KIF18A inhibitors

Abstract

Provided are compounds of Formula (I) as defined herein: (I) and synthetic intermediates thereof, which are capable of modulating the KIF18A protein, thereby affecting the cell cycle and cell proliferation processes to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions comprising the compounds and methods for treating conditions associated with KIF18A activity. # 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 major cause of death worldwide. In the effort to find effective treatments or cures for one or more of the many different cancers, many groups have invested a great deal of time, energy, 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 normally dividing cells and cancer cells.

[0004] Kinesins are molecular motors that play important roles in cell division and intracellular vesicle and organelle transport. 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, the ATPase activity of which 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 cancer, and ovarian cancer. In addition, 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 by apoptosis, mitotic catastrophe, or lethality driven by polyploidy 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 the development of new anticancer agents. Summary of the Invention

[0007] The present invention provides a new class of compounds that are used alone or in a binding complex with microtubules to modulate the KIF18A protein for the treatment of KIF18A-mediated disorders and / or diseases, including cancer, inflammation, or ciliary pathologies.

[0008] The compounds provided by the present invention have MT-based KIF18A modulating activity, and in particular, KIF18A inhibitory activity. To this end, the present invention also provides the use of these compounds and 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 (I), a compound of formula I:

[0010]

[0011] or any of its pharmaceutically acceptable salts, wherein:

[0012] X1 is N or -CR 6 ;

[0013] R 1 is -CN or the group -Z-R 12 , where Z is -C 0-4 alkyl-, -NR 11 -, -NR 11 SO2-, -SO2NR 11 -, -NR 11 -, -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, C 0-4 alkyl-O-, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O); or

[0014] the group -Z-R 12 is -N=S(=O)-(R 12 )2, where the two Rs 12 may alternatively combine with the sulfur atoms to which they are respectively attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0015] R 2 is halogen or the group -Y-R 13 , where Y is -C 0-4 alkyl-, -N(C 0-1 alkyl)-C 0-4 alkyl-, -C(=O)NR a R a (C 1-4 alkyl), -O-C 0-4 alkyl-, S, S=O, S(=O)2, -SO2NR 13 or -S(=O)(=NH)-;

[0016] R 3 is H, C 1-4 alkyl or C 1-4 haloalkyl;

[0017] R 4 is H, halogen, R 4a or R 4b ;

[0018] R 5 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl;

[0019] R6 is H, a halogen, C 1-8 alkyl, C 1-4 haloalkyl, -O-C 1-8 alkyl or -O-R 6a , where R 6a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S;

[0020] R 7 is H, a halogen, C 1-8 alkyl or C 1-4 haloalkyl;

[0021] R 8 is H, a halogen, C 1-8 alkyl, C 1-4 haloalkyl, -OH, -O-R 8a or -O-R 8b ;

[0022] R 9 is H, a halogen, C 1-8 alkyl or C 1-4 haloalkyl;

[0023] R x is selected from the group consisting of:

[0024] R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j each of which is H, a halogen, R 10k or R 10l ;

[0025] or alternatively, R 10a and R 10b pair, R 10c和 R 10d pair, R 10e和 R 10f pair, R 10g and R 10h pair or R 10i and R 10j pair in each case may independently combine with the respective carbon atom to which they are attached to form a spiro linkage to R xSaturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic rings; wherein the 3-, 4-, 5-, 6-membered monocyclic rings contain 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-, 4-, 5-, 6-membered monocyclic rings are 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;

[0026] R 11 is H, R 11a or R 11b ;

[0027] R 12 is H, R 12a or R 12b ;

[0028] R 13 is R 13a or R 13b ;

[0029] R 4a 、R 8a 、R 10k 、R 11a 、R 12a and R 13a are each independently selected from the group consisting of saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are 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, -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 alkylNR aR 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 、 R 14 and oxo;

[0030] R 4b 、 R 8b 、 R 10l 、 R 11b 、 R 12b and R 13bIndependently selected in each case from the group consisting of: selected from F, Cl, Br, -OR a 、-OC 1-4 C alkyl substituted with 0, 1, 2, 3, 4 or 5 groups selected from haloalkyl or CN 1-6 alkyl;

[0031] R 14 Independently selected in each case from the group consisting of: saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic or 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic 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 the following: 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 alkylNR a R a 、-OC 2-6 alkylOR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a [[ID=6l]]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(Ra )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 and oxo;

[0032] R a is independently H or R b ;and

[0033] R b In each case, independently C 1-6 Alkyl, phenyl or benzyl, where C 1-6 The alkyl group is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of 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 and phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of halogen, C 1-4 Alkyl, C 1-3 Halogenated alkyl, -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.

[0034] In embodiment 2, the present invention provides compounds wherein X 1 is N; having formula (Ia):

[0035]

[0036] In Example 3, the present invention provides a compound, wherein X 1 is -CR 6 ; having the formula (Ib):

[0037]

[0038] In Example 4, the present invention provides a compound, wherein R 3 is H or methyl; preferably, R 3 is H.

[0039] In Example 5, the present invention provides a compound, wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i and R 10j is H, halogen, C 1-6 alkyl or C 1-4 haloalkyl; and each of the pairs of R 10a and R 10b combines with the respective carbon atoms to which they are attached to form a saturated 3-, 4- or 5-membered monocyclic ring that is spiro-fused to the R x ring; wherein the ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S.

