d, J = 11.6 Hz, 1H), 3.33 (m, 1H), 2.58 (td, J = 11.7, 3.3 Hz, 1H), 2.27 (q, J = 10.9, 10.3 Hz, 1H), 1.13 (dd, J = 9.6, 5.7 Hz, 3H). m / z (ESI): 211.2 (M + H) + 。

[0354] Intermediate 2: (R)-4-Fluoro-3-(2-methylmorpholino)aniline 。

[0355]

[0356] Step 1 : A mixture of 2-bromo-1-fluoro-4-nitrobenzene (3.0 g, 13.64 mmol, Apollo Technology Co., Ltd.), (R)-2-methylmorpholine (1.94 g, 19.23 mmol, Abbo Chemical Co., Ltd.), 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 dioxane (15 mL) was heated at 100 °C for 16 h. The reaction mixture was filtered through a bed and washed with EtOAc. The filtrate was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 0%-20% EtOAc in hexane) to give (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine as a yellow solid (0.7 g, 2.91 mmol, 21% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 7.89 (ddd, J = 8.9, 3.9, 2.8 Hz, 1H), 7.79 (dd, J = 7.6, 2.8 Hz, 1H), 7.46 (dd, J = 12.2, 8.9 Hz, 1H), 3.90 (ddd, J = 11.5, 3.2, 1.5 Hz, 1H), 3.68 - 3.77 (m, 2H), 3.27 - 3.40 (m, 2H), 2.85 (td, J = 11.6, 3.2 Hz, 1H), 2.56 (dd, J = 11.6, 10.0 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H). m / z (ESI): 241.1 (M + H)+ .

[0357] Step 2 : To a solution of (R)-4-(2-fluoro-5-nitrophenyl)-2-methylmorpholine (0.7 g, 2.91 mmol) in MeOH (10 mL) and THF (10 mL) was added palladium on carbon (0.35 g, 3.29 mmol, Hindustan Platinum) and the reaction mixture was stirred under H2 pressure (14 psi) for 16 h. The reaction mixture was filtered through a bed, washed with MeOH, and concentrated to give (R)-4-fluoro-3-(2-methylmorpholino)

[0358] aniline as a beige solid, which was used directly in the next step without purification. 1 1H NMR (400 MHz, DMSO-d6): δ ppm 6.75 (dd, J = 12.9, 8.5 Hz, 1H), 6.22 (dd, J = 7.7, 2.6 Hz, 1H), 6.10 (dt, J = 8.6, 3.1 Hz, 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, 3.2 Hz, 1H), 2.32 (t, J = 10.7 Hz, 1H), 1.10 (d, J = 6.3 Hz, 3H). m / z (ESI): 211.2 (M + H) + .

[0359] Table 1: Preparation of Intermediates 2-1 and 2-2 according to a procedure similar to the preparation of Intermediate 2:

[0360]

[0361] Intermediate 3: 3-(4,4-Difluoropiperidin-1-yl)-5-methylaniline.

[0362] Step 1: A mixture of 1-bromo-3-methyl-5-nitrobenzene (5 g, 23.14 mmol), 4,4-difluoropiperidine (4.21 g, 34.7 mmol), sodium tert-butoxide (6.67 g, 69.4 mmol), Pd2(dba)3 (2.12 g, 2.31 mmol), and xantphos (1.34 g, 2.31 mmol) in toluene (50 mL) was stirred at 100 °C for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography using 10% EtOAc in petroleum ether to afford 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine as a gray solid (3.70 g, 14.44 mmol, 62% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 7.55 (t, J = 2.3 Hz, 1H), 7.45 (s, 1H), 7.32 (d, J = 2.3 Hz, 1H), 3.46 (t, J = 5.8 Hz, 4H), 2.38 (s, 3H), 1.96 - 2.04 (m, 4H). m / z (ESI): 257.1 (M+H) + 。

[0363] Step 2: A mixture of 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine (3.7 g, 14.44 mmol), iron powder (8.06 g, 144 mmol), and ammonium chloride (7.72 g, 144 mmol) in EtOH (30 mL) and water (7 mL) was stirred at 75 °C for 16 h. The reaction mixture was filtered through a pad, washed with methanol, and the filtrate was concentrated. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (eluting with 30 - 40% EtOAc in petroleum ether) to afford 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline as a brown solid (2.6 g, 11.49 mmol, 80% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 6.00 (s, 2H), 5.89 (s, 1H), 4.81 (s, 2H), 3.16 - 3.22 (m, 4H), 2.09 (s, 3H), 1.94 - 2.04 (m, 4H). m / z (ESI): 227.1 (M+H) + 。

[0364] Table 2: Preparation of Intermediate 3-1 according to a procedure similar to the preparation of Intermediate 3:

[0365]

[0366] Intermediate 4: 3-(4,4-Difluoropiperidin-1-yl)-2-fluoroaniline.

[0367]

[0368] To a solution of 4,4-difluoropiperidine hydrochloride (0.91 g, 5.79 mmol) and lithium bis(trimethylsilyl)amide (1.0 M in THF, 11.84 mL, 11.84 mmol) in THF (50 mL) was added a solution of 3-bromo-2-fluoroaniline (0.5 g, 2.63 mmol) in THF (20 mL) and Ruphos Pd G-3 (0.13 g, 0.16 mmol, Strem chemicals). The reaction mixture was stirred at 60 °C for 6 h, 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 silica gel column chromatography (eluting with 5%-10% EtOAc in petroleum ether) to afford 3-(4,4-difluoropiperidin-1-yl)-2-fluoroaniline as a black oil (0.45 g, 1.96 mmol, 74% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 6.75 (td, J = 8.0, 1.4 Hz, 1H), 6.43 (td, J = 8.1, 1.5 Hz, 1H), 6.25 (td, J = 7.9, 1.6 Hz, 1H), 5.01 (s, 2H), 3.03 - 3.10 (m, 4H), 2.02 - 2.17 (m, 4H). m / z (ESI): 231.1 (M+H) + 。

[0369] Intermediate 5: 2-((3-Amino-2-fluorophenyl)amino)-2-methylpropan-1-ol.

[0370]

[0371] Step 1: Charge a pressure-reduced vial with copper(I) iodide (0.025 g, 0.132 mmol) and sodium iodide (0.789 g, 5.26 mmol). The vial was evacuated / backfilled with nitrogen (3x). Add dioxane (5 mL), followed by 3-bromo-2-fluoroaniline (0.50 mL, 2.63 mmol, Oakwood Inc., Estill, SC, USA) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.041 mL, 0.263 mmol). Cap the vial and stir the reaction in a preheated 120 °C oil bath for 24 h. Partition the reaction between 9:1 saturated NH4Cl:saturated NH4OH and EtOAc. Separate the organic phase, wash with brine, dry over magnesium sulfate and concentrate in vacuo to give 2-fluoro-3-iodoaniline (0.63 g, 2.66 mmol, 100% yield) as a dark brown oil, which was used without further purification. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.08 (ddd, J = 7.52, 5.55, 1.87 Hz, 1H) 6.63 - 6.76 (m, 2H) 3.78 (br s, 2H). m / z (ESI, +ve ion): 238.1 (M+H) + .

[0372] Step 2: Charge a pressure-reduced vial with copper(I) iodide (0.024 g, 0.127 mmol) and sodium hydroxide (0.101 g, 2.53 mmol). Seal the vial and evacuate / backfill with nitrogen (3x). Add isopropanol (6 mL), then add 2-fluoro-3-iodoaniline (0.30 g, 1.27 mmol) and 2-amino-2-methyl-1-propanol (0.13 mL, 1.52 mmol, Combi-Block). Cap the vial and stir the reaction in a preheated 90 °C oil bath for 16 h. Partition the reaction between saturated NH4Cl:NH4OH (9:1) and EtOAc. Separate the organic phase, wash with brine, dry over magnesium sulfate and concentrate in vacuo. Purify the crude material by silica gel chromatography (eluent: 50% - 100% EtOAc:heptane) to afford 2-((3-amino-2-fluorophenyl)amino)-2-methylpropan-1-ol (0.123 g, 0.620 mmol, 49% yield) as a brown oil. 11H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (td, J = 8.03, 1.14 Hz, 1H) 6.20 (td, J = 7.88, 1.24 Hz, 1H) 6.10 (td, J = 8.09, 1.24 Hz, 1H) 5.03 (t, J = 5.49 Hz, 1H) 4.80 (s, 2H) 4.31 (br d, J = 3.94 Hz, 1H) 3.33 (s, 1H) 1.19 (s, 6H). m / z (ESI, +ve ion): 199.2 (M+H) + 。

[0373] Intermediate 6: (3-Aminophenyl)(tert-butyl)((tert-butyldimethylsilyl)imino)-sulfonamide 。

[0374]

[0375] Step 1: To a solution of 3-bromoaniline (5 g, 29.1 mmol) in dioxane (30 mL) was added 2-methylpropane-2-thiol (2.88 g, 32.0 mmol), K2CO3 (4.02 g, 29.1 mmol), Pd2(dba)3 (26.6 g, 29.1 mmol), then Xantphos (16.82 g, 29.1 mmol) was added, and the reaction mixture was heated at 100 °C for 14 h. The reaction mixture was filtered through a pad and washed with EtOAc. The filtrate was taken out and washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (using 10% EtOAc in petroleum ether) to afford 3-(tert-butylthio)aniline (3.5 g, 19.31 mmol, 66% yield). 1 1H NMR (400 MHz, chloroform-d): δ ppm 7.17 (t, J = 7.8 Hz, 1H), 6.97 - 7.06 (m, 2H), 6.81 (ddd, J = 7.9, 2.4, 1.0 Hz, 1H), 4.34 (s, 2H), 1.32 (d, J = 3.1 Hz, 9H).

[0376] Step 2: At 0 °C, 3-chlorobenzenecarboperoxoic acid (3.33 g, 19.31 mmol) was added to a solution of 3-(tert-butylthio)aniline (3.5 g, 19.31 mmol) in DCM (100 mL), and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with 100 mL of saturated NaHCO3 solution and extracted with DCM (2x). The combined organic extracts were dried over Na2SO4 and concentrated to give the crude product, which was purified by silica gel column chromatography (using 60% EtOAc in petroleum ether) to afford 3-(tert-butylsulfinyl)aniline (2.8 g, 14.19 mmol, 73% yield). m / z (ESI): 198.2 (M+H) + 。

[0377] Step 3: At 0 °C, Et3N (2.87 g, 28.4 mmol) was added to a solution of 3-(tert-butylsulfinyl)aniline (2.8 g, 14.19 mmol) in chloroform (20 mL), then acetyl chloride (1.67 g, 21.29 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice water and extracted with chloroform (2x). The combined organic extracts were dried over Na2SO4 and concentrated to give the crude material. Purification by silica gel column chromatography (using 50% EtOAc in petroleum ether) afforded N-(3-(tert-butylsulfinyl)phenyl)acetamide (3.0 g, 12.53 mmol, 88% yield). 1 H NMR (300 MHz, DMSO-d6): δ ppm 10.18 (s, 1H), 7.84 (t, J = 1.9 Hz, 1H), 7.63 - 7.73 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.19 (dt, J = 7.8, 1.2 Hz, 1H), 2.04 (s, 3H), 1.05 (s, 9H). m / z (ESI): 240.1 (M+H) + 。

[0378] Step 4: To a solution of N-(3-(tert-butylsulfinyl)phenyl)acetamide (3.0 g, 12.53 mmol) in methanol (60 mL) was added phenyl-λ 3Iodosodiacetate (10.1 g, 31.3 mmol), then ammonium carbonate (4.19 g, 62.7 mmol) was added portionwise and the reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (2x). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (using 90% EtOAc in petroleum ether) to give N-(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)acetamide as an off-white solid (2.4 g, 75% yield). 1 H NMR (300 MHz, DMSO-d6): δ ppm 10.26 (s, 1H), 8.09 (d, J = 2.1 Hz, 1H), 7.89 (dt, J = 7.1, 2.2 Hz, 1H), 7.48 - 7.53 (m, 2H), 4.03 (s, 1H), 2.06 (s, 3H), 1.21 (s, 9H). m / z (ESI): 255.1 (M+H) + 。

[0379] Step 5: At 0 °C, imidazole (1.28 g, 18.87 mmol), DMAP (0.57 g, 4.72 mmol) were added to a solution of N-(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)acetamide (2.4 g, 9.44 mmol) in DCM (48 mL), followed by TBS-Cl (1.7 g, 11.32 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mass was quenched with water and then with 10% aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography (eluting with a gradient of 50%-60% EtOAc in petroleum ether) to afford N-(3-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)phenyl)acetamide as a pale yellow liquid (3.2 g, 92% yield). 1 H NMR (300 MHz, DMSO-d6): δ ppm 10.24 (s, 1H), 8.13 (t, J = 1.9 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.34 - 7.58 (m, 2H), 2.06 (s, 3H), 1.18 (s, 9H), 0.87 (s, 9H), -0.06 (s, 3H), -0.07 (s, 3H). m / z (ESI): 369.2 (M+H) + 。

[0380] Step 6: To a solution of N-(3-(N-(tert-butyldimethylsilyl)-2-methylpropan-2-ylsulfonimidoyl)phenyl)acetamide (3.2 g, 8.68 mmol) in methanol (32 mL) was added 2.5 M sodium hydroxide solution (64 mL), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The crude material was purified by silica gel column chromatography (using 20% EtOAc in petroleum ether) to afford (3-aminophenyl)(tert-butyl)((tert-butyldimethylsilyl)imino)-λ 6 -sulfonamide (2.1 g, 6.43 mmol, 74% yield). 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.18 (t, J = 7.9 Hz, 1H), 6.99 (t, J = 2.1 Hz, 1H), 6.87 (ddd, J = 7.7, 1.8, 1.0 Hz, 1H), 6.75 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H), 5.51 (s, 2H), 1.17 (d, J = 2.3 Hz, 9H), 0.87 (d, J = 2.5 Hz, 9H), -0.06 (s, 3H), -0.07 (s, 3H). m / z (ESI): 327.2 (M+H).

[0381] Table 3: Intermediate 6-1 was prepared according to a procedure similar to the preparation of Intermediate 6:

[0382]

[0383] Intermediate 7: 3-(N-(tert-Butyldimethylsilyl)azetidine-1-sulfonimido)aniline .

[0384]

[0385] Step 1: A solution of 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol, Combi-Block Inc.) in THF (10 mL) was treated with ammonia (20 mL, 40.0 mmol, 2 M in methanol) and stirred at ambient temperature for 24 h. The solvent was evaporated under reduced pressure and the residue was diluted with water to afford a solid material, which was filtered and dried to give 3-nitrobenzenesulfonamide as an off-white solid (1.3 g, 6.43 mmol, 71% yield). 11H NMR (400 MHz, DMSO-d6): δ ppm 8.59 (t, J = 2.0 Hz, 1H), 8.45 (dd, J = 8.3, 2.3 Hz, 1H), 8.24 (dd, J = 7.9, 1.6 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.71 (s, 2H). m / z (ESI): 201.0 (M-H).