[0040] In Example 6, the present invention provides a compound, wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i and R 10j is H, methyl or ethyl; and each of the pairs of R 10a and R 10b combines with the respective carbon atoms to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl ring that is spiro-fused to the R x ring.

[0041] In Example 7, the present invention provides a compound according to any one of Examples 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the group is selected from

[0042] In Example 8, the present invention provides a compound according to any one of Examples 1 to 7 or a pharmaceutically acceptable salt thereof, wherein the group is

[0043] In embodiment 9, the present invention provides a compound according to embodiment 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 1 is -CN or -ZR 12 , wherein Z is a bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and R 12 Selected from:

[0044] (a)H;

[0045] (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl,

[0046]

[0047] wherein each of the rings is substituted by 0, 1, 2 or 3 groups selected from the group consisting of OH, F, methyl, -CH2OH, -C(=O)OCH3,

[0048] -C(=O)OC(CH3)3, NH2, CN and oxo; or

[0049] (c) C substituted with 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 alkyl.

[0050] In embodiment 10, the present invention provides a compound according to embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 1 -CN or -ZR 12 , wherein Z is none, -NH-, -NHSO2-, -SONH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-; and

[0051] (a)R 12 is H;

[0052] (b)R 12 is oxetane or cyclopropyl; or

[0053] (c)R 12 is C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl.

[0054] In embodiment 11, the present invention provides a compound according to embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the group -ZR 12 -N=S(=O)-(R 12 )2, where two R 12 The pairs may alternatively combine with their respective attached sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; which is selected from:

[0055]

[0056] In embodiment 12, the present invention provides a compound according to embodiments 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 1 For the group -ZR 12 , where Z is -NHSO2- or

[0057] -SO2NH-; and R 12 is oxetane, cyclopropyl, or R 12 is C substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl.

[0058] In embodiment 13, the present invention provides a compound according to embodiments 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R 1 For the group -ZR 12 , where Z is -NHSO2-, and R 12 It is -CH2-CH2-OH.

[0059] In embodiment 14, the present invention provides a compound according to embodiments 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen or group -YR 13 , where Y is a bond, -NH-, -NH-(CH2) 0-4 -or-O-(CH2) 0-4 ; and R 13 is a saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocyclic ring or a 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted by 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 Alkyl, C 1-4 Halogenated alkyl, -OH, -OC 1-4 Haloalkyl, CN, R 14 and oxo; or

[0060] R13 is substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, -OH, -OC 1-4 alkyl substituted by 0, 1, 2, 3, 4 or 5 groups selected from haloalkyl or CN 1-6 alkyl.

[0061] In Example 15, the present invention provides a compound according to Examples 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each said ring contains 0, 1 or 2 N atoms and 0 or 1 O atom, and wherein each said ring is substituted by 0, 1, 2 or 3 groups selected from: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -OH, -OC 1-4 haloalkyl, CN, R 14 and oxo.

[0062] In Example 16, the present invention provides a compound according to Examples 1 to 15 or a pharmaceutically acceptable salt thereof, wherein R 2 is (a) a halogen; (b) a group -Y-R 13 , wherein Y is a bond; and R 13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl,

[0063]

[0064] wherein each said ring is substituted by 0, 1, 2 or 3 groups selected from: F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN and oxo; or (c) a group -Y-R 13 , wherein Y is NH, -O-, -O-(CH2)-, -O-(CH2)-(CH2)- or -O-(CH2)-(CH2)-(CH2)-, and wherein R 13 is or R 13 is C 1-6 alkyl substituted by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, methyl, CF3, -OH or CN.

[0065] In Example 17, the present invention provides a compound according to Examples 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 2 is morpholinyl or piperidinyl substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 , CN or oxo.

[0066] In Example 18, the present invention provides a compound according to Examples 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 2 is a morpholinyl group substituted with 1, 2 or 3 methyl groups.

[0067] In Example 19, the present invention provides a compound according to Examples 1 to 18 or a pharmaceutically acceptable salt thereof, wherein R 2 is a piperidinyl group substituted with 1, 2 or 3 fluorine groups.

[0068] In Example 20, the present invention provides a compound according to Examples 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0069]

[0070] In Example 21, the present invention provides a compound according to Examples 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Z is a bond, -NH-, -NHSO2-, -SO2NH-, -N═S(═O)<(R a )2 (wherein each R 11 is independently selected from the group consisting of: H, methyl or isopropyl), -S(═O)(═NH)-, -S-, -S(═O)-, -SO2-, -(C═O)-, -(C═O)NH- or -NH(C═O)-.

[0071] In Example 22, the present invention provides a compound according to Examples 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from (a) H; (b) C 1-6 alkyl substituted with 0, 1, 2 or 3 groups selected from F, Cl, Br, -OH, -OCH3 or cyclopropyl; or (c) a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which is substituted with 0, 1, 2 or 3 groups selected from the following: F, Cl, Br, C 1-6 alkyl, C 1-4 haloalkyl, -C 1-6 alkylOH, -OH, -OCH3, -NH2 or oxo.

[0072] In Example 23, the present invention provides a compound according to Examples 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl or 1,3,4-oxathiazinanyl.

[0073] In embodiment 24, the present invention provides a compound according to embodiments 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4 selected from (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups 1-6 or (c) cyclopropyl.

[0074] In embodiment 25, the present invention provides a compound according to embodiments 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

[0075] In embodiment 26, the present invention provides a compound according to embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 5 For H.

[0076] In embodiment 27, the present invention provides a compound according to embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 6 H or F.

[0077] In embodiment 28, the present invention provides a compound according to embodiments 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R 7 H or F.

[0078] In embodiment 29, the present invention provides a compound according to embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 8 For H.

[0079] In embodiment 30, the present invention provides a compound according to embodiments 1 to 29 or a pharmaceutically acceptable salt thereof, wherein R 9 For H.

[0080] In Example 31, the present invention provides a compound or a pharmaceutically acceptable salt thereof selected from:

[0081]

[0082]

[0083]

[0084]

[0085]

[0086] or any pharmaceutically acceptable salt thereof.

[0087] In sub - embodiment 31a, the present invention provides N-(2-((1 - hydroxy - 2 - methylpropan - 2 - yl)amino)-6 - methylpyrimidin - 4 - yl)-4-(methylsulfonyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0088] In sub - embodiment 31b, the present invention provides N-(2-((1 - hydroxy - 2 - methylpropan - 2 - yl)amino)-6 - methylpyrimidin - 4 - yl)-4-(N-(3 - methyloxetan - 3 - yl)sulfamoyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0089] In sub - embodiment 31c, the present invention provides N-(2-(2 - hydroxypropan - 2 - yl)pyrimidin - 4 - yl)-4-(N-(3 - methyloxetan - 3 - yl)sulfamoyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0090] In sub - embodiment 31d, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)pyridin - 4 - yl)-4-(N-(3 - methyloxetan - 3 - yl)sulfamoyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0091] In sub - embodiment 31e, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((1 - methylcyclopropane)-1 - sulfonamido)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0092] In sub - embodiment 31f, the present invention provides (R)-4-((2 - hydroxyethyl)sulfonamido)-N-(6 - methyl - 2-(2 - methylmorpholino)pyrimidin - 4 - yl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0093] In sub - embodiment 31g, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxyethyl)sulfonamido)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0094] In sub - embodiment 31h, the present invention provides (R)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxy - 1 - methylethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0095] In sub - embodiment 31i, the present invention provides (S)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxy - 1 - methylethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0096] In sub - embodiment 31j, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-(ethylsulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0097] In sub - embodiment 31k, the present invention provides N-(2-(3,3 - difluoroazetidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxyethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0098] In sub - embodiment 31l, the present invention provides (R)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-5 - fluoro - 4-((2 - hydroxy - 1 - methylethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0099] In sub - embodiment 31m, the present invention provides (S)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-5 - fluoro - 4-((2 - hydroxy - 1 - methylethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0100] In sub - embodiment 31n, the present invention provides (R)-N-(2-(3,3 - difluoroazetidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxypropyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0101] In sub - embodiment 31o, the present invention provides (S)-N-(2-(3,3 - difluoroazetidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxypropyl)sulfonamido)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0102] In sub - embodiment 31p, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxyethyl)sulfonyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0103] In sub - embodiment 31q, the present invention provides (S)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((1 - hydroxypropan - 2 - yl)sulfonyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0104] In sub - embodiment 31r, the present invention provides (R)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((1 - hydroxypropan - 2 - yl)sulfonyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0105] In sub - embodiment 31s, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((1 - hydroxy - 2 - methylpropan - 2 - yl)sulfonyl)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0106] In sub - embodiment 31t, the present invention provides N-(2-(4,4 - difluorocyclohexyl)-6 - methylpyrimidin - 4 - yl)-4-((2 - hydroxyethyl)sulfonamido)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0107] In sub - embodiment 31u, the present invention provides (R)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - fluoro - 1-(hydroxymethyl)ethyl)sulfonamido)-2-(6 -azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0108] In sub - embodiment 31v, the present invention provides (S)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((2 - fluoro - 1-(hydroxymethyl)ethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0109] In sub - embodiment 31w, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)pyridin - 4 - yl)-4-(N-(2 - hydroxyethyl)sulfamoyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0110] In sub - embodiment 31x, the present invention provides 2-(6 - azaspiro[2.5]oct - 6 - yl)-4-(R - cyclopropylsulfinyl)-N-(2-(4,4 - difluoro - 1 - piperidinyl)-6 - methyl - 4 - pyrimidinyl)benzamide or a pharmaceutically acceptable salt thereof.

[0111] In sub - embodiment 31y, the present invention provides 2-(6 - azaspiro[2.5]oct - 6 - yl)-4-(S - cyclopropylsulfinyl)-N-(2-(4,4 - difluoro - 1 - piperidinyl)-6 - methyl - 4 - pyrimidinyl)benzamide or a pharmaceutically acceptable salt thereof.

[0112] In sub - embodiment 31z, the present invention provides (N 1 -(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-2-(6 - azaspiro[2.5]oct - 6 - yl)terephthalamide or a pharmaceutically acceptable salt thereof.

[0113] In sub - embodiment 31aa, the present invention provides 4-(azetidin - 3 - ylsulfonyl)-N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0114] In sub - embodiment 31ab, the present invention provides N-(2-(4,4 - difluoropiperidin - 1 - yl)-6 - methylpyrimidin - 4 - yl)-4-((1 - methylazetidin - 3 - yl)sulfonyl)-2-(6 - azaspiro[2.5]oct - 6 - yl)benzamide or a pharmaceutically acceptable salt thereof.

[0115] In embodiment 32, the present invention provides a pharmaceutical composition, which comprises a compound according to any one of embodiments 1 to 31 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0116] In Example 33, the present invention provides a method for treating a disorder treatable with a KIF18a inhibitor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to Examples 1 to 31 or a composition according to Example 31.