[0386] Step 2: At 0 °C, Et3N (2.69 mL, 19.29 mmol) was added to a solution of 3-nitrobenzenesulfonamide (1.3 g, 6.43 mmol) in CH2Cl2 (26 mL), and then TBS-Cl (1.45 g, 9.64 mmol) was added. The reaction mixture was stirred at rt for 16 h, then quenched with cold water and extracted with CH2Cl2. The CH2Cl2 layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (using a 0%-10% EtOAc gradient in petroleum ether) to afford N-(tert-butyldimethylsilyl)-3-nitrobenzenesulfonamide as a light yellow solid (1.0 g, 3.16 mmol, 49% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, J = 2.0 Hz, 1H), 8.44 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H), 8.22 (dt, J = 7.9, 1.4 Hz, 1H), 7.96 (s, 1H), 7.89 (td, J = 8.0, 1.6 Hz, 1H), 0.87 (d, J = 1.7 Hz, 9H), 0.11 (s, 3H), 0.12 (s, 3H). m / z (ESI): 315.1 (M-H) - 。

[0387] Step 3: Add perchloroethane (0.82 g, 3.48 mmol, Aldrich) to a solution of Ph3P (0.91 g, 3.48 mmol) in chloroform (10 mL) and heat the reaction mixture at 70 °C for 6 h. Cool the solution to 0 °C and treat with Et3N (0.66 mL, 4.74 mmol), then treat with N-(tert-butyldimethylsilyl)-3-nitrobenzenesulfonamide (1.0 g, 3.16 mmol) in chloroform (5 mL), and stir for 30 min. Finally, add azetidine (0.361 g, 6.32 mmol, Chempure) in chloroform (1.5 mL) dropwise at 0 °C, and stir the reaction mixture at rt for 16 h. Quench the reaction mixture with cold water, extract with CH2Cl2, wash with brine, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (using a 0%-20% EtOAc gradient in petroleum ether) to give 1-(N-(tert-butyldimethylsilyl)-3-nitrophenylsulfonimidoyl)azetidine (0.85 g, 2.39 mmol, 76% yield) as a clear slurry. 1 1H NMR (400 MHz, DMSO-d6): δ ppm 8.51 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.19 (dt, J = 7.8, 1.4 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 3.57 (dq, J = 20.9, 7.7 Hz, 4H), 1.89 (pent, J = 7.6 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H).

[0388] Step 4: Add iron powder (1.33 g, 23.91 mmol) and ammonium chloride (1.28 g, 23.91 mmol) to a mixture of 1-(N-(tert-butyldimethylsilyl)-3-nitrophenylsulfonimidoyl)azetidine (0.85 g, 2.39 mmol) in ethanol (7 mL) and water (3 mL). Heat the reaction mixture at 60 °C for 4 h, then filter through a bed and wash with EtOAc. Wash the filtrate with water, 10% NaHCO3 solution, brine, dry over anhydrous Na2SO4, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (using a 0%-35% EtOAc gradient in petroleum ether) to give 3-(N-(tert-butyldimethylsilyl)azetidine-1-sulfonimidoyl)aniline (0.54 g, 1.66 mmol, 69% yield) as a clear slurry. m / z (ESI): 326.2 (M+H) + 。

[0389] Ring Ar 2 Preparation of the intermediate:

[0390] Intermediate 8: 4-Iodo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid.

[0391]

[0392] To a solution of 2-fluoro-4-iodobenzoic acid (300 g, 1.13 mol, Combi-Blocks) in DMSO (2.10 L) at 20 °C was added 6-azaspiro[2.5]octane hydrochloride (216 g, 1.47 mol, Wuxi AppTec). Then K2CO3 (468 g, 3.38 mol) was added, and the reaction mixture was stirred at 140 °C under N2 for 48 h. The reaction solution was slowly poured into ice water (4.20 L), and then extracted with hexane (2 L x 3). The aqueous phase was separated and adjusted to pH = 6 with HCl (2 M). A solid precipitated and was collected. The solid was washed with water (700 mL x 3) and filtered. The wet solid was spread on a large watch glass and dried in air at 25 °C for 72 h. 4-Iodo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid as a pale yellow solid was obtained (280 g, 777 mmol, 69% yield). 400 MHz DMSO-d6 δ ppm 8.07 (s, 1H), 7.76 - 7.66 (m, 2H), 3.10 (t, J = 5.2 Hz, 4H), 1.55 (br s, 4H), 0.41 (s, 4H).

[0393] Table 4: Intermediates 8-1 to 8-4 were prepared according to a procedure similar to the preparation of Intermediate 8:

[0394]

[0395]

[0396] Intermediate 9: 4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid .

[0397]

[0398] Step 1: To a solution of 2-fluoro-4-(methylsulfonyl)benzoic acid (90.0 g, 412.1 mmol) in N,N-dimethylformamide (1.0 L) at 0 °C was added benzyl bromide (78.1 g, 454.0 mmol) and sodium carbonate (52.5 g, 495 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 x 1 L). The combined organic extracts were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 0%-30% EtOAc in hexane to afford benzyl 2-fluoro-4-(methylsulfonyl)benzoate (100 g, 79% yield) as a white solid. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 8.16 (dd, J = 8.2, 6.9 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.48 - 7.31 (m, 5H), 5.40 (s, 2H), 3.33 (s, 3H).

[0399] Step 2: To a solution of benzyl 2-fluoro-4-(methylsulfonyl)benzoate (55 g, 178 mmol) in DMSO (550 mL) was added DIPEA (57.6 g, 446 mmol), followed by 6-azaspiro[2.5]octane (29.8 g, 268 mmol), and the reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 x 1 L). The combined organic layers were washed with brine solution (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (230 - 400 mesh) using 0%-10% EtOAc in hexane to afford benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (55 g, 77% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (d, J = 8.0 Hz, 1H), 7.52 - 7.45 (m, 4H), 7.43 - 7.35 (m, 3H), 5.35 (s, 2H), 3.25 (s, 3H), 3.05 (t, J = 5.3 Hz, 4H), 1.36 (t, J = 5.3 Hz, 4H), 0.30 (s, 4H). m / z (ESI): 400.1 (M+H) + 。

[0400] Step 3: To a solution of benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (65 g, 163 mmol) in THF (108 mL) and methanol (36 mL) at 60 °C was added 1N aqueous sodium hydroxide solution (407 mL, 407 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was concentrated under reduced pressure to remove THF and methanol. The remaining aqueous solution was acidified to pH ~2 with 1.5N HCl solution. The precipitated solid was filtered, washed with water (200 mL), then washed with hexane (200 mL), and dried in vacuo for 12 h to give 4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid as an off-white solid (42 g, 83% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 16.13 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 3.29 (s, 3H), 3.17 (b s, 4H), 1.55 (b s, 4H), 0.41 (s, 4H). m / z (ESI): 308.1 (M-H) + 。

[0401] Intermediate 10: 4-(((1-Methylcyclopropyl)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)ben zoic acid 。

[0402]

[0403] Step 1: To a 250 mL sealed tube was added benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (9 g, 22.48 mmol, Intermediate 8-4) in dioxane (90 mL), 1-methylcyclopropane-1-sulfonamide (3.95 g, 29.2 mmol, Combiolab), and K2CO3 (6.21 g, 45.0 mmol), and the reaction mixture was degassed and purged with nitrogen for 5 min. To the reaction mixture was added Xantphos (1.30 g, 2.25 mmol), followed by Pd2(dba)3 (1.03 g, 1.12 mmol), the tube was sealed and stirred at 110 °C for 18 h. The reaction mixture was quenched with water (250 mL) and extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with water (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of 0%-15% EtOAc in hexane to give benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate as an orange oil (6.1 g, 59% yield).1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.06 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.48 - 7.31 (m, 5H), 6.98 (s, 1H), 6.81 (d, J = 8.5 Hz, 1H), 5.27 (s, 2H), 2.92 (t, J = 4.96 Hz, 4H), 1.40 - 1.30 (m, 7H), 1.16 (dd, J = 6.4, 4.7 Hz, 2H), 0.81 (dd, J = 6.4, 4.7 Hz, 2H), 0.28 (s, 4H). m / z (ESI): 455.2 (M+H) + 。

[0404] Step 2: Under a nitrogen atmosphere, 10% Pd-C (1.05 g, 50% wt / wt) was added to a solution of benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.1 g, 4.62 mmol) in MeOH (20 mL) and EtOAc (10 mL). The reaction mixture was degassed and stirred under a hydrogen pressure (1 atm, balloon pressure) for 4 h. The reaction mixture was filtered through a bed and washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid as an off-white solid (1.2 g, 71% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.20 (s, 1H), 10.33 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 2.99 (s, 4H), 1.56 (s, 4H), 1.39 (s, 3H), 1.18 (t, J = 4.8 Hz, 2H), 0.83 (t, J = 4.7 Hz, 2H), 0.42 (s, 4H). m / z (ESI): 363.2 (M-H).

[0405] Intermediate 11: 4-((Methylsulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid 。

[0406]

[0407] Step 1: To a solution of methyl 2-fluoro-4-methylbenzoate (10.0 g, 59.5 mmol) in carbon tetrachloride (200 mL) at rt was added NBS (11.6 g, 65.4 mmol) and AIBN (0.98 g, 5.95 mmol). The reaction mixture was stirred at 70 °C for 3 h, then quenched with water (250 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-fluoro-4-methylbenzoate as a pale yellow oil (14.0 g, crude). 1 1H NMR (400 MHz, chloroform-d): δ 8.04 - 7.88 (m, 1H), 7.27 - 7.13 (m, 2H), 4.46 (s, 2H), 3.96 (s, 3H).

[0408] Step 2: A mixture of methyl 2-fluoro-4-methylbenzoate (14.0 g, 56.7 mmol) and sodium methanesulfinate (12.15 g, 119 mmol) in DMF (42 mL) was irradiated in a microwave (Biotage initiator+) at 120 °C for 30 min. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were washed with saturated brine solution (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 2-fluoro-4-((methylsulfonyl)methyl)benzoate as an off-white solid (6 g, crude).

[0409] Step 3: A mixture of methyl 2-fluoro-4-((methylsulfonyl)methyl)benzoate (6.0 g, 24 mmol) and 6-azaspiro[2.5]octane (2.71 g, 24.4 mmol) in DMSO (30 mL) was irradiated in a microwave at 150 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate as an off-white solid (4.0 g, crude). The material was used as such without any further purification for the next step. 11H NMR (400 MHz, chloroform-d) δ 7.72 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 6.96 (dd, J = 7.8, 1.6 Hz, 1H), 4.24 (s, 2H), 3.93 (s, 3H), 3.12 (t, J = 5.4 Hz, 4H), 2.78 (s, 3H), 1.55 (t, J = 5.5 Hz, 4H), 0.37 (s, 4H). m / z (ESI): 338.1 (M-H) + 。

[0410] Step 4: To a solution of methyl 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.0 g, 3.0 mmol) in THF (15 mL) was added sodium hydroxide (0.474 g, 11.8 mmol) in water (7 mL) and the mixture was stirred at RT for 12 h. The reaction mixture was acidified to pH ~3 with 1.5 N HCl solution and extracted with EtOAc (5 x 20 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid as a white solid (1.0 g, 10% yield over 3 steps). m / z (ESI): 324.1 (M-H) + 。

[0411] Intermediate 12: 4-(N-(3-Methyloxetan-3-yl)aminosulfonyl)-2-(6-azaspiro[2.5]oct-6- yl)benzoic acid 。

[0412]

[0413] Step 1: To a solution of 3-methyl-3-oxetanamine hydrochloride (5.50 g, 44.5 mmol) and DIPEA (23.26 mL, 134 mmol) in DCM (200 mL) at 0 °C was added methyl 4-(chlorosulfonyl)-2-fluorobenzoate (12.37 g, 49.0 mmol) and the mixture was stirred from 0 °C to RT for 1 h. The mixture was diluted with 1.0 N HCl (200 mL) and extracted with DCM (150 mL x 2). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by eluting with 0%-30% EtOAc-EtOH (3:1) in heptane on a Biotage SNAP 100 g column to afford methyl 2-fluoro-4-(N-(3-methyloxetan-3-yl)sulfamoyl)benzoate as a white solid (13.59 g, 44.8 mmol, 100% yield). 11H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.11 (t, J = 7.37 Hz, 1H), 7.76 - 7.82 (m, 1H), 7.69 - 7.76 (m, 1H), 4.56 (d, J = 6.23 Hz, 2H), 4.18 (d, J = 6.75 Hz, 2H), 3.90 (s, 3H), 1.42 (s, 3H).

[0414] Step 2: A mixture of N,N-diisopropylethylamine (16.23 mL, 93 mmol), 6-azaspiro[2.5]octane (6.22 g, 55.9 mmol), and methyl 2-fluoro-4-(N-(3-methyloxetan-3-yl)sulfamoyl)benzoate (14.13 g, 46.6 mmol) in anhydrous dioxane was stirred at 100 °C for 20 h. The mixture was cooled to RT, quenched with water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried and evaporated to dryness under reduced pressure. The crude product was purified using a Biotage SNAP 340 g column eluting with 0%-40% 3:1 EtOAc-EtOH in heptane to afford methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (14.15 g, 35.9 mmol, 77% yield) as an off-white solid. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 8.42 (s, 1H), 7.72 (d, J = 8.04 Hz, 1H), 7.47 (d, J = 1.56 Hz, 1H), 7.36 (dd, J = 1.82, 8.04 Hz, 1H), 4.55 (d, J = 5.97 Hz, 2H), 4.14 (d, J = 6.49 Hz, 2H), 3.85 (s, 3H), 3.02 - 3.09 (m, 4H), 1.44 - 1.50 (m, 4H), 1.42 (s, 3H), 0.35 (s, 4H).

[0415] Step 3: A mixture of methyl 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (14.15 g, 35.9 mmol) and lithium hydroxide monohydrate (22.58 g, 538 mmol) in THF-water-MeOH (1:1:1, 300 mL) was stirred overnight at RT. The mixture was concentrated under reduced pressure to remove the organic solvents in part. The solution was acidified to pH < 3 with 2N HCl. The precipitated solid was filtered and dried in air to afford 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (9.94 g, 26.1 mmol, 73% yield) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.51 (s, 1H), 8.04 (d, J = 8.04 Hz, 1H), 7.89 (d, J = 1.30 Hz, 1H), 7.66 (dd, J = 1.69, 8.17 Hz, 1H), 4.55 (d, J = 6.23 Hz, 2H), 4.09 - 4.17 (m, 2H), 3.06 - 3.19 (m, 4H), 1.56 (t, J = 5.19 Hz, 4H), 1.40 (s, 3H), 0.40 (s, 4H).