[0117] In Example 34, the present invention provides the method according to Example 33, wherein the disorder is a cancer selected from the group consisting of: (a) a solid or blood-borne 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, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of lymphoid origin selected from the following: leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma; (c) a hematopoietic tumor of myeloid origin 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.

[0118] In sub - embodiment 34a, the present invention provides a method according to embodiment 33, 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. In sub - embodiment 34b, the present invention provides a method according to embodiment 33, wherein the disease is any one of the cancers specified in embodiments (a), (b), (c), (d), (e) or (f).

[0119] In embodiment 35, 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 any one of embodiments 1 to 31 or a composition according to embodiment 32.

[0120] In Example 36, 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 any one of Examples 1 to 31 or a composition according to Example 32.

[0121] In Example 37, the present invention provides a method for inhibiting KIF18A in a cell, the method comprising contacting the cell with a compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt thereof or a composition according to Example 32.

[0122] In Example 38, the present invention provides the use of a compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition according to Example 32, in the manufacture of a medicament for treating a disorder treatable with a KIF18a inhibitor.

[0123] In Example 39, the present invention provides the use according to Example 38, wherein the disorder is a cancer selected from the group consisting of: (a) a solid or blood-derived 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, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of lymphoid origin selected from the following: leukemia, acute lymphoblastic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkitt lymphoma; (c) a hematopoietic tumor of myeloid origin 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.

[0124] In sub-Example 39a, the present invention provides the use according to Example 33, wherein the disorder is any one of the cancers specified in Examples (a), (b), (c), (d), (e), or (f).

[0125] In Example 40, the present invention provides the use of a compound according to any one of Examples 1 to 31 or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition according to Example 32, in the manufacture of a medicament for reducing the size of a solid tumor in a subject.

[0126] In embodiment 41, the present invention provides use of a compound according to any one of embodiments 1 to 31 or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to embodiment 32, for the preparation of a medicament for treating a cell proliferative disorder in a subject.

[0127] In embodiment 42, the present invention provides use of a compound according to any one of embodiments 1 to 31 or a pharmaceutically acceptable salt of said compound, or a pharmaceutical composition according to embodiment 32, for the preparation of a medicament for inhibiting KIF18A in a cell.

[0128] In Example 43, the present invention provides a process for preparing a compound of formula (I) as described herein.

[0129] In Example 44, the invention provides an intermediate compound for use in the process of preparing a compound of formula (I) as described herein.

[0130] It should be understood that any reference above to any embodiment is intended to include any and all sub-embodiments thereof. For example, a reference to embodiment 31 includes a reference to sub-embodiments 31a to 31ab.

[0131] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0132] Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen, e.g. 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C and 14 C; isotopes of chlorine, e.g. 38 Cl; isotopes of fluorine, e.g. 18 F; isotopes of iodine, e.g. 123 I and 125 I; isotopes of nitrogen, e.g. 13 N and 15 N; isotopes of oxygen, e.g. 15 O. 17 O and 18 O; isotopes of phosphorus, e.g. 32 P and sulfur isotopes, e.g. 35 S.

[0133] Certain isotopically labeled compounds of the present invention, for example compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H, and carbon-14, i.e.14 C is particularly suitable for this purpose because of its ease of incorporation and existing detection means.

[0134] Replacement with a heavier isotope (e.g., deuterium, i.e., 2 H) can provide certain therapeutic advantages (e.g., extended in vivo half-life or reduced dose requirements) stemming from higher metabolic stability and is thus preferred in some cases.

[0135] Replacement 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.

[0136] 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 similar to those described in the appended examples and preparations, using appropriately isotopically labeled reagents in place of the previously employed unlabeled reagents.

[0137] Pharmaceutically acceptable solvents according to the present invention include those in which the crystallization solvent can be replaced by an isotope, such as D2O, d6-acetone, d6-DMSO.

[0138] Specific 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.

[0139] Unless otherwise specified, the following definitions apply to the terms used in this specification and claims:

[0140] “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 designation of C0 alkyl represents a direct bond. C 1-6 alkyl examples include, but are not limited to, the following:

[0141]

[0142] “Benzo group” alone or in combination means the divalent group C4H4═, where one represents -CH═CH-CH═CH-, which forms a benzene-like ring when attached ortho to another ring - such as tetralin, indole, etc.

[0143] The terms “oxo” and “thio” represent ═O (such as in a carbonyl group) and ═S (such as in a thiocarbonyl group), respectively.

[0144] "Halogenated" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0145] "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 is replaced by F, Cl, Br, or I.

[0146] 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:

[0147]

[0148] 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:

[0149]

[0150] "Bicyclic" means a group having two linked rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2, or 3 heteroatoms, such as N, O, or S). Both of these rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetrahydronaphthalene). Bicyclic includes (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:

[0151]

[0152] (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:

[0153]

[0154]

[0155] ; and (c) bridged bicyclic compounds, wherein the two rings share three or more atoms and the two bridgehead atoms are separated by a bridge comprising 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 ring sharing three of their five carbon atoms. Examples of bridged bicyclic rings include, but are not limited to:

[0156]

[0157] Unless otherwise indicated, "carbocycle" or "carbocyclic" means, by itself or in combination with other terms, a ring comprising "C α-β Examples of carbocycles include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene, and the like.

[0158] "Heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may appear in the claims include, but are not limited to, the following:

[0159]

[0160]

[0161] "Pharmaceutically acceptable salts" means salts prepared by conventional means and are well known to those skilled in the art. "Pharmaceutically acceptable salts" include alkaline salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, and the like. When the compounds of the present invention contain an acidic functional group such as a carboxyl group, then suitable pharmaceutically acceptable cation pairs for the carboxyl group are well known to those skilled in the art and include alkali metals, alkaline earth metals, ammonium, quaternary ammonium cations, and the like. For additional examples of "pharmaceutically acceptable salts," see below and Berge et al., J. Pharm. Sci. [Journal of Pharmaceutical Sciences] 66:1 (1977).

[0162] "Saturated, partially saturated or unsaturated" includes substituents saturated with hydrogen, substituents completely unsaturated with hydrogen and substituents partially saturated with hydrogen.

[0163] "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, and the like. Preferred leaving groups are indicated herein where appropriate.

[0164] "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, 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. and salts (such as phosphonium salts and ammonium salts). Examples of aryl include phenyl, naphthyl, indanyl, anthryl, 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, for example, a primary amino group can be protected by both aralkyl and aralkyloxycarbonyl. Amino protecting groups can also form heterocycles with the nitrogen to which they are attached, for example, 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 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. For example, aralkyl. Alkyl is also a group suitable for protecting hydroxyl and mercapto, such as tert-butyl.

[0165] 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 the 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.

[0166] 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, by hydrogenolysis with palladium on carbon in a suitable solvent system (such as an alcohol, acetic acid, etc. or a mixture thereof) to remove a benzyloxycarbonyl group. 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 (such as 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.

[0167] 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:

[0168]

[0169] Although one form is named, described, shown, and / or claimed herein, all tautomeric forms are intended to be inherently included in this name, description, showing, and / or claim.

[0170] 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 by physiological actions such as hydrolysis, metabolism, etc. after administration of the prodrug to a patient to form a compound of the present invention. The art of preparing and using prodrugs is 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 (e.g., imidazole, imide, indole, etc.) have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4 / 11 / 81) discloses Mannich base hydroxamic acid prodrugs, their preparation, and uses.

[0171] This specification and the claims contain species lists (sometimes called 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.

[0172] Drug Compositions, Routes of Administration and Administration

[0173] Also provided herein are pharmaceutical compositions that comprise a compound as disclosed herein and a pharmaceutically acceptable excipient, such as a diluent or 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 hereinafter.

[0174] A suitable pharmaceutical formulation 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, or in vivo release rate and clearance rate of the administered agent. Depending on the route of administration, the suitable dosage can be calculated based on body weight, body surface area, or organ size. One of ordinary skill in the art can, without undue experimentation, further refine the calculations required to determine the appropriate therapeutic dosage, particularly in light of the dosage information and assays disclosed herein and the pharmacokinetic data obtainable from animal or human clinical trials, in a conventional manner.

[0175] The phrase “pharmaceutically acceptable” or “pharmacologically acceptable” refers 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. Except in cases where any conventional medium or agent is incompatible with the therapeutic composition, its use in the therapeutic composition is contemplated. 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, copper 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.

[0176] The compound can be present in the pharmaceutical composition as a pharmaceutically acceptable salt. As used herein, “pharmaceutically acceptable salts” include, for example, base addition salts and acid addition salts.

[0177] 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 metals, alkaline earth metals, ammonium and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium or ferric, etc. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

[0178] 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, 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 carboxylic acids, sulfonic acids, sulfonic group acids or phosphoric group 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-cyclohexylsulfamic acid (for the formation of cyclamate), or salts with other acidic organic compounds, such as ascorbic acid.

[0179] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulating, dragee preparation, grinding, emulsifying, encapsulating, entrapping or lyophilization processes. Suitable formulations depend on the chosen route of administration.

[0180] 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 as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding solid excipients to a compound as 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 necessary. 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, sweetening and flavoring agents, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various types of formulations.

[0181] When orally administering a therapeutically effective amount of a compound disclosed herein, the composition typically is in the form of a solid (e.g., tablet, capsule, pill, powder, or lozenge) or a liquid formulation (e.g., aqueous suspension, solution, elixir, or syrup).

[0182] When administered in tablet form, the composition can additionally contain functional solids and / or solid carriers, such as gelatin or adjuvants. Tablets, capsules, and powders can contain from about 1% to about 95% compound, and preferably from about 15% to about 90% compound.

[0183] 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 a compound disclosed herein, and preferably from about 1% to about 50% of a compound disclosed herein. In one embodiment contemplated, 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.

[0184] When administering a therapeutically effective amount of the compounds 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, with due consideration for pH, isotonicity, stability, etc., 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 typically 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 conditions of storage and use, these preparations can optionally contain preservatives to prevent the growth of microorganisms.

[0185] Injectable compositions can include sterile aqueous solutions, suspensions or dispersions, as well as 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, by, for example, the inclusion of a preservative. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one embodiment contemplated, the carrier is non-aqueous or substantially non-aqueous. Suitable fluidity can be maintained, for example, by the use of a coating, such as lecithin; in the case of dispersions, by maintaining the desired particle size of the compound; 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 the injectable composition can be achieved by the use of absorption delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0186] 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, and then filtering sterilizing. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and other required ingredients from those enumerated above. 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 desired ingredients from its previously sterile-filtered solution.

[0187] It is also possible to prepare slow-release or sustained-release formulations to achieve controlled release of the active compound upon 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 rate-limiting 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 in the polymeric matrix. Controlled-release formulations are also obtained by encapsulating the dispersed microparticles or emulsified droplets via known dispersion or emulsion coating techniques.