[0416] Intermediate 13: 4-(N-(tert-Butyl)aminosulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid 。

[0417]

[0418] Step 1: A solution of benzyl 4-bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoate (25 g, 62 mmol, Intermediate 8-4), DIPEA (21.8 mL, 125 mmol), xantphos (1.81 g, 3.12 mmol), Pd2(dba)3 (1.14 g, 1.25 mmol) and benzyl mercaptan (10 g, 81 mmol) in dioxane (250 mL) was degassed and purged with nitrogen for 15 min. The reaction mixture was heated at 100 °C for 16 h in a sealed pressure vessel, then quenched with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60 - 120 mesh) using 5% - 10% EtOAc in hexane to afford benzyl 4-(benzylthio)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (20 g, 72% yield) as a pale yellow liquid. 11H NMR (400 MHz, DMSO-d6): δ 7.57 - 7.53 (m, 1H), 7.48 - 7.26 (m, 10H), 6.93 - 6.87 (m, 2H), 5.27 (s, 2H), 4.32 (s, 2H), 2.95 - 2.87 (m, 4H), 1.35 (t, J = 5.3 Hz, 4H), 0.28 (s, 4H). m / z (ESI): 442.2 (M-H) + 。

[0419] Steps 2 and 3: At 0 °C, sulfuryl chloride (18.3 mL, 225 mmol) was added to a solution of benzyl 4-(benzylthio)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (20 g, 45 mmol) in DCM (160 mL) and water (40 mL). The reaction mixture was stirred for 1 h, then diluted with water (200 mL) and extracted with DCM (200 mL). The organic extract was dried over anhydrous Na2SO4, filtered and cooled to 0 °C. tert-Butylamine (47.8 mL, 451 mmol) was added to the above solution. The reaction mixture was stirred at RT for 1 h, then quenched with water (200 mL) and extracted with DCM (2 x 100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60 - 120 mesh) using 15% EtOAc in hexane to afford benzyl 4-(N-(tert-butyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate as a pale yellow solid (12 g, 61% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.55 - 7.46 (m, 3H), 7.45 - 7.33 (m, 4H), 5.33 (s, 2H), 3.01 (b s, 4H), 1.38 (b s, 4H), 1.10 (s, 9H), 0.31 (2, 4H). m / z (ESI): 457.2 (M-H) + 。

[0420] Step 4: At RT under a nitrogen atmosphere, 10% palladium on carbon (4.66 g, 4.38 mmol) was added to a solution of benzyl 4-(N-(tert-butyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (10 g, 21.9 mmol) in ethanol (50 mL) and EtOAc (50 mL). The reaction mixture was degassed and stirred under a hydrogen atmosphere (1 atm) at RT for 16 h. The reaction mixture was passed through The bed was filtered and the filter bed was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure. The crude residue was triturated with diethyl ether (200 mL) to afford the title compound as an off-white solid (6.0 g, 75% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J = 8.2 Hz, 1H), 7.98 (s, 1H), 7.73 - 7.68 (m, 2H), 3.12 (t, J = 5.3 Hz, 4H), 1.57 (t, J = 5.3 Hz, 4H), 1.10 (s, 9H), 0.43 (s, 4H). m / z (ESI): 365.2 (M - H) + 。

[0421] Intermediate 14: 4-(((2-Hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid 。

[0422]

[0423] Step 1: To a stirred solution of methyl 2-fluoro-4-methylbenzoate (7.5 g, 44.6 mmol) in carbon tetrachloride (75 mL) was added NBS (7.94 g, 44.6 mmol) and AIBN (0.366 g, 2.23 mmol), and the mixture was stirred at 70 °C for 4 h. The reaction mixture was quenched with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were washed with brine solution (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-(bromomethyl)-2-fluorobenzoate as a gummy solid (8.5 g, crude). The crude material showed a mixture of the monobromo compound and the dibromo compound and was thus used in the next step without any purification. m / z (ESI): 247.1 [M + 1]

[0424] Step 2: A mixture of methyl 4-(bromomethyl)-2-fluorobenzoate (7 g, 28.3 mmol) and 2-mercaptoethanol (2.214 g, 28.3 mmol) in N,N-dimethylformamide (25.0 mL) was placed in a microwave vial. The vial was sealed and irradiated in a microwave reactor at 120 °C for 1 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine solution (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 50% EtOAc in hexane to afford methyl 2-fluoro-4-(((2-hydroxyethyl)thio)methyl)benzoate as a viscous oil (2 g, 29% yield). 11H NMR (300 MHz, chloroform-d): δ 8.06 - 7.86 (m, 1H), 7.17 (td, J = 10.5, 3.8 Hz, 2H), 3.90 (s, 3H), 3.85 - 3.67 (m, 4H), 2.65 (td, J = 6.0, 1.4 Hz, 2H), 1.42 - 1.18 (m, 1H). m / z (ESI): 245.1 [M+1].

[0425] Step 3: At 0 °C, mCPBA (2.826 g, 16.38 mmol) was added to a stirred solution of methyl 2-fluoro-4-(((2-hydroxyethyl)thio)methyl)benzoate (2 g, 8.19 mmol) in DCM (20 mL) and the mixture was stirred at RT for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (25 mL) and extracted with DCM (2 x 25 mL). The organic layer was washed with brine solution (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a gummy solid. The crude residue was triturated with diethyl ether (40 mL) to afford methyl 2-fluoro-4-(((2-hydroxyethyl)sulfonyl)methyl)benzoate as an off-white solid (1.0 g, 44% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.07 - 7.78 (m, 1H), 7.50 - 7.23 (m, 2H), 5.29 (br s, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.85 - 3.79 (m, 2H), 3.21 (t, J = 5.8 Hz, 2H). m / z (ESI): 277.1 [M+1].

[0426] Step 4: A glass tube was charged with methyl 2-fluoro-4-(((2-hydroxyethyl)sulfonyl)methyl)benzoate (1.0 g, 3.62 mmol), 6-azaspiro[2.5]octane (0.48 g, 4.34 mmol), DIPEA (0.76 mL, 4.34 mmol) and DMSO (10 mL). The tube was sealed and heated at 100 °C for 72 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated with diethyl ether (100 mL) to afford methyl 4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate as a gummy oil (900 mg, 67% yield). 11H NMR (300 MHz, DMSO-d6): δ 7.55 (d, J = 7.6 Hz, 1H), 7.13 - 7.01 (m, 2H), 5.24 (s, 1H), 4.48 (s, 2H), 3.88 - 3.72 (m, 5H), 3.31 (bs, 2H), 3.16 (bs, 4H), 1.43 (t, J = 6.5 Hz, 4H), 0.31 (s, 4H). m / z (ESI): 368.1 [M+1].

[0427] Step 5: To a stirred solution of methyl 4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (0.9 g, 2.45 mmol) in THF (6 mL) and methanol (4 mL) was added sodium hydroxide (98 mg, 2.45 mmol) in water (4 mL) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvents. The resulting aqueous layer was acidified to pH ~2 with 6N HCl aqueous solution and extracted with 10% methanol in DCM (3 x 50 mL). The organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was triturated with diethyl ether (50 mL) to afford 4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid as a white solid (0.6 g, 69% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.03 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 5.28 (t, J = 4.9 Hz, 1H), 4.60 (s, 2H), 3.88 - 3.80 (m, 2H), 3.22 (t, J = 5.8 Hz, 2H), 3.09 (t, J = 5.4 Hz, 4H), 1.72 - 1.47 (m, 4H), 0.44 (s, 4H). m / z (ESI): 352.1 [M-1]. [Note: COOH proton not observed].

[0428] Intermediate Intermediate 15: 4-((3-Methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)ben zoic acid 。

[0429]

[0430] Step 1: Under a nitrogen atmosphere, in a glass microwave reaction vessel (20 mL), to a solution of methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (2.0 g, 5.39 mmol, Intermediate 8-3) in DMSO (15.0 mL) was added potassium metabisulfite (2.40 g, 10.78 mmol), TBAB (1.91 g, 5.93 mmol), sodium formate (0.81 g, 11.85 mmol), triphenylphosphine (0.212 g, 0.81 mmol), 1,10-phenanthroline (0.146 g, 0.81 mmol) and palladium(II) acetate (0.060 g, 0.27 mmol). The reaction mixture was degassed and purged with nitrogen for 10 min. The reaction vessel was sealed and heated at 70 °C for 3 h. The reaction mixture was cooled to RT and 3-iodooxetane (2.39 g, 12.97 mmol) was added and stirred at 120 °C for 4 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a silica plug (60 - 120 mesh) and purified by silica gel chromatography through a Redi-Sep prepacked silica gel column (40 g) (with a gradient of 1% - 40% EtOAc in hexane) to give methyl 4-(oxetan-3-ylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate as a yellow solid (360 mg, 15% yield). 1 1H NMR (400 MHz, chloroform-d): δ 7.79 (dd, J = 8.1, 1.6 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.8 Hz, 1H), 4.98 (dd, J = 7.4, 6.2 Hz, 2H), 4.80 (dd, J = 8.4, 7.1 Hz, 2H), 4.45 (tt, J = 8.4, 6.2 Hz, 1H), 3.94 (s, 3H), 3.22 - 3.10 (m, 4H), 1.52 (t, J = 5.2 Hz, 4H), 0.38 (s, 4H). m / z (ESI): 366.1 [M+1].

[0431] Step 2: Under a nitrogen atmosphere, at -78 °C, to a solution of methyl 4-(oxetan-3-ylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (350 mg, 0.96 mmol) in THF (5 mL) was added LiHMDS (1.0 M solution in hexanes, 1.92 mL, 1.91 mmol) and the mixture was stirred for 1 h. Methyl iodide (71.9 μL, 1.15 mmol) was slowly added to the reaction mixture and the mixture was slowly warmed to RT. The reaction mixture was quenched with saturated aqueous NH4Cl (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a silica plug (60 - 120 mesh) and purified by silica gel chromatography through a Redi-Sep prepacked silica column (12 g) (eluting with a gradient of 1% - 50% EtOAc in hexanes) to give methyl 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (260 mg, 72% yield) as a pale yellow solid. 1 1H NMR (400 MHz, chloroform-d): δ 7.82 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 5.20 (d, J = 6.9 Hz, 2H), 4.43 (d, J = 6.9 Hz, 2H), 3.97 (s, 3H), 3.24 - 3.12 (m, 4H), 1.70 (s, 3H), 1.58 (t, J = 5.4 Hz, 4H), 0.40 (s, 4H). m / z (ESI): 380.2 [M+1].

[0432] Step 3: To a solution of methyl 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (250 mg, 0.66 mmol) in THF (5 mL), water (5 mL) and methanol (1 mL) was added lithium hydroxide (63 mg, 2.64 mmol) and the mixture was stirred at RT for 5 h. The reaction mixture was acidified to pH ~4 with 1.5 N HCl. The aqueous layer was extracted with EtOAc (3 x 50 mL), washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 83% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 16.01 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 5.01 (d, J = 7.4 Hz, 2H), 4.48 (d, J = 7.4 Hz, 2H), 3.19 (t, J = 5.2 Hz, 4H), 1.60 - 1.52 (m, 7H), 0.41 (s, 4H). m / z (ESI): 366.2 [M+1].

[0433] Intermediate 16: 4-(3-Methyloxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid 。

[0434]

[0435] Step 1: At 0 °C, thionyl chloride (92.1 g, 772 mmol) was added to a solution of 2-(4-bromo-3-fluorophenyl)acetic acid (180 g, 772 mmol) in EtOH (1500 mL) and the mixture was heated at 70 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue was extracted with EtOAc (3 x 1000 mL) and washed with saturated sodium bicarbonate solution (2 x 2000 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give ethyl 2-(4-bromo-3-fluorophenyl)acetate as a colorless gum (155 g, 77% yield). 1 1H NMR (400 MHz, chloroform-d): δ 7.54 - 7.48 (m, 1H), 7.11 (dd, J = 9.3, 2.1 Hz, 1H), 6.98 (ddt, J = 8.2, 2.0, 0.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.60 (s, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0436] Step 2: At -78 °C, to a solution of ethyl 2-(4-bromo-3-fluorophenyl)acetate (155 g, 594 mmol) in anhydrous THF (1500 mL) was added LDA (2.0 M solution in THF, 297 mL, 594 mmol) and the mixture was stirred at -78 °C for 1 h. Ethyl cyanoformate (64.7 g, 653 mmol) was added to the reaction mixture at -78 °C and the reaction mixture was stirred at -78 °C for 1 h. The mixture was quenched with 1.5 N HCl solution (1 L) and extracted with EtOAc (3 x 2 L). The organic layer was washed with water (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60 - 120 mesh) using 10% EtOAc in hexane to give diethyl 2-(4-bromo-3-fluorophenyl)malonate as a viscous oil (120.0 g, 60% yield). 1 H NMR (400 MHz, chloroform-d): δ 7.59 - 7.49 (m, 1H), 7.31 - 7.25 (m, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 4.59 (s, 1H), 4.37 - 4.14 (m, 4H), 1.36 - 1.24 (m, 6H).

[0437] Step 3: At 0 °C, to a solution of diethyl 2-(4-bromo-3-fluorophenyl)malonate (60.0 g, 180 mmol) in DMF (600 mL) was added sodium hydride (8.64 g, 360 mmol), then methyl iodide (30.7 g, 216 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice and extracted with EtOAc (3 x 1 L). The combined organic extracts were washed with water (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 10% EtOAc in hexane to give diethyl 2-(4-bromo-3-fluorophenyl)methylmalonate as a light brown gum (45.0 g, 72% yield). 1 H NMR (400 MHz, chloroform-d): δ 7.53 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 7.11 - 7.05 (m, 1H), 4.25 (q, J = 7.1 Hz, 4H), 1.85 (s, 3H), 1.27 (t, J = 7.1 Hz, 6H).

[0438] Step 4: At 0 °C, lithium aluminum hydride (2.0 M solution in THF, 130 mL, 260 mmol) was added to a solution of diethyl 2-(4-bromo-3-fluorophenyl)methylmalonate (45.0 g, 130 mmol) in anhydrous THF (500 mL), and the reaction mixture was stirred at RT for 2 h. The reaction mixture was quenched with MeOH (40 mL), and then 1.5 N HCl (500 mL) was added. The mixture was extracted with EtOAc (3 x 500 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using 20% EtOAc in hexane to give 2-(4-bromo-3-fluorophenyl)-2-methylpropane-1,3-diol as a gum (20 g, 59% yield). 1 1H NMR (400 MHz, chloroform-d): δ 7.53 (dd, J = 8.4, 7.5 Hz, 1H), 7.29 - 7.21 (m, 1H), 7.12 (dd, J = 8.4, 2.2 Hz, 1H), 3.92 (d, J = 11.0 Hz, 2H), 3.77 (d, J = 11.0 Hz, 2H), 2.44 (br s, 2H), 1.25 (s, 3H).

[0439] Step 5: At 0 °C, n-butyllithium (2.5 M solution in hexane, 3.8 mL, 9.5 mmol) was added to a solution of 2-(4-bromo-3-fluorophenyl)-2-methylpropane-1,3-diol (2.5 g, 9.50 mmol) in anhydrous THF (30 mL), and the mixture was stirred for 30 min. At 0 °C, p-toluenesulfonyl chloride (1.08 g, 5.70 mmol) was added to the reaction mixture and stirred at RT for 1 h. After cooling the reaction mixture to 0 °C, n-butyllithium (3.8 mL, 9.5 mmol) was added at 0 °C and slowly heated to 70 °C and maintained for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 5% EtOAc in hexane to give 3-(4-bromo-3-fluorophenyl)-3-methyloxetane as a white solid (0.25 g, 11% yield). 1 1H NMR (400 MHz, chloroform-d): δ 7.54 (td, J = 7.6, 7.1 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.92 (dd, J = 8.2, 2.2 Hz, 1H), 4.89 (d, J = 5.7 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 1.72 (s, 3H).

[0440] Step 6: At -78 °C, n-butyllithium (4.9 mL, 12.24 mmol) was added to a solution of 3-(4-bromo-3-fluorophenyl)-3-methyloxetane (2.5 g, 10.20 mmol) in THF (50 mL) and the reaction mixture was stirred at -78 °C for 15 min. At -78 °C, ethyl cyanoformate (1.21 g, 12.24 mmol) was added thereto and the reaction mixture was slowly warmed to 0 °C. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography using 10% EtOAc in hexane to give ethyl 2-fluoro-4-(3-methyloxetan-3-yl)benzoate (1.25 g, 51% yield) as a white solid. 1 1H NMR (400 MHz, chloroform-d): δ 7.95 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 7.03 - 6.97 (m, 1H), 4.93 (d, J = 5.7 Hz, 2H), 4.67 (d, J = 5.7 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.74 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). m / z (ESI): 239.2 [M+1].

[0441] Step 7: To a solution of ethyl 2-fluoro-4-(3-methyloxetan-3-yl)benzoate (0.5 g, 2.10 mmol) in DMSO (5 mL) was added azaspiro[2.5]octane (0.28 g, 2.52 mmol) and heated in a microwave to 130 °C for 6 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using 10% EtOAc in hexane to give ethyl 4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (0.4 g, 58% yield) as a white solid. 11H NMR (400 MHz, chloroform-d): δ 7.70 (d, J = 8.0 Hz, 1H), 6.94 - 6.79 (m, 2H), 4.97 (d, J = 5.6 Hz, 2H), 4.64 (d, J = 5.6 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.12 (s, 4H), 1.74 (s, 3H), 1.55 (bs, 4H), 1.41 (t, J = 7.1 Hz, 3H), 0.37 (s, 4H). m / z (ESI): 330.8 [M+1].

[0442] Step 8: To a solution of ethyl 4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.8 g, 2.428 mmol) in THF (5 mL), water (5 mL) and MeOH (3 mL) was added lithium hydroxide monohydrate (117 mg, 4.86 mmol) and stirred at RT for 12 h. The reaction mixture was diluted with water (30 mL) and neutralized with 1.5 N HCl solution to a pH of about 7. The reaction mixture was extracted with EtOAc (3 x 70 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with diethyl ether (20 mL), filtered and dried in vacuo to afford 4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid as a white solid (0.45 g, 62% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.30 (dd, J = 8.4, 1.6 Hz, 1H), 4.85 (d, J = 5.6 Hz, 2H), 4.58 (d, J = 5.6 Hz, 2H), 3.13 (t, J = 5.4 Hz, 4H), 1.65 (s, 3H), 1.60 (dd, J = 8.7, 4.6 Hz, 4H), 0.44 (s, 4H). Note: Acid proton not visible. m / z (ESI): 302.2 [M+1].

[0443] Intermediate 17: 4-(3-Hydroxyloxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid 。

[0444]

[0445] Step 1: At -78 °C, n-butyllithium (2.5 M solution in hexanes, 36.5 mL, 91 mmol) was added to a solution of 4-bromo-2-fluorobenzoic acid (10.0 g, 45.7 mmol) in THF (150 mL), and the mixture was stirred at -78 °C for 30 min. At -78 °C, oxetan-3-one (6.5 g, 91.4 mmol) was added to the reaction mixture and stirring was continued for 1 h. The reaction mixture was quenched with 2.0 M aqueous sodium hydroxide (100 mL) and extracted with EtOAc (100 mL). The organic layer was discarded, and the aqueous layer was cooled to 0 °C, acidified to pH ~5 with 2.0 N HCl, and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography, eluting with 50% EtOAc in hexanes, to give 2-fluoro-4-(3-hydroxyoxetan-3-yl)benzoic acid as a white solid (1.7 g, 17% yield). 1 1H NMR (300 MHz, DMSO-d6): δ 7.92 (t, J = 8.0 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.45 (d, J = 12.3 Hz, 1H), 6.65 (s, 1H), 4.78 (d, J = 6.6 Hz, 2H), 4.67 (d, J = 6.6 Hz, 2H). Note: Acid proton not visible. m / z (ESI): 211.1 [M - 1].

[0446] Step 2: 6-Azaspiro[2.5]octane (4.0 g, 35.8 mmol) was added to a solution of 2-fluoro-4-(3-hydroxyoxetan-3-yl)benzoic acid (3.8 g, 17.91 mmol) in DMSO (40 mL), and the mixture was heated to 160 °C in a microwave (Biotagemicrowave initiator+) for 4 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse-phase silica gel chromatography, using 40% CH3CN in water, to give 4-(3-hydroxyoxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid as a white solid (1.1 g, 20% yield). 11H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J = 8.2, 1.8 Hz, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7.69 (dt, J = 8.3, 1.8 Hz, 1H), 6.62 (d, J = 1.7 Hz, 1H), 4.79 (d, J = 6.4 Hz, 2H), 4.72 (d, J = 6.4 Hz, 2H), 3.14 - 3.08 (m, 4H), 1.59 (bs, 4H), 0.44 (s, 4H). Note: Acid protons are not visible. m / z (ESI): 302.2 [M - 1].

[0447] Intermediate 18: 4-Bromo-2-(6-azaspiro[2.5]oct-6-yl)aniline 。

[0448]

[0449] Step 1: A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.4 mmol, Combi-Blocks), 6-azaspiro[2.5]octane hydrochloride (2.45 g, 16.57 mmol, Alchemist Technologies), and potassium carbonate (5.97 g, 43.2 mmol, Sigma-Aldrich) in DMSO (12 mL) was heated in an oil bath at 60 °C for 10 min and then heated to 90 °C for 1 h. The mixture was cooled to RT, treated with 20 mL of water, and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (2 x 5 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified on a silica gel column (15% - 45% EtOAc in heptane) to afford 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane as an orange solid (4.26 g, 13.7 mmol, 95% yield). m / z (ESI): 311.0 / 313.0 (M + H) + 。

[0450] Step 2: Iron powder (3.13 g, 56.1 mmol, Sigma-Aldrich) was added to a mixture of 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (2.91 g, 9.35 mmol) and NH4Cl (1.50 g, 28.1 mmol, Sigma-Aldrich) in EtOH (16 mL) and water (4 mL). The heterogeneous mixture was heated in an oil bath at 85 °C for 2 h. The dark mixture was diluted with 50 mL of MeOH and filtered through Pad filtration. The filter cake was rinsed with 2 x 5 mL of MeOH and the filtrate was concentrated in vacuo. The residue was partitioned between 10 mL of water and 75 mL of EtOAc. The organic layer was removed, dried over Na2SO4 and concentrated to afford 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline as a brown oil (2.23 g, 7.95 mmol, 85% yield). 1 H NMR (400 MHz, METHANOL-d4) δ 6.87 (d, J = 2.28 Hz, 1H), 6.77 (dd, J = 2.18, 8.40 Hz, 1H), 6.48 (d, J = 8.50 Hz, 1H), 4.65 (s, 4H), 1.23 - 1.50 (br s, 4H), 0.18 (s, 4H). m / z (ESI): 281.0 / 283.0 (M + H) + 。

[0451] AR 1 and AR 2 Coupling of the intermediate

[0452] Intermediate 19: N-(3-(N-(tert-Butyl)aminosulfonyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]oct-6- yl)benzamide.

[0453]

[0454] Step - 1: At RT, 3-amino-N-(tert-butyl)benzenesulfonamide (1.72 g, 7.52 mmol), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinium hexafluorophosphate (3.86 g, 9.02 mmol) and N-methylmorpholine (2.48 mL, 22.56 mmol) were slowly added to a solution of 2-fluoro-4-iodobenzoic acid (2.0 g, 7.52 mmol) in DMF (20 mL) and stirred for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a silica plug and purified by flash chromatography through a Redi-Sep pre-packed silica column (eluting with a 0 - 50% EtOAc gradient in hexane) to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-fluoro-4-iodobenzamide as a yellow solid (2.8 g, 78% yield). 11H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 8.29 (s, 1H), 7.86 - 7.71 (m, 3H), 7.61 - 7.51 (m, 3H), 7.48 (t, J = 7.83 Hz, 1H), 1.12 (s, 9H). m / z (ESI): 475.0 [M - 1].

[0455] Step - 2: Under a nitrogen atmosphere, 6 - azaspiro[2.5]octane (1.87 g, 16.80 mmol) and DIPEA (2.93 mL, 16.80 mmol) were added to a solution of N-(3-(N-(tert - butyl)sulfamoyl)phenyl)-2 - fluoro - 4 - iodobenzamide (8.0 g, 16.80 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with water (150 mL). The precipitated solid was filtered out, washed with water (200 mL), and dried under vacuum. The solid cake was adsorbed onto a silica gel plug and purified by flash chromatography through a Redi - Sep pre - packed silica gel column (eluting with a 0 - 30% EtOAc gradient in hexane) to afford N-(3-(N-(tert - butyl)sulfamoyl)phenyl)-4 - iodo - 2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide as an off - white foamy solid (6.0 g, 63% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 8.32 (s, 1H), 7.90 (d, J = 4.4 Hz, 1H), 7.59 - 7.54 (m, 5H), 7.47 - 7.44 (m, 1H), 3.35 (s, 4H), 1.41 (s, 4H), 1.18 (s, 9H), 0.28 (s, 4H). m / z (ESI): 568.1 [M + 1].

[0456] Table 5: Intermediates 19 - 1 and 19 - 2 were prepared according to a procedure similar to the preparation of Intermediate 19.

[0457]

[0458] Intermediate 20: 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-2-(6-azaspiro[2.5] oct-6-yl)benzamide.

[0459]

[0460] A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.47 g, 7.96 mmol, Intermediate 8-1), N-ethyl-N-isopropylpropan-2-amine (2.57 g, 19.89 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in EtOAc, 12.66 g, 19.89 mmol), and 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (1.5 g, 6.63 mmol, Intermediate 3) in DCM (15 mL) was stirred at RT for 6 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography using 60%-70% EtOAc in petroleum ether to afford 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a light brown oil (1 g, 1.93 mmol, 29% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 11.19 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.17 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.61 (s, 1H), 3.30 - 3.34 (m, 4H), 3.02 (t, J = 5.2 Hz, 4H), 2.27 (s, 3H), 1.97 - 2.13 (m, 4H), 1.49 (t, J = 5.2 Hz, 4H), 0.32 (s, 4H). m / z (ESI): 518.1 (M+H) + 。

[0461] Intermediate 21: 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl)-2-(6-azaspiro[2.5]oct- 6-yl)benzamide.

[0462]

[0463] A mixture of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.2 g, 0.64 mmol, Intermediate 8-1), oxalyl dichloride (0.123 g, 0.97 mmol), and catalytic DMF in DCM (3 mL) was stirred at 0 °C for 30 min. The reaction mixture was concentrated and the residue was dissolved in dioxane (2 mL). This solution was treated with a solution of 3-(4,4-difluoropiperidin-1-yl)-2-fluoroaniline (0.15 g, 0.64 mmol, Intermediate 4) and Et3N (0.27 mL, 1.93 mmol) in dioxane (4 mL). The reaction mixture was stirred at 100 °C 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 silica gel column chromatography (eluting with 10%-20% EtOAc in petroleum ether) to afford 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-2-fluorophenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as an off-white solid (0.160 g, 0.31 mmol, 48% yield). 1 1H NMR (300 MHz, DMSO-d6): δ ppm 11.86 (s, 1H), 7.99 (t, J = 7.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.8 Hz, 1H), 7.13 (t, J = 8.2 Hz, 1H), 6.92 (t, J = 8.2 Hz, 1H), 3.16 (t, J = 6.0 Hz, 4H), 3.03 (t, J = 5.3 Hz, 4H), 2.07 - 2.22 (m, 4H), 1.53 (s, 4H), 0.36 (s, 4H). m / z (ESI): 524.1 (M+H) + 。

[0464] Table 6: Intermediates 22 to 26 were prepared according to a preparation similar to that of Intermediate 20 or 21:

[0465]

[0466]

[0467] Intermediate 27: 4-Bromo-N-(3-(2-hydroxy-2-methylpropoxy)phenyl)-2-(6-azaspiro[2.5]oct-6- yl)benzamide.

[0468]

[0469] Step 1: A mixture of 3-aminophenol (5 g, 45.8 mmol) and Boc-anhydride (9.0 g, 41.2 mmol) in THF (50 mL) was stirred at 70 °C for 24 h. The reaction mixture was diluted with EtOAc and washed with 1.5 N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 15%-20% EtOAc in petroleum ether) to afford tert-butyl (3-hydroxyphenyl)carbamate as an off-white solid (8.0 g, 38.2 mmol, 83% yield). 1 1H NMR (400 MHz, DMSO-d6): δ ppm 9.25 (d, J = 1.7 Hz, 1H), 9.20 (s, 1H), 6.90 - 7.13 (m, 2H), 6.74 - 6.90 (m, 1H), 6.35 (ddt, J = 1.3, 2.7, 8.1 Hz, 1H), 1.47 (s, 9H).