[0188] For administration by inhalation, the compounds of the invention are conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, such as of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0189] 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 form (e.g., in an ampoule or in a multi-dose container) and added with a preservative. The composition 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.

[0190] 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 permit the preparation of highly concentrated solutions. Alternatively, the compositions of the invention can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0191] The compounds disclosed herein can also be formulated in rectal compositions, such as suppositories or retention enemas (e.g., containing conventional suppository bases). In addition to the formulations described previously, the compounds can be formulated as long-acting preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

[0192] In particular, the compounds disclosed herein can be administered orally, buccally, or sublingually in the form of tablets containing excipients (such as starch or lactose), or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid formulations can be prepared with pharmaceutically acceptable additives (such as suspending agents). The compounds can also be injected parenterally, such as intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the compounds are preferably used in the form of a sterile aqueous solution, which can contain other substances, such as salts or sugar alcohols (such as mannitol) or glucose, to render the solution isotonic with blood.

[0193] For veterinary use, the compounds disclosed herein are administered as suitably acceptable formulations according to regular veterinary practice. A veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0194] 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 can 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 a deliverable form of the medicament; and / or a device for delivering such medicaments; and / or any agent for combination therapy with the compounds disclosed herein; and / or a disease treatment instruction sheet packaged with the medicament. The instruction sheet can be fixed in any tangible medium, such as a printed paper, or a computer-readable magnetic or optical medium, or instructions referring to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0195] "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 disclosures provided herein, determination of an effective amount is well within the capabilities of those of ordinary skill 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.

[0196] The amount of the compound administered may depend on the subject being treated, the subject's age, health status, gender 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 may also depend on the pharmacodynamic effect on arterial oxygen 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 as a single dose or can be divided into multiple doses.

[0197] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is generally 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.

[0198] As used herein, the terms "treat", "treating" and "treatment" refer to therapies, including but not limited to curative therapies, prophylactic therapies, and preventive therapies. 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.

[0199] 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.

[0200] The term "comprising / including" means open-ended, including the one or more components indicated, but not excluding other elements.

[0201] The term "Formula I" includes any sub-formulas, such as (Ia), (Ib), (Ic), (Id), etc.

[0202] Methods of using KIF18A inhibitors

[0203] This disclosure provides compounds generally having MT-based KIF18A regulatory 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 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.

[0204] In addition, the compounds of the 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 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 myelogenous 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).

[0205] The compounds of the 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.

[0206] Based on the ability to modulate kinesin and affect angiogenesis, the compounds of the present invention can also be used in the treatment and therapy of proliferative diseases. In particular, these compounds can be used to treat inflammatory diseases, especially to treat the manifestations of the locomotor apparatus, 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 can be found at or in the affected part of the body), seronegative spondyloarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis or arthropathy; or any further combination thereof.

[0207] 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, fractures, 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 vascular hyperplasia in the ovarian stroma, a characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)), since such diseases require vascular cell proliferation for growth and / or metastasis.

[0208] In addition to being used for human treatment, these compounds can also be used in 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.

[0209] Combination

[0210] 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.

[0211] 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 drug combination effect, 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.

[0212] 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).

[0213] 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.

[0214] There are a large number of anti-cancer agents that are commercially available, available for clinical evaluation and 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.

[0215] This disclosure also provides methods for combination therapy, in which 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 this disclosure or their pharmaceutically acceptable salts. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of this disclosure with chemotherapeutic agents, therapeutic antibodies, small molecule targeting agents, and radiation therapy to provide a synergistic or additive therapeutic effect.

[0216] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of this 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, cyclothiazide, metandienone, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; glucuronolactone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; 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; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing.;

[0217] 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)-imidazoles, 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 RFS2000; difluoromethylornithine (DMFO).

[0218] 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 thiosemicarbazide, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, Antineoplastic agents, Antitumorigenic herbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine Sulfoxidesulfoximine), CBV (chemotherapy), Calyculin, cell cycle non-specific antineoplastic 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).

[0219] The present disclosure further relates to methods for inhibiting abnormal cell growth or treating hyperproliferative disorders in mammals 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 compound of the present disclosure in such combination therapies can be determined as described herein.

[0220] Radiation therapy can be applied by one of several methods or a combination of methods, including but not limited to external beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to the radiation therapy delivered by a spatially confined radioactive material that is inserted into the body at or near a tumor or other proliferative tissue diseased site. The term is intended to include, without limitation, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioisotopes). Suitable radioactive sources for use as cell conditioning agents of the present 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 produced using a slurry of a suitable fluid containing small particles of solid radionuclides (e.g., Au-198, Y-90). In addition, one or more radionuclides can be embedded in a gel or radioactive microspheres.

[0221] The compounds or pharmaceutical compositions of the present disclosure may 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.

[0222] Angiogenesis inhibitors can be used in combination with the compounds of the present disclosure and the pharmaceutical compositions described herein. Such 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 931788, WO 90 / 05719, WO 99 / 52910, WO99 / 52889, WO 99 / 29667, WO 1999007675, European Patent Publication EP 1786785, European Patent Publication No. EP1181017, US Publication No. US20090012085, US Patent US 5863949, 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 MMP-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 RS 13-0830.