[0470] Step 2: A mixture of tert-butyl (3-hydroxyphenyl)carbamate (3.0 g, 14.34 mmol), K2CO3 (5.94 g, 43.0 mmol) and ethyl 2-bromoacetate (2.39 mL, 21.51 mmol) in methyl ethyl ketone (40 mL) was stirred at 78 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 10%-15% EtOAc in petroleum ether) to afford ethyl 2-(3-((tert-butoxycarbonyl)amino)phenoxy)acetate as a colorless oil (3.4 g, 11.51 mmol, 80% yield). 1 1H NMR (300 MHz, DMSO-d6): δ ppm 9.32 (s, 1H), 6.98 - 7.14 (m, 3H), 6.49 (dd, J = 2.6, 8.0 Hz, 1H), 4.67 (s, 2H), 3.75 - 4.37 (m, 2H), 1.45 (s, 9H), 1.20 (t, J = 7.2 Hz, 3H). m / z (ESI): 196.1 (M - Boc) + 。

[0471] Step 3: A solution of ethyl 2-(3-((tert-butoxycarbonyl)amino)phenoxy)acetate (1.0 g, 3.39 mmol) and TFA (1.30 mL, 16.93 mmol) in DCM (10 mL) was stirred at RT for 6 h. The reaction was concentrated, neutralized with saturated aqueous sodium bicarbonate and extracted with DCM. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated to afford ethyl 2-(3-aminophenoxy)acetate as a yellow oil (0.6 g, 3.07 mmol, 91% yield). 1 H NMR (300 MHz, DMSO-d6): δ ppm 7.27 (t, J = 8.1 Hz, 2H), 6.66 - 6.80 (m, 3H), 4.77 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). m / z (ESI): 196.1 (M + H) + 。

[0472] Step 4: A mixture of 4-bromo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (0.5 g, 1.61 mmol, Intermediate 8-1), ethyl 2-(3-aminophenoxy)acetate (0.47 g, 2.42 mmol), DIPEA (0.84 mL, 4.84 mmol) and T3P (50% in EtOAc, 2.05 g, 3.22 mmol) in DCM (10 mL) was stirred at rt for 48 h. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 10% EtOAc in petroleum ether) to afford ethyl 2-(3-(4-bromo-2-(6-azaspiro[2.5]oct-6-yl)benzamido)phenoxy)acetate as a pale yellow oil (0.41 g, 0.84 mmol, 52% yield). 1 HNMR (300 MHz, DMSO-d6): δ ppm 11.16 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 7.40 (dd, J = 1.8, 14.8 Hz, 1H), 7.32 (d, J = 17.3 Hz, 1H), 7.28 - 7.32 (m, 2H), 6.64 - 6.70 (m, 1H), 4.76 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.03 (t, J = 6.4 Hz, 4H), 1.46 (br s, 4H), 1.21 (t, J = 7.4 Hz, 3H), 0.32 (s, 4H). m / z (ESI): 487.1 (M + H) + 。

[0473] Step 5: At 0 °C, methylmagnesium bromide (2.05 mL, 6.16 mmol) was added to a solution of ethyl 2-(3-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)phenoxy)acetate (0.5 g, 1.03 mmol) in THF (15 mL), and the reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 15% EtOAc in petroleum) to afford 4-bromo-N-(3-(2-hydroxy-2-methylpropoxy)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as an off-white solid (0.26 g, 0.55 mmol, 53% yield). 1 HNMR (300 MHz, DMSO-d6): δ ppm 11.18 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 2.2 Hz, 1H), 7.29 - 7.48 (m, 2H), 7.18 - 7.30 (m, 2H), 6.66 - 6.70 (m, 1H), 4.66 (s, 1H), 3.70 (s, 2H), 3.02 (t, J = 5.4 Hz, 4H), 1.46 (br s, 4H), 1.21 (s, 6H), 0.32 (s, 4H). m / z (ESI): 473.1 (M+H) + 。

[0474] Intermediate 28: Ethyl 2-sulfamoylpropionate

[0475]

[0476] Step 1: nBuLi (1.6 M in hexanes, 608.0 mL, 973.0 mmol) was slowly added to a solution of N,N-bis(4-methoxybenzyl)ethanesulfonamide (200.0 g, 572.0 mmol) in THF (4000 mL) at -78 °C, and the mixture was stirred for 30 min. Ethyl chloroformate (92.0 mL, 973.0 mmol) in THF (50 mL) was added to the reaction mixture, and the mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with HCl (1.5 N, 3000 mL) and extracted with EtOAc (2 x 3000 mL). The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude material of ethyl 2-(N,N-bis(4-methoxybenzyl)aminosulfonyl)propionate (250.0 g, 60% purity) as a yellow oil, which was used in the next step without any purification.

[0477] Step 2: To a solution of ethyl 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)propionate (600.0 g, 1.4 mol) in trifluoroacetic acid (2.50 L, 32.45 mol) was added anisole (500.0 mL, 4.57 mol) and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure, quenched with 10% aqueous NaHCO3 (3 L) and extracted with EtOAc (2 x 3 L). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 25% EtOAc in hexane to give a pale yellow solid (168 g), which was dissolved in DCM (1 L) and precipitated by addition of hexane (3000 mL). The solid was filtered and dried in vacuo to give the title compound as a white solid (109.0 g, 42% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14 (s, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.98 (q, J = 7.0 Hz, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). m / z (ESI): 180.1 (M-H) + 。

[0478] Examples

[0479] Example 100: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-methyloxetan-3-yl)sulfonyl yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0480]

[0481] At RT, to a solution of 4-((3-methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (120 mg, 0.33 mmol, Intermediate 15) in DMF (2 mL) was added HATU (187 mg, 0.49 mmol) and DIPEA (143 μL, 0.821 mmol) and the mixture was stirred for 10 min. To this reaction mixture was added 3-amino-N-(tert-butyl)benzenesulfonamide (82 mg, 0.36 mmol) and the mixture was stirred at RT for 12 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using 30% EtOAc in hexane to give the title compound as an off-white solid (110 mg, 58% yield). 11H NMR (400 MHz, chloroform-d): δ 12.33 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.06 - 7.95 (m, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 1.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 5.19 (d, J = 7.0 Hz, 2H), 4.52 (s, 1H), 4.47 (d, J = 7.0 Hz, 2H), 3.16 (t, J = 5.5 Hz, 4H), 1.73 (s, 3H), 1.70 - 1.60 (broad s, 3H), 1.30 (s, 9H), 0.48 (s, 4H). m / z (ESI): 576.2 [M+1].

[0482] Table 7: Examples 100-1 to 100-15 were prepared according to a preparation similar to that of Example 100:

[0483]

[0484]

[0485]

[0486]

[0487] Example 101: N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan -3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0488]

[0489] To a solution of 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.25 g, 0.66 mmol, Intermediate 12) and 2-((3-aminophenyl)amino)-2-methylpropan-1-ol (0.130 g, 0.72 mmol, Intermediate 2-2) in DMF (3 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.291 g, 0.986 mmol) and the mixture was stirred at rt for 18 h. The reaction was partitioned between water and EtOAc. The organic phase was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by preparative SFC gave N-(3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.26 g, 0.48 mmol, 73% yield). 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.61 (s, 1H) 8.16 (s, 1H) 7.87 (d, J = 8.48 Hz, 1H) 7.26 (d, J = 2.06 Hz, 1H) 7.17 (t, J = 1.95 Hz, 1H) 7.05 - 7.10 (m, 2H) 6.99 - 7.04 (m, 1H) 6.42 - 6.46 (m, 1H) 3.39 (s, 2H) 3.18 (s, 3H) 2.96 (br t, J = 5.16 Hz, 4H) 1.58 (br s, 4H) 1.42 (s, 3H) 1.26 (s, 6H) 1.18 - 1.22 (m, 2H) 0.84 (d, J = 2.06 Hz, 2H) 0.37 (s, 4H). m / z (ESI, +ve ion): 527.3 (M + H) + 。

[0490] Table 8: Examples 101-1 to 101-3 were prepared according to a preparation similar to Example 101:

[0491]

[0492] Example 102: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-methylcyclopropyl)-1-sulfonamido)- 2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0493]

[0494] Charge a 250-mL glass tube with a solution of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (15.0 g, 26.4 mmol, Intermediate 19) and DMF (100 mL). To this solution, add tripotassium phosphate (16.83 g, 79.0 mmol), copper(I) iodide (1.26 g, 6.61 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (1.0 mL, 6.61 mmol), and 1-methylcyclopropane-1-sulfonamide (4.3 g, 31.7 mmol). Degas the reaction mixture and purge with nitrogen for 10 min. Seal the tube and stir at 100 °C for 16 h. Cool the reaction mixture to RT and quench with saturated aqueous NH4Cl (100 mL). Extract the reaction mixture with DCM (3 x 50 mL) and wash with water (50 mL). Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude residue by silica gel chromatography, eluting with a 40% EtOAc gradient in hexanes to give a brown solid. Further purify the solid by trituration with heptane (75 mL) and EtOAc (25 mL) to afford the title compound as a white solid (10.0 g, 66% yield). 1 1H NMR (400 MHz, DMSO-d6): δ 11.63 (s, 1H), 10.16 (s, 1H), 8.34 (d, J = 2.1 Hz, 1H), 7.91 (dt, J = 8.0, 1.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.62 - 7.52 (m, 3H), 7.22 (d, J = 2.1 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 2.96 (t, J = 5.4 Hz, 4H), 1.48 (d, J = 5.6 Hz, 4H), 1.42 (s, 3H), 1.21 (q, J = 4.5 Hz, 2H), 1.12 (s, 9H), 0.89 - 0.80 (m, 2H), 0.33 (s, 4H). m / z (ESI): 575.2 [M+1].

[0495] Table 9: Examples 102-1 to 102-6 were prepared according to a preparation similar to Example 102:

[0496]

[0497]

[0498] Example 103: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6- azaspiro[2.5]oct-6-yl)benzamide.

[0499]

[0500] Step 1: Take N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.25 g, 0.44 mmol, Intermediate 19) in dioxane (2.5 mL) in a sealed tube (10 mL). To this solution, add ethyl 2-sulfamoylacetate (0.15 g, 0.88 mmol) and potassium carbonate (0.15 g, 1.10 mmol) at RT. Degas the reaction mixture and purge with nitrogen for 10 min. Add Xantphos (0.013 g, 0.022 mmol) and Pd2dba3 (0.020 g, 0.022 mmol) thereto. Seal the reaction tube and stir at 110 °C for 16 h. Quench the reaction mixture with water (20 mL) and extract with EtOAc (2 x 50 mL). Wash the organic layer with brine (10 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Purify the crude residue by column chromatography (using 50% EtOAc in hexane on silica gel (60 - 120 mesh)) to obtain ethyl 2-(N-(4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (100 mg, 37% yield) as a brown spongy solid. 1 HNMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 10.45 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.90 - 7.70 (m, 1H), 7.54 - 7.44 (m, 3H), 7.12 - 6.97 (m, 2H), 4.33 (s, 2H), 4.09 (q, J = 7.08 Hz, 2H), 3.07 (s, 1H), 3.00 (bs, 4H), 1.47 (bs, 4H), 1.20 - 1.02 (m, 12H), 0.33 (s, 4H). m / z (ESI): 607.2 [M+1].

[0501] Step 2: At 0 °C, lithium borohydride (2.0 M in THF, 0.22 mL, 0.445 mmol) was added to a solution of ethyl 2-(N-(4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.18 g, 0.297 mmol) in THF (4 mL) and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with saturated brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (using 50% EtOAc in hexanes on silica gel) to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 48% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 10.10 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 7.52 Hz, 1H), 7.77 (d, J = 8.48 Hz, 1H), 7.60 - 7.51 (m, 3H), 7.14 (s, 1H), 7.01 (d, J = 8.48 Hz, 1H), 4.98 (t, J = 5.44 Hz, 1H), 3.76 (dt, J = 6.24, 5.44 Hz, 2H), 3.34 (t, J = 6.24 Hz, 2H), 2.98 (br s, 4H), 1.48 (br s, 4H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 565.2 [M+1].

[0502] Table 10: Examples 103-1 to 103-4 were prepared according to a preparation similar to that of Example 103:

[0503]

[0504]

[0505] Example 104: N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfonamido yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0506]

[0507] A mixture of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.5 g, 0.96 mmol, Intermediate 20), potassium phosphate (0.614 g, 2.89 mmol), 2-hydroxyethane-1-sulfonamide (0.181 g, 1.45 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.069 g, 0.48 mmol) and copper(I) iodide (0.092 g, 0.48 mmol) in DMF (5 mL) was stirred at 90 °C for 16 h. The reaction mixture was quenched with ice water and filtered through a bed, and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography using 40% EtOAc in petroleum ether to afford N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.31 g, 0.54 mmol, 56% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 11.55 (s, 1H), 10.09 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.12 - 7.16 (m, 3H), 7.03 (dd, J = 8.5, 2.1 Hz, 1H), 6.60 (s, 1H), 4.97 (br s, 1H), 3.76 (t, J = 6.6 Hz, 2H), 3.30 - 3.34 (m, 6H), 2.97 (t, J = 5.3 Hz, 4H), 2.27 (s, 3H), 2.00 - 2.10 (m, 4H), 1.55 (br s, 4H), 0.36 (s, 4H). m / z (ESI): 563.2 (M + H) + 。

[0508] Table 11: Examples 104-1 to 104-2 were prepared according to a preparation similar to that of Example 104:

[0509]

[0510] Examples 105-1 and 105-2: (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methyl ethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (R)-N-(3-(N-(tert-Butyl)sulfamoyl yl)phenyl)-4-((2-hydroxy-1-methyl ethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0511]

[0512]

[0513] Step 1: Charge a glass tube with N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-iodo-2-(6-azaspiro[2.5]oct-6-yl)benzamide (1.0 g, 1.76 mmol, Intermediate 19) and dioxane (10 mL). To this solution, add ethyl 2-sulfamoylpropionate (0.64 g, 3.52 mmol, Intermediate 28) and potassium carbonate (0.61 g, 4.41 mmol). Degas the reaction mixture and purge with nitrogen for 10 min. Add Xantphos (0.051 g, 0.088 mmol) and Pd2dba3 (0.081 g, 0.088 mmol) to the reaction mixture. Seal the reaction vessel and stir at 110 °C for 16 h. Quench the reaction mixture with water (50 mL) and extract with EtOAc (2 x 50 mL). Wash the combined organic extracts with brine (50 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Purify the crude residue by column chromatography (using 50% EtOAc in hexanes on silica gel) to afford ethyl 2-(N-(4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)propionate (400 mg, 38% yield) as a brown solid. 1 H NMR (400 MHz, chloroform-d): δ 8.28 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.66 (t, J = 9.0 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.39 (s, 1H), 7.21 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 93.0 Hz, 1H), 4.59 (d, J = 9.7 Hz, 1H), 4.28 (dd, J = 8.0, 5.6 Hz, 2H), 3.83 - 3.66 (m, 8H), 3.10 (d, J = 5.3 Hz, 3H), 1.29 (bs, 12H), 0.45 (s, 4H). m / z (ESI): 621.2 [M+1].

[0514] Step 2: At 0 °C, lithium borohydride (2 M in THF, 0.387 mL, 0.773 mmol) was added to a solution of 2-(N-(4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)propionate (0.4 g, 0.64 mmol) in THF (4 mL) and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (25 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with saturated brine solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (using 50%-100% EtOAc in hexanes on silica gel) to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methylethyl)sulfamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (300 mg, 80% yield) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.66 - 7.47 (m, 3H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J = 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 - 2.92 (m, 4H), 1.48 (bs, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1]. The racemic material was resolved by preparative SFC using Chiralpak AD-H (250×30 mm, 5 μm), with mobile phase of 75% liquid CO2 and 25% MeOH, flow rate of 100 mL / min, to afford the compounds of Examples 105-1 and 105-2 as follows:

[0515] Example 105-1: (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methyl ethyl)sulfon amido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0516] First elution peak, ee 100%; 11H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.66 - 7.47 (m, 3H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J = 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 - 2.92 (m, 4H), 1.48 (bs, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1].

[0517] Example 105-2: (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methyl ethyl)sulfon amido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0518] The second elution peak, ee 97.5%; 1 1H NMR (400 MHz, DMSO-d6): δ 11.53 (s, 1H), 10.11 (s, 1H), 8.34 (d, J = 1.9 Hz, 1H), 7.90 (dt, J = 7.8, 1.8 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.66 - 7.47 (m, 3H), 7.16 (d, J = 2.1 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 5.06 (d, J = 6.6 Hz, 1H), 3.85 (dd, J = 9.8, 5.2 Hz, 1H), 3.49 (s, 1H), 3.25 (dt, J = 7.6, 3.9 Hz, 1H), 3.04 - 2.92 (m, 4H), 1.48 (bs, 4H), 1.30 (d, J = 6.8 Hz, 3H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 579.1 [M+1].

[0519] The stereochemistry determination is arbitrary.

[0520] Example 106: N-(3-(2-Hydroxy-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2- (6-azaspiro[2.5]oct-6-yl)benzamide.

[0521]

[0522] Step 1: A mixture of 4-bromo-N-(3-(2-hydroxy-2-methylpropoxy)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.260 g, 0.549 mmol, Intermediate 27), methyl 2-sulfamoylacetate (0.126 g, 0.82 mmol), tripotassium phosphate (0.233 g, 1.10 mmol), copper(I) iodide (0.105 g, 0.55 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.039 g, 0.27 mmol) in DMF (5 mL) was stirred at 90 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 40%-50% EtOAc in petroleum ether) to afford methyl 2-(N-(4-((3-(2-hydroxy-2-methylpropoxy)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (0.260 g, 0.476 mmol, 87% yield) as a pale yellow oil. 1 H NMR (300 MHz, DMSO-d6): δ ppm 11.53 (s, 1H), 10.53 (s, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.14 - 7.20 (m, 1H), 6.96 - 7.07 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.65 (s, 1H), 4.36 (s, 2H), 3.70 (s, 2H), 3.65 (s, 3H), 2.95 - 3.02 (m, 4H), 1.53 (br s, 4H), 1.21 (s, 6H), 0.35 (s, 4H). m / z (ESI): 546.2 (M + H) + 。

[0523] Step 2: At 0 °C, lithium borohydride (0.95 mL, 1.91 mmol) was added to a solution of methyl 2-(N-(4-((3-(2-hydroxy-2-methylpropoxy)phenyl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (0.260 g, 0.476 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel column chromatography (eluting with 45%-50% EtOAc in petroleum ether) to give N-(3-(2-hydroxy-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.032 g, 0.062 mmol, 13% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.54 (s, 1H), 10.08 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.47 (t, J = 2.1 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 7.19 - 7.10 (m, 2H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.75 - 6.64 (m, 1H), 4.95 (s, 1H), 4.65 (s, 1H), 3.82 - 3.62 (m, 4H), 2.94 - 3.01 (m, 4H), 1.52 (br s, 4H), 1.40 - 1.46 (m, 2H), 1.21 (s, 6H), 0.34 (s, 4H). m / z (ESI): 518.2 (M+H) + .

[0524] Example 107: 4-(Azetidin-1-ylsulfonyl)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2- (6-azaspiro[2.5]oct-6-yl)benzamide.

[0525]

[0526] Step 1: Under Ar atmosphere, 4-bromo-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (3.98 g, 7.65 mmol, Intermediate 19-1), xantphos (0.227 g, 0.39 mmol), Pd2dba3 (0.18 g, 0.2 mmol) and dioxane (25 mL) were charged into a 250-mL round-bottom flask. While degassing the mixture by bubbling Ar through it, DIPEA (2.96 mL, 22.94 mmol) was added, and then benzyl mercaptan (0.95 mL, 8.03 mmol) was added. The reaction mixture was heated at 100 °C for 1 h. The mixture was cooled to rt and partitioned between water (40 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (30 mL). The organic phase was dried over a Chem Elut extraction column eluted with EtOAc (2 x 10 mL), and the solvent was removed in vacuo. The crude product was used for the next step. 1 H NMR (400 MHz, chloroform-d) δ 12.78 (s, 1H), 8.28 (s, 1H), 8.18 (d, J = 8.22 Hz, 1H), 7.98 (dd, J = 1.08, 8.12 Hz, 1H), 7.63 (d, J = 7.82 Hz, 1H), 7.45 - 7.52 (m, 1H), 7.28 - 7.40 (m, 5H), 7.22 (dd, J = 1.66, 8.31 Hz, 1H), 7.17 (d, J = 1.56 Hz, 1H), 4.56 (s, 1H), 4.22 (s, 2H), 2.99 (t, J = 5.28 Hz, 4H), 1.60 - 1.67 (m, 4H), 1.28 (s, 9H), 0.43 (s, 4H). In DMSO-d6: 1 H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.32 (s, 1H), 7.88 (br d, J = 7.24 Hz, 1H), 7.70 (d, J = 8.61 Hz, 1H), 7.50 - 7.59 (m, 3H), 7.44 (d, J = 7.24 Hz, 2H), 7.33 (t, J = 7.34 Hz, 2H), 7.22 - 7.29 (m, 1H), 7.14 (dd, J = 2.54, 4.11 Hz, 2H), 4.36 (s, 2H), 2.96 (br t, J = 4.99 Hz, 4H), 1.45 (br s, 4H), 1.11 (s, 9H), 0.31 (s, 4H).

[0527] Step 2: Charge 4-(benzylthio)-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (1.01 g, 1.781 mmol), ACN (8 mL), water (0.2 mL), and acetic acid (0.3 mL) into a 100-mL round-bottom flask. Cool the mixture in an ice-water bath and add 1,3-dichloro-5,5-dimethylhydantoin (0.57 g, 2.91 mmol) portionwise. Stir the mixture at 0 °C for 20 min, then add saturated NaHCO3 (20 mL) and extract with EtOAc (2 x 20 mL). Wash the combined organic extracts with brine and dry over a Chem Elut extraction column eluted with EtOAc (2 x 10 mL). Concentrate the organic extract and purify by silica gel chromatography (2%-50% EtOAc in hexane) to afford 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)benzenesulfonyl chloride. 1 1H NMR (400 MHz, chloroform-d) δ 12.14 (s, 1H), 8.48 (d, J = 8.22 Hz, 1H), 8.30 (s, 1H), 7.91 - 8.00 (m, 3H), 7.69 (d, J = 7.82 Hz, 1H), 7.51 - 7.57 (m, 1H), 4.62 (s, 1H), 3.18 (t, J = 5.18 Hz, 4H), 1.67 (br s, 4H), 1.29 (s, 9H), 0.47 (s, 4H).

[0528] Step 3: Charge 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)benzene-1-sulfonyl chloride (0.085 g, 0.157 mmol), DIPEA (0.082 mL, 0.47 mmol), azetidine (0.013 mL, 0.19 mmol), and DCM (1 mL) into a glass vial. Stir the mixture at rt for 20 min, then concentrate. Purify the crude material by Biotage (SNAP25, Ultra, eluent: 20%-80% EtOAc in heptane), then lyophilize to afford 0.071 g of the title compound as a white solid. 11H NMR (400 MHz, DMSO-d6) δ = 11.05 (s, 1H), 8.33 (s, 1H), 7.98 - 7.91 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.58 (br d, J = 6.2 Hz, 3H), 7.50 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 3.73 (t, J = 7.6 Hz, 4H), 3.10 (br t, J = 4.7 Hz, 4H), 2.03 (quin, J = 7.7 Hz, 2H), 1.41 (br s, 4H), 1.12 (s, 9H), 0.28 (s, 4H).

[0529] Table 12: Examples 107-1 to 107-8 were prepared according to a preparation similar to that of Example 107:

[0530]

[0531]

[0532] Examples 108-1 and 108-2: (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxyprop 2-(6-azaspiro[2.5]octan-6-yl)-N-(propane-2-yl)benzamide and (S)-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide Example 109: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-imidazol-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0533]

[0534] Step 1: A solution of benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10.0 g, 25 mmol, Intermediate 8-4) in dioxane (100 mL) was placed in a glass tube (250 mL). At RT, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5 g, 27.5 mmol) and an aqueous Na2CO3 solution (2 M solution, 31.2 mL, 62.5 mmol) were added to the reaction mixture. The reaction mixture was degassed and purged with nitrogen for 15 min. Tetrakis(triphenylphosphine)palladium (1.44 g, 1.25 mmol) was added to the reaction mixture, and the reaction vessel was sealed and heated at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (using EtOAc in hexane (0 - 10%) on silica gel) to afford benzyl 4-(prop-1-en-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate as a yellow oil (8.0 g, 89% yield). 11H NMR (400 MHz, chloroform-d): δ 7.72 (d, J = 8.12 Hz, 1H), 7.47 (d, J = 7.24 Hz, 2H), 7.31 - 7.42 (m, 3H), 7.13 (s, 1H), 7.04 (d, J = 8.12 Hz, 1H), 5.40 (s, 1H), 5.36 (s, 2H), 5.14 (s, 1H), 3.03 - 3.13 (m, 4H), 2.14 (s, 3H), 1.44 - 1.51 (m, 4H), 0.31 (s, 4H). m / z (ESI): 362.2 [M+1].

[0535] Step 2: At RT, 4-methylmorpholine-N-oxide (5.19 mL, 44.3 mmol) and osmium tetroxide (4 wt% in H2O, 3.47 mL, 11.07 mmol) were added to a solution of benzyl 4-(prop-1-en-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (8.0 g, 22.13 mmol) in acetone (80 mL) and water (40 mL), and the mixture was stirred for 3 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford benzyl 4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2,5]octan-6-yl)benzoate (9.0 g, crude) as a viscous oil. The crude product was used without any purification. m / z (ESI): 396.2 [M+1].

[0536] Step 3: Under a nitrogen atmosphere, 2,2-dimethoxypropane (8.34 mL, 68.1 mmol) and p-toluenesulfonic acid monohydrate (0.864 g, 4.54 mmol) were added to a stirred solution of benzyl 4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2,5]octan-6-yl)benzoate (9.0 g, 22.70 mmol) in THF (90 mL), and the reaction mixture was heated at 60 °C for 5 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford benzyl 2-(6-azaspiro[2,5]octan-6-yl)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)benzoate (7.0 g, crude) as a yellow viscous oil. The crude product was used without any purification. m / z (ESI): 436.2 [M+1].

[0537] Step 4: Under N2 atmosphere, ammonium formate (2.02 g, 32.1 mmol) and Pd-C (10%, 5.12 g, 4.81 mmol) were added to a stirred solution of benzyl 2-(6-azaspiro[2.5]oct-6-yl)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)benzoate (7.0 g, 16.03 mmol) in EtOH and heated at 60 °C for 30 min. The reaction mixture was cooled to RT and filtered through a bed filter and filtered with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The crude residue was extracted with EtOAc (200 mL) and washed with water (100 mL) and brine solution (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-(6-azaspiro[2.5]oct-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinic acid (5.0 g, crude) as an off-white solid. The crude product was used without any purification. 1 H NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 8.22 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J = 1.27, 8.12 Hz, 1H), 4.11 - 4.17 (m, 1H), 4.04 - 4.09 (m, 1H), 3.10 (t, J = 5.38 Hz, 4H), 1.59 (bs, 4H), 1.52 (s, 3H), 1.45 (s, 3H), 1.31 (s, 3H), 0.44 (s, 4H).

[0538] Step 5: At rt, 3-amino-N-(tert-butyl)benzenesulfonamide (1.32 g, 5.77 mmol), HATU (2.195 g, 5.77 mmol), and DIPEA (1.01 mL, 5.77 mmol) were added to a solution of 2-(6-azaspiro[2.5]oct-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinic acid (2.0 g, 5.77 mmol) in DMF (20 mL) and stirred for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL), filtered, and dried in vacuo to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinamide (2.0 g, 62% yield) as an off-white solid. 1HNMR (400 MHz, chloroform-d): δ 12.94 (s, 1H), 8.31 (s, 1H), 8.27 (bs, 1H), 8.01 (d, J = 8.22 Hz, 1H), 7.64 (d, J = 7.82 Hz, 1H), 7.46 - 7.55 (m, 2H), 7.23 (d, J = 8.22 Hz, 1H), 4.54 (d, J = 8.61 Hz, 1H), 4.08 - 4.17 (m, 1H), 3.04 - 3.18 (m, 4H), 1.66 (s, 3H), 1.67 - 1.59 (m, 4H), 1.57 (s, 3H), 1.43 (s, 3H), 1.29 (s, 9H), 0.45 (s, 4H). m / z (ESI): 556.2 [M + 1].

[0539] Step 6: To a stirred solution of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinamide (2.1 g, 3.78 mmol) in dioxane (21 mL) was added hydrochloric acid (2 N, 8.89 mL, 37.8 mmol) and the mixture was stirred at RT for 5 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was triturated with diethyl ether to give a solid. The solid was filtered and dried to afford N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (1.4 g, 72% yield) as an off-white solid. 11H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.51 - 7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J = 8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J = 5.77 Hz, 1H), 3.44 (d, J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H). m / z (ESI): 516.2 [M + 1]. The racemic mixture was separated by preparative SFC using Chiralpak IC (250 × 30 mm, 5 μm) with a mobile phase of 60% liquid CO2 and 40% MeOH at a flow rate of 100 mL / min to yield:

[0540] Example 108 - 1: (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. First elution peak, ee 100%; 1 1H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.51 - 7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J = 8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J = 5.77 Hz, 1H), 3.44 (d, J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H). m / z (ESI): 516.2 [M + 1].