[0223] The compounds of the present invention can also be used in combination therapies with other anti-tumor agents, which other anti-tumor agents are, for example, acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancesim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, bromodeoxyuridine, capecitabine, cimelukast, 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, epoetin beta, 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 alpha 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, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, polyethylene glycol interferon-alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit anti-thymocyte polyclonal antibody, polyethylene glycol interferon-alpha-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 decoxide, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, 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, diazocone, 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 MAbs (Japan Pharmaceutical Development), HER-2 and Fc MAbs (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techniclone), polymorphic epithelial mucin-yttrium-90 MAb (Antisoma), marimastat, menolipin, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), lupinotecan, satraplatin, sodium phenylacetate, sparrosic acid, SRL 172 (SRPharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl esteretiopurpurin), 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.

[0224] The compounds of the invention can further be 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, WO 04 / 07481, WO 04 / 07458, WO 04 / 09784, WO 02 / 59110, WO 99 / 45009, WO 00 / 59509, WO 99 / 61422, US 5,990,141, WO 00 / 12089, and WO 00 / 02871.

[0225] 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. Agents can be agonists, antagonists, allosteric modulators, toxins, or more generally, can be used to inhibit or stimulate their targets (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or prevent cell growth.

[0226] 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".

[0227] 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 of integrin-ligand binding (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 their patent families), 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).

[0228] Other anti-angiogenic / antitumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US 5712291); 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: antiangiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko Kogyo Co., Ltd., Japan); Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA);SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Angiostatin (EntreMed, USA); Angiogenesis inhibitor (Tripep, Sweden); Serine protease inhibitor (maspin) (Sosei, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Flutamide (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 (OxfordBioMedica, 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); Wenyujine (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 RES2622 (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); 2-Methoxyestradiol (EntreMed, USA) within a drug delivery system, intraocular; Picotamide (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); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada);BAY RES2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (ChongKun Dang, South Korea); MAb, vascular endothelial growth factor (Xenova, UK); irsogladine (INN) (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine (pINN) (Genaera, USA); RPI 4610 (Sirna, USA); cancer therapy (Marinova, Australia); heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VEGF receptor modulator (Pharmacopeia, USA); VE-cadherin-2 antagonist (ImClone Systems, USA);Angiostatin (National Institutes of Health, USA); Vaccine, 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 inhibitor (Allegheny Health, Education and Research Foundation, USA).;

[0229] 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 inhibit protein expression can be used, and these proteins include, but are not limited to, ATG5 (which is involved in autophagy).

[0230] 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 AMG706 or a pharmaceutically acceptable salt thereof.

[0231] 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, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin, daunomycin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin, 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, p38 MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab)), HSP90 inhibitors (e.g., 17AAG and KOS 953), PI3K / 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 analogs or derivative variants of the foregoing items.

[0232] The compounds of the present invention can also be used in combination with radiotherapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0233] 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, mapracorat, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25 - diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednisolone valerate, prednylidene, rimocidin, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts and / or derivatives. 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 that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0234] The compounds or pharmaceutical compositions of the present disclosure can also be used in combination with an amount of one or more substances selected from the following: EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and immunotherapies, including anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

[0235] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful EGFR antibody inhibitors include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently lapatinib (TykerB). See, for example, Yan L et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005; 39(4):565-8 and Paez J G et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004; 304(5676):1497-500.

[0236] Non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitor described in the following patent publications, as well as all pharmaceutically acceptable salts and solvates of said EGFR inhibitor: 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 WO 97 / 30044, published August 21, 1997; PCT International Publication WO 97 / 38994, published October 23, 1997; PCT International Publication WO 97 / 49688, published December 31, 1997; European Patent Application EP 837063, published April 22, 1998; PCT International Publication WO 98 / 02434, published January 22, 1998; PCT International Publication WO 97 / 38983, published October 23, 1997; PCT International Publication WO 95 / 19774, published July 27, 1995; PCT International Publication WO 95 / 19970, published July 27, 1995; PCT International Publication WO 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, 199PCT 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, issued on August 4, 1998; U.S. Patent No. 5,650,415, issued on July 22, 1997; U.S. Patent No. 5,656,643, issued on August 12, 1997; PCT International Publication WO 99 / 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 inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.;

[0237] 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.

[0238] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0239] 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)-methylene]-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.

[0240] 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: NSC 154020; Yang et al., 2004, Cancer Res., 64, 4394-9).

[0241] 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; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Application No. 60 / 528,340).

[0242] 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. Includes: 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).

[0243] 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.: WO2007 / 133822, PCT Publication No.: WO 2005 / 055808, PCT Publication No.: WO 99 / 40196, PCT Publication No.: WO 2001 / 03720, PCT Publication No.: WO99 / 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.

[0244] The compounds described herein can be used in combination with the agents or other suitable agents disclosed herein, 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 the second agent. Such combination administration can include administering both agents simultaneously in the same dosage form, simultaneously in separate dosage forms, and 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 scenario, the administration of the compounds disclosed herein and any of the above agents is separated by a few minutes, or a few hours, or a few days.

[0245] 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 a combination of individual pharmaceutical compositions in kit form. 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 individual components of the combination is required by the prescribing healthcare professional.

[0246] Experiment

[0247] Abbreviations: The following abbreviations may be used herein:

[0248]

[0249]

[0250]

[0251]

[0252] Unless otherwise indicated, all materials were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all parts are by weight and temperatures are in degrees Celsius. All microwave-assisted reactions were carried out using Biotage TM Smith Synthesizer TM and 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 indicated, reactions were carried out at room temperature.

[0253] 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, etc. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), etc.

[0254] 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.