[0541] Example 108 - 2: (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. Second elution peak, ee 100%; 11H NMR (400 MHz, DMSO-d6): δ 11.95 (s, 1H), 8.35 (s, 1H), 7.90 (d, J = 7.43 Hz, 1H), 7.77 (d, J = 8.22 Hz, 1H), 7.51 - 7.61 (m, 3H), 7.47 (s, 1H), 7.28 (d, J = 8.41 Hz, 1H), 5.04 (s, 1H), 4.73 (t, J = 5.77 Hz, 1H), 3.44 (d, J = 4.89 Hz, 2H), 3.02 (t, J = 4.89 Hz, 4H), 1.49 (s, 4H), 1.41 (s, 3H), 1.12 (s, 9H), 0.33 (s, 4H). m / z (ESI): m / z: 516.2 [M+1].

[0542] The determination of stereochemistry is arbitrary.

[0543] Example 110: N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide Terephthalamide of 2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0544]

[0545] 4-Bromo-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (94 mg, 0.181 mmol, Intermediate 19-1), tetrakis(triphenylphosphine)palladium, polymer-bound (0.06 mmol / g) (300 mg, 0.260 mmol, Sigma-Aldrich), 1-methyl-2-(tributylstannyl)imidazole (0.087 mL, 0.271 mmol, Alfa Aesar), and dioxane (2 mL) were added to a round-bottom flask. The solution was stirred at 90 °C for 48 h. The reaction was cooled to RT and filtered through a pad. The residue was washed with EtOAc (2 x 10 mL). The filtrate was adsorbed onto a silica plug and chromatographed through a pre-packed silica column (eluting with 0 - 100% EtOAc in heptane) to afford the title compound as a pale yellow solid (6 mg, 0.012 mmol, 7% yield). 11H NMR (400 MHz, chloroform-d) δ ppm 12.82 (s, 1H), 8.31 - 8.38 (m, 2H), 8.01 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.34 (dd, J = 8.1, 1.3 Hz, 1H), 7.20 - 7.25 (m, 1H), 4.57 (s, 1H), 3.75 (s, 3H), 3.14 (t, J = 5.3 Hz, 4H), 1.58 - 1.64 (m, 4H), 1.30 (s, 9H), 0.46 (s, 4H). m / z (ESI): 522.2 (M+H) + 。

[0546] Table 13: Examples 109-1 to 109-3 were prepared according to a preparation similar to that of Example 109:

[0547]

[0548]

[0549] Examples 112-1 and 112-2: (R)-N-(3-(azetidine-1-sulfinyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (S)-N-(3-(azetidine-1-sulfinyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide Example 112-2: (S)-N-(3-(azetidine-1-sulfinyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0550]

[0551] Step 1: Add 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (10 mg, 0.015 mmol, Sigma-Aldrich), tris(dibenzylideneacetone)dipalladium(0) (8.7 mg, 9.50 μmol, Strem Chemicals) and toluene (1 mL) to an RBF. Stir the solution for 5 min. Then treat the reaction with 4-bromo-N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (103 mg, 0.198 mmol, Intermediate 19-1), 1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-amine (59 mg, 0.290 mmol), and sodium tert-butoxide (63 mg, 0.656 mmol, Sigma-Aldrich). Stir the solution at 90 °C for 16 h.

[0552] Cool the reaction to RT and dilute with water (20 mL) and EtOAc (10 mL). Separate the layers and extract the aqueous layer with EtOAc (10 mL). Concentrate the combined EtOAc layers in vacuo and adsorb onto a silica plug and pass through Chromatography was performed on a prepacked silica gel column (eluting with 0%-75% EtOAc in heptane) to afford the title compound as a golden film (38 mg, 0.059 mmol, 30% yield). m / z (ESI): 643.2 (M+H) + .

[0553] Step 2: At 0 °C, tetrabutylammonium fluoride (1 M in THF, 0.124 mL, 0.124 mmol, Sigma-Aldrich) was added to a solution of N-(3-(N-(tert-butyl)sulfamoyl)phenyl)-4-((1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (38 mg, 0.041 mmol) in THF (1 mL). The solution was stirred in a cooling bath (subsequently expired). After 20 h, the reaction was concentrated in vacuo and adsorbed onto a silica plug and chromatographed on a prepacked silica gel column (eluting with 0%-70% EtOAc in heptane) to afford the title compound as an off-white solid (18 mg, 0.034 mmol, 82% yield). 1 1H NMR (400 MHz, chloroform-d) δ ppm 12.92 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.68 (br d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 6.67 (dd, J = 8.6, 2.2 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H), 5.29 (s, 1H), 3.77 (s, 2H), 2.89 (br t, J = 4.9 Hz, 4H), 1.39 - 1.45 (m, 6H), 1.16 - 1.35 (m, 13H), 0.38 (s, 4H). [Note: Protons of OH and 1NH are not visible]. m / z (ESI): 529.1 (M+H) + .

[0554] Table 14: Example 110-1 was prepared according to a preparation similar to Example 110:

[0555]

[0556] Example 111: N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(2-Hydroxyethyl)-2-(6-azaspiro Example 115: N-(4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1-yl)benzamide

[0557]

[0558] Step 1: To a solution of methyl 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)benzoate (197 mg, 0.394 mmol, Intermediate 19-2) and THF:MeOH (3:2, 8 mL) was added LiOH (2 mL, 2 mmol, 1 M). The solution was stirred at RT for 16 h. The reaction was concentrated in vacuo to remove the organic solvents. The aqueous solution was acidified with 2N HCl and extracted with EtOAc (3 x 10 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to afford the crude title compound as a white solid (200 mg, 0.412 mmol), which was used without further purification. m / z (ESI): 486.0 (M+H) + 。

[0559] Step 2: To a solution of 4-((3-(N-(tert-butyl)sulfamoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)benzoic acid (60 mg, 0.124 mmol) and DMF (2 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (51.3 mg, 0.185 mmol, Sigma-Aldrich). The solution was stirred at RT for 30 min, then ethanolamine (17 μL, 0.283 mmol, Sigma-Aldrich) was added and the mixture was stirred at rt for 2 h. The reaction was diluted with water (25 mL) and stirred for 30 min. The aqueous solution was extracted with EtOAc (3 x 10 mL). The combined EtOAc extracts were concentrated in vacuo and adsorbed onto a silica plug and chromatographed through a pre-packed silica column (eluting with 0 - 75% EtOAc:EtOH (3:1) in heptane) to afford the title compound as a white solid (52 mg, 0.1 mmol, 80% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.58 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.35 (s, 1H), 7.92 (br d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.54 - 7.62 (m, 3H), 4.75 (br s, 1H), 3.53 (q, J = 5.6 Hz, 2H), 3.34 - 3.39 (m, 2H), 3.05 (br t, J = 4.9 Hz, 4H), 1.47 (br s, 4H), 1.12 (s, 9H), 0.32 (s, 4H). m / z (ESI): 529.1 (M+H) + 。

[0560] Table 15: Examples 111-1 to 111-4 were prepared according to a preparation similar to Example 111:

[0561]

[0562] Biological Examples ​ ​

[0563]

[0564] Step 1: A solution of 4-bromo-N-(3-(N-(tert-butyldimethylsilyl)azetidine-1-sulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.2 g, 0.32 mmol, Intermediate 26) in DMF (3 mL) was treated with methyl 2-sulfamoylacetate (0.074 g, 0.486 mmol), tripotassium phosphate (0.137 g, 0.65 mmol), copper(I) iodide (0.062 g, 0.324 mmol), followed by treatment with (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.023 g, 0.162 mmol), and the resulting mixture was heated at 90 °C for 16 h. The reaction was quenched with cold water and filtered through a pad, washed with EtOAc. The filtrate was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (using a 0%-35% EtOAc gradient in petroleum ether) to give methyl 2-(N-(4-((3-(N-(tert-butyldimethylsilyl)azetidine-1-sulfonimidoyl)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (0.18 g, 0.26 mmol, 81% yield) as a pale yellow gum. 11H NMR (400 MHz, DMSO-d6): δ ppm 11.66 (s, 1H), 10.53 (s, 1H), 8.10 - 8.17 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 4.32 (s, 2H), 3.64 (s, 3H), 3.53 (dt, J = 22.3, 7.6 Hz, 4H), 2.98 (t, J = 5.3 Hz, 4H), 1.85 - 1.87 (m, 2H), 1.48 (s, 4H), 0.88 (s, 9H), 0.30 (s, 4H), 0.08 (s, 3H), 0.06 (s, 3H). m / z (ESI): 690.2 (M+H) + 。

[0565] Step 2: At 0 °C, tetrabutylammonium fluoride (1.0 M in THF, 0.391 mL, 0.391 mmol) was added dropwise to a solution of methyl 2-(N-(4-((3-(N-(tert-butyldimethylsilyl)azetidine-1-sulfonamido)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (0.18 g, 0.261 mmol) in THF (4 mL) and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with ammonium chloride solution and extracted with EtOAc (2x). The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated to afford methyl 2-(N-(4-((3-(azetidine-1-sulfonamido)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate as an off-white solid (0.13 g, 0.23 mmol, 87% yield). 11H NMR (400 MHz, DMSO-d6): δ ppm 11.68 (s, 1H), 10.52 (s, 1H), 8.29 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.7 Hz, 1H), 7.64 (td, J = 7.9, 2.6 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.99 - 7.05 (m, 1H), 4.34 (d, J = 2.6 Hz, 2H), 4.26 (d, J = 2.6 Hz, 1H), 3.64 (d, J = 2.6 Hz, 3H), 3.57 (t, J = 7.5 Hz, 4H), 2.98 (d, J = 6.2 Hz, 4H), 1.81 - 1.92 (m, 2H), 1.49 (s, 4H), 0.31 (d, J = 2.6 Hz, 4H). m / z (ESI): 576.2 (M + H) + 。

[0566] Step 3: At 0 °C, lithium borohydride (2.0 M in THF, 0.226 mL, 0.452 mmol) was added dropwise to a solution of methyl 2-(N-(4-((3-(azetidine-1-sulfonamido)phenyl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)acetate (0.13 g, 0.226 mmol) in THF (2 mL) and the mixture was stirred at rt for 3 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford N-(3-(azetidine-1-sulfonamido)phenyl)-4-((2-hydroxyethyl)sulfamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.1 g, 0.18 mmol, 81% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 10.11 (s, 1H), 8.30 (t, J = 1.9 Hz, 1H), 8.13 - 8.05 (m, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.4, 2.1 Hz, 1H), 4.98 (s, 1H), 4.27 (s, 1H), 3.77 (t, J = 6.5 Hz, 2H), 3.62 - 3.54 (m, 4H), 3.35 (s, 1H), 3.32 (s, 1H), 2.99 (t, J = 5.0 Hz, 4H), 1.86 - 1.88 (m, 2H), 1.49 (d, J = 5.7 Hz, 4H), 0.31 (s, 4H). m / z (ESI): 548.1 (M+H) + 。

[0567] The racemic compound was subjected to chiral separation by SFC [column: Chiralpak IC (250 x 30 mm, 5 μm); mobile phase: 70:30 (A:B), A = liquid CO2, B = methanol, flow rate: 120 mL / min.] to afford the compounds of Examples 112-1 and 112-2 as follows:

[0568] Example 112-1: (R)-N-(3-(azetidine-1-sulfonylimino)phenyl)-4-((2-hydroxyethyl)sulfamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. First elution peak; 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (s, 1H), 8.29 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.82 - 7.75 (m, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.11 (s, 1H), 6.98 (d, J = 8.5 Hz, 1H), 4.31 - 4.23 (m, 1H), 3.80 - 3.70 (m, 2H), 3.58 (t, J = 7.7 Hz, 4H), 3.31 - 3.27 (m, 2H), 2.99 (d, J = 5.3 Hz, 4H), 1.86 - 1.88 (m, 2H), 1.51 (d, J = 5.4 Hz, 4H), 0.32 (s, 4H). m / z (ESI): 548.1 (M+H) + 。

[0569] ​ ​

[0570] Second elution peak; 1 H NMR(400MHz,DMSO-d6)δppm 11.86(s,1H),8.30(s,1H),8.08(d,J=8.1Hz,1H),7.78(d,J=8.5Hz,1H),7.64(t,J=7.9Hz,1H),7.55(d,J=7.7Hz,1H),7.10(s,1H),6.98(d,J=8.7Hz,1H),4.26(s,1H),3.76(t,J=6.6Hz,2H),3.58(t,J=7.9Hz,4H),3.28(t,J=6.5Hz,2H),2.98(t,J=5.1Hz,4H),1.86-1.88(m,2H),1.51(s,4H),0.32(s,4H). m / z(ESI):548.1(M+H) + 。

[0571] Table 16: The preparations of Examples 113-1 to 113-2 and 114-1 to 114-2 are similar to the preparation of Examples 112-1 and 112-2:

[0572]

[0573] ​ ​

[0574]

[0575] Step 1: At 0 °C, add T3P (50% wt. in EtOAc) (1.58 mL, 2.67 mmol) to a solution of 3-piperidinylbenzoic acid (0.40 g, 1.95 mmol, Matrix Innovation Inc.), 4-bromo-2-(6-azaspiro[2.5]oct-6-yl)aniline (0.50 g, 1.78 mmol, Intermediate 18) and Et3N (0.49 mL, 3.56 mmol) in DCM (10 mL). Stir the mixture at RT for 3 h, then dilute with 50 mL of DCM, wash with 5 mL of water, and then wash with 5 mL of 1N NaOH. Concentrate the organic layer in vacuo and adsorb onto a silica plug and pass through Chromatography was performed on a prepacked silica gel column (eluting with 10%-35% EtOAc in heptane) to afford N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1-yl)benzamide as a brown amorphous solid (0.77 g, 1.64 mmol, 92% yield). m / z (ESI): 468.1 / 470.1 (M+H) + 。 1 H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.15 (d, J = 8.71 Hz, 1H), 7.27 - 7.46 (m, 5H), 7.17 (dd, J = 1.97, 8.19 Hz, 1H), 3.22 - 3.28 (m, 4H), 2.88 (t, J = 5.29 Hz, 4H), 1.47 - 1.67 (m, 10H), 0.35 (s, 4H).

[0576] Step 2: A mixture of 2-hydroxyethane-1-sulfonamide (90 mg, 0.72 mmol, Enamine), potassium phosphate (381 mg, 1.79 mmol), dimethylglycine (37 mg, 0.36 mmol, Oakwood), copper(I) iodide (34 mg, 0.17 mmol, Strem) in 3 mL of DMF in a glass tube was degassed for 3 min. The mixture was heated at 50 °C under argon for 5 min and then treated with N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1-yl)benzamide (168 mg, 0.36 mmol). The glass tube was sealed and then heated at 100 °C for 24 h. The mixture was cooled to RT and then partitioned between 5 mL of water and 50 mL of EtOAc. The layers were separated. The organic layer was washed with 3 mL of brine and concentrated. The residue was purified on a silica gel column (15%-90% EtOAc in heptane) to afford N-(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-3-(piperidin-1-yl)benzamide as an off-white solid (151 mg, 0.29 mmol, 82% yield). m / z (ESI): 513.2 (M+H) + 。 11H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.06 (d, J = 8.71 Hz, 1H), 7.35 - 7.46 (m, 2H), 7.27 - 7.31 (m, 1H), 7.15 (d, J = 7.65 Hz, 1H), 7.10 - 7.13 (m, 1H), 6.96 (d, J = 8.91 Hz, 1H), 6.73 (s, 1H), 4.88 (t, J = 5.70 Hz, 1H), 3.12 - 3.28 (m, 8H), 2.85 (m, 4H), 1.43 - 1.71 (m, 10H), 0.35 (s, 4H).

[0577] ​

[0578] The following assay was used to test exemplary compounds of the present invention. Data for those examples tested according to the following procedure are shown in Table A below.

[0579] KIF18A enzyme assay: The KIF18A enzyme activity after treatment with the compound was measured using a microtubule-stimulated ATPase activity assay. The compound was serially diluted 2-fold in DMSO (Sigma Inc) over a range of 22 concentration points. Recombinant human KIF18A (1 - 467 His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography from Amgen Inc. The concentrations of KIF18A protein, microtubules (MT), and ATP in the reaction were optimized for a standardized homogeneous enzyme assay using an ADP-Glo TM kinase / ATPase assay kit (Promega Inc). The assay measures ADP formed by the ATPase reaction. A 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 RT for 15 minutes. Next, ATP (K m , 75 μM) was added to the reaction mixture and incubated at RT for an additional 15 minutes. 5 μl of ADP-Glo TMThe reagent was mixed with 2.5 μl of the reaction mixture and incubated at RT for 40 minutes. 10 μl of ADP-Glo TM detection reagent was added and incubated at RT for 40 minutes. Luminescence was read using an EnVision microplate reader with a superluminescence module (Perkin Elmer Inc). Concentration-response curve fitting and IC 50 determination were performed using Genedata Screener software (version 15.0.1, Genedata Inc) with a four-parameter logistic regression fitting model.

[0580] Table A provides data for the compounds of the examples in this application and its priority documents. As representative compounds of the present invention, the following are provided: chemical names (named by ACD software or ChemDraw (Professional 15.0)) and biological data (IC 50 , in μM). Ex.# refers to the example number.

[0581] Table A: Biological data

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589] 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. Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. Thus, the scope of the present invention should not be determined with reference to the above description, but rather should be determined with reference to the following appended claims and the full scope of equivalents to which such claims are entitled.

[0590] For all purposes, all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety as if each individual patent, patent application, or publication were so individually indicated.

Claims

1. A compound of formula I: or any pharmaceutically acceptable salt thereof, wherein: R X For R 1 is the group -Z-R 12 ; where Z is absent, is -C 0-4 alkyl-S-C 0-4 alkyl-, C 0-4 alkyl-S(=O)-C 0-4 alkyl-, -C 0-4 alkyl-SO2-C 0-4 alkyl-, -C 0-4 alkyl-NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 SO2-C 0-4 alkyl-, -C 0-4 alkyl-SO2NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 SO2NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-O-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-O-C 0-4 alkyl-, -C 0-4 alkyl-(C=O)NR 11 -C 0-4 alkyl-, -C 0-4 alkyl-NR 11 (C=O)-C 0-4 alkyl-, -C 0-4 alkyl-S(=O)(=NH)-, -N=S(=O)<, -(C=O)-, or -C(=N-OH)-; R 2 is the group -Y-R 13 , where Y is -C 0-4 alkyl-S-C 0-4 alkyl-, C 0-4 alkyl-S(=O)-C 0-4 alkyl-, -C 0-4 alkyl-SO2-C 0-4 alkyl-, -C 0-4 alkyl-NR 13c -C 0-4 alkyl-, -C 0-4 alkyl-SO2NR 13c -C 0-4 alkyl-, -C 0-4 alkyl-NR 13c SO2-C 0-4 alkyl-, -C 0-4 alkyl-S(=O)(=NH)-, -C 0-4 alkyl-O-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-C 0-4 alkyl-, -C 0-4 alkyl-C(=O)-O-C 0-4 alkyl-, -C 0-4 alkyl-(C=O)NR 13c -C 0-4 alkyl-, -C 0-4 alkyl-NR 13c (C=O)-C 0-4 alkyl-, - or -N=S(=O)<; R 3 is H, a halogen group, C 1-4 alkyl, or C 1-4 haloalkyl; R 4 is H, a halogen group, C 1-4 alkyl, or C 1-4 haloalkyl; R 5 is H, a halogen group, C 1-8 alkyl, or C 1-4 haloalkyl; R 6 is H, a halogen group, C 1-8 alkyl, or C 1-4 haloalkyl; R 7 is H, a halogen group, C 1-4 alkyl, or C 1-4 haloalkyl; R 8 is H, a halogen group, C 1-8 alkyl, or C 1-4 haloalkyl; Alternatively, R 2 and R 8 may combine with their respective attached carbon atoms to form a saturated or partially saturated 5- or 6-membered monocyclic ring fused to the benzene ring; wherein the 5- or 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein the 5- or 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OR a , -OC 1-4 haloalkyl, CN, -NR a R a , or oxo; R 9 is H, a halogen group, C 1-4 alkyl, or C 1-4 haloalkyl; L is -(C=O)-NR 10 - or -NR 10 -(C=O)-; R 10 is H or C 1-4 alkyl; R 11 is H or C 1-4 alkyl; R 12 is H, a halogen group, OH, CN, R 12a , or R 12b ; R 13 is a halogen group, R 13a or R 13b ; R 13c is H or C 1-4 alkyl; R 12a and R 13a is independently selected, in each case, from the group consisting of: saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 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, which are substituted with 0, 1, 2 or 3 groups selected from the group consisting of: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -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 、saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocyclic, and oxo; R 12b and R 13b is independently selected, in each case, from the group consisting of C 1-6 alkyl groups which are substituted with 0, 1, 2, 3, 4 or 5 groups selected from the group consisting of: F, Cl, Br, -CH2F, -CHF2, -CF3, -C(=O)OR a , -OR a , -OC 1-4 haloalkyl, CN, NH2, NH(CH3), N(CH3)2, and saturated, partially saturated or unsaturated 3-, 4-, 5- or 6-membered monocycles; R a H or R, independently in each case b ; and R b independently for each case, C 1-6 is alkyl, phenyl or benzyl, wherein C 1-6 alkyl is substituted with 0, 1, 2 or 3 substituents selected from: halogen, -OH, -OC 1-4 alkyl, -NH2, -NHC 1-4 alkyl, -OC(=O)C 1-4 alkyl, or -N(C 1-4 alkyl)C 1-4 alkyl; and the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from: halogen, C 1-4 alkyl, C 1-3 haloalkyl, -OH, -OC 1-4 alkyl, -NH2, -NHC 1-4 alkyl, -OC(=O)C 1-4 alkyl, or -N(C 1-4 alkyl)C 1-4 alkyl.

2. The compound according to claim 1, wherein L is -NR 10 -(C=O)-.

3. The compound according to claim 1, wherein L is -(C=O)-NR 10 -.

4. The compound according to claim 1, wherein R 10 is H or methyl.

5. The compound according to claim 1, wherein Z is absent, is -SO2-, -CH2-SO2, -NH-, -NHSO2-, -SO2NH-, -SO2N(CH3)-, -O-, -(C=O)O-, -(C=O)NH-, -(C=O)N(CH3)-, -S(=O)(=NH)-, -CH2-N(CH3)-, or -C(=N-OH)-.

6. The compound according to claim 1, wherein R 12 is selected from: a) H, F, Br, OH, or CN; b) R 12a selected from saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocycles containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted with 0, 1, 2 or 3 groups selected from: F, Cl, Br, methyl, ethyl, -CF3, -CH2OH, -OH, -OCH3, -NH2, or oxo; or c) R 12b C alkyl substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, -CF3 or -OH 1-6 alkyl 7. The compound according to claim 1, wherein R 12 is: R 12a is selected from cyclopropyl, oxetanyl, imidazolyl, isothiazolidinyl, azetidinyl, oxazolyl, pyrazolyl or diaziridinyl; each of which is independently substituted with 0, 1, 2 or 3 groups selected from the following: methyl, ethyl, -CF3, or oxo; or R 12b is selected from methyl, ethyl, isopropyl, tert-butyl, -vinyl, which is substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, -CF3 or -OH.

8. The compound according to claim 1, wherein R 1 is the group -Z-R 12 , wherein Z is absent, -SO2-, -CH2SO2-, -(C=O)NH-, -NH-, -NHSO2- or -SO2NH-; and R 12 is cyclopropyl, oxetanyl, azetidinyl or imidazolyl ring, each independently substituted with 0, 1 or 2 groups selected from the following: methyl, -CF3, or oxo; or R 12 is methyl, ethyl, isopropyl or tert-butyl, each independently substituted with 0, 1, 2 or 3 F, -CF3 or OH groups.

9. The compound according to claim 1, wherein R 1 is the group -Z-R 12 , wherein Z is -NHSO2- and R 12 is -CH2-CH2-OH or -CH(CH3)CH2OH.

10. The compound according to claim 1, wherein Y is absent, is -SO2NH-, NH-, -SO2-, -S(=O)(=NH)-, or -O-.

11. The compound according to claim 1, wherein R 13 is H or F; R 13a is selected from morpholinyl, piperidinyl, cyclopentyl, cyclopropyl, azetidinyl or oxetanyl; wherein each said ring is substituted with 0, 1, 2 or 3 OH groups selected from methyl or -OH; or R 13b is selected from methyl, ethyl, propyl, isopropyl, tert-butyl or isopentyl; which are each independently substituted with 0, 1, 2 or 3 OH groups.

12. The compound according to claim 1, wherein R 2 and R 8 may combine with the respective carbon atoms to which they are attached to form a saturated or partially saturated 6-membered monocyclic ring fused to the benzene ring; wherein the 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and further wherein the 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 haloalkyl, or oxo.

13. The compound according to claim 1, wherein R 4 is H.

14. The compound according to claim 1, wherein R 5 is H.

15. The compound according to claim 1, wherein R 6 is H or F.

16. The compound according to claim 1, wherein R 7 is H or F.

17. The compound according to claim 1, wherein R 8 is H, F or methyl; or alternatively, R 2 and R 8 may combine with the respective carbon atoms to which they are attached to form a saturated 6-membered monocyclic ring fused to the benzene ring; selected from the group consisting of:

18. The compound according to claim 1, wherein R 2 is: a) group -Y-R 13a , where Y is absent or is -S(=O)(=NH)-; and R 13 is piperidinyl or azetidinyl; where each said ring is independently substituted with 0, 1, 2 or 3 F groups; b) group -Y-R 13b , where Y is -SO2NH-, -O-, NH-; and where R 13b is a tert-butyl group substituted with 0, 1, 2 or 3 OH groups; or c) Alternatively, the carbon atom combination attached to R 2 and R 8 forms a saturated 6-membered monocyclic ring fused to the benzene ring; it is wherein the 6-membered monocyclic ring is unsubstituted.

19. The compound according to claim 1, wherein R 2 is a -SO2NH-tert-butyl group or a -NH-tert-butyl-OH group.

20. The compound according to claim 1, wherein R 8 is H.

21. The compound according to claim 1, wherein R 9 is H.

22. The compound according to claim 1, wherein R 10 is H.

23. A compound or its pharmaceutically acceptable salt having any of the following formulas:

24. The compound according to claim 1 or 23, or its pharmaceutically acceptable salt, said compound being selected from the group consisting of: N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((3-Methyloxetan-3-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-Isopropylphenyl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-Cyclopropylphenyl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(tert-Butyl)phenyl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; 4-(Methylsulfonyl)-N-(quinolin-8-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(4-Methylquinolin-8-yl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(Chroman-8-yl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(Benzofuran-7-yl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(Benzo[b]thiophen-7-yl)-4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; 4-(Methylsulfonyl)-N-(3-Morpholinophenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((Methylsulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(((2-hydroxyethyl)sulfonyl)methyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; 4-(N-(tert-Butyl)sulfamoyl)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(3-methyloxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(3-hydroxyoxetan-3-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(2-Fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-((1-Hydroxy-2-methylpropan-2-yl)amino)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(cyclopropanesulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1,1-dimethylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,1-dioxoisothiazolidin-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfamoyl)-N-(3-(2-methylmorpholino)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-N-(2-Fluoro-3-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-N-(3-Fluoro-5-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-N-(4-Fluoro-3-(2-methylmorpholino)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(4,4-Difluoropiperidin-1-yl)-5-methylphenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(4,4-Difluoropiperidin-1-yl)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(4,4-Difluoropiperidin-1-yl)-2-fluorophenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(2-Hydroxy-2-methylpropoxy)phenyl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; 4-(Azetidin-1-ylsulfonyl)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N,N-dimethylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-methylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(oxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-cyclopropylsulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(N-(1-methylcyclopropyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)-4-sulfamoylbenzamide; (R)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (S)-N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-imidazol-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(1-methyl-1H-pyrazol-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-(oxazol-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N-(3-(N-(tert-Butyl)sulfamoyl)phenyl)-4-((2-hydroxyethyl)amino)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(2-Hydroxyethyl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide; N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -methyl-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide; N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(2-hydroxyethyl)-N 4 -methyl-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide; N 1 -(3-(N-(tert-Butyl)sulfamoyl)phenyl)-N 4 -(1-Hydroxy-2-methylpropan-2-yl)-2-(6-azaspiro[2.5]oct-6-yl)terephthalamide; N 1 -(3-(Cyclopentanesulfonyl)phenyl)-N 4 -(2-Hydroxyethyl)-2-(6-azaspiro[2.5]oct-6-yl)terephthalamide; (R)-N-(3-(azetidine-1-sulfonimidoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (S)-N-(3-(azetidine-1-sulfonimidoyl)phenyl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(S-methylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (R)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; (S)-4-((2-hydroxyethyl)sulfonamido)-N-(3-(2-methylpropan-2-ylsulfonimidoyl)phenyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide; or N-(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)phenyl)-3-(piperidin-1-yl)benzamide.

25. The compound according to claim 1 or 23, wherein the compound is selected from the group consisting of: ； or any pharmaceutically acceptable salt thereof.

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

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