[0255] 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 typically 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 (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. All observed protons were reported in parts per million (ppm) at low field relative to tetramethylsilane (TMS) or other internal reference in the appropriate solvent specified. The data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant, and number of protons. Low-resolution mass 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.

[0256] For clarity purposes in this general synthesis section, the compound of formula (I) defined in the Summary of the Invention may be schematically depicted to include the Ar 1 ring and the Ar 2 ring, as follows:

[0257] wherein the group -NR 3 -(C=O)- is a linker, the Ar 1 ring is located to the left of the linker, and the Ar 2 ring is located to the right of the linker.

[0258] Generally, the compound of formula (I) can be synthesized as follows through the following three general steps:

[0259] Step 1: Prepare the Ar 1 compound

[0260] Step 2: Prepare the Ar 2 compound

[0261] Step 3: Couple the Ar 1 compound with the Ar 2 compound

[0262] The following General Schemes A - E 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, time, temperature, etc. can be modified as needed, which are entirely within the skill and judgment of the person of ordinary skill in the art.

[0263] Protocol A

[0264] According to Scheme A, in one embodiment, the compound of formula (I) as disclosed herein can be synthesized as follows:

[0265] Step 1a: Prepare the Ar 1 compound

[0266]

[0267] Step 1a: Preparation of ring Ar 1 Compound Compound A-1 (where W 1 is a halogen, such as fluorine or chlorine) can be reacted with the R 2The reagent of the group reacts to form Compound A-2. Compound A-1 is commercially available or can be synthesized by those skilled in the art through known methods. Examples of Compound A-1 include, but are not limited to, 2-chloropyrimidin-4-amine, 2-chloro-6-methylpyrimidin-4-amine, 2-fluoro-6-methylpyridin-4-amine, 2-chloropyridin-4-amine, 2-chloro-6-methylpyridin-4-amine, 2-chloro-6-ethylpyrimidin-4-amine, or 2-chloro-6-cyclopropylpyrimidin-4-amine. R 2 Examples of the reagent include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol. Examples of the base include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0268] Step 1b: Preparation of Ring Ar 1 Compound

[0269]

[0270] Alternatively, it can be carried out by reacting with a suitable organoboron R 2 reagent (R 2 -BY2, where Y is an organic functional group, such as 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-(4-fluorocyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) and a suitable palladium catalyst and base (such as PdCl2(dppf)-DCM adduct and tripotassium phosphate) to carry out the Suzuki cross-coupling reaction to convert the compound A-1 defined in Step 1a into the compound A-2 defined in Step 1a. After this step, reduction is 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. When the R 2 group is connected to the Ar 1 ring through a carbon-carbon bond, this alternative Suzuki reaction can be used.

[0271] Step 2a: Prepare ring Ar 2 Compound

[0272]

[0273] In Step 2a, Compound A-3 (where W 2 and W 3 each independently is a halogen, such as fluorine, chlorine, bromine, or iodine) can be reacted with R xA reagent (e.g., (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride) is reacted to form compound A-4.

[0274] Step 3a: Couple the ring Ar 1 compound with the ring Ar 2 compound, and then introduce R 1 :

[0275]

[0276] In step 3a, the compound A-4 obtained from step 2a can be reacted with an activating agent (e.g., acid chloride (COCl) 2 or SOCl 2) in a suitable organic solvent (e.g., tetrahydrofuran, dichloromethane, etc.) to form an acid chloride derivative, which can then be reacted with compound A-2 to form compound A-5. Alternatively, compound A-2 can be directly coupled with the compound A-4 obtained from step 2a in the presence of a coupling reagent (e.g., N, N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazol-1-yl)-N, N, N', N'tetramethyluronium hexafluorophosphate, carbonyldiimidazole, and polyphosphonic anhydride) in a suitable organic solvent (e.g., acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.). Those of ordinary synthetic chemists will readily appreciate that other coupling agents can be used. The reaction can be carried out by reacting a metal catalyst and R in a suitable organic solvent (such as DMSO, acetonitrile, tetrahydrofuran, DMF, etc.). 1 The halogen group W is further treated by a conversion reaction in the presence of a reagent (e.g., metal-catalyzed sulfonamidation, sulfurization, or sulfonylation). 3 To form compound (I), the R 1 Reagents such as (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-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethan-1-ol, or (11) cyclopropanethiol. Those of ordinary skill will readily appreciate that coupling reactions (e.g., as shown in Step 3a) can be carried out under well-known conditions.

[0277] Protocol B

[0278] Step 1a or 1b: Prepare ring Ar 1 For the compound, see Scheme A above

[0279] Step 2b: Preparation of ring Ar 2 Compound

[0280]

[0281] Scheme B provides an alternative method for forming the compounds of formula (I) disclosed herein. After step 1a or step 1b as described in Scheme A, the R 1 group can alternatively be introduced into ring Ar 2 in step 2b rather than in step 3a of Scheme A. According to step 2b, compound B-1 (where each of W 4 and W 5 is independently a halogen, such as fluorine, chlorine, bromine or iodine) can be reacted with a suitable carboxylic acid protecting group (PG1 reagent, such as methyl iodide) to form a methyl ester or with other suitable protecting groups 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 each of W 4 and W 5 is as defined in compound B-1. Then, compound B-2 can be reacted with an 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 an R 1 reagent through a transformation reaction (such as 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 (such as copper iodide, Pd2(dba)3) 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.

[0282] Step 3b: Couple the ring Ar 1 compound with the ring Ar 2 compound

[0283]

[0284] Step 3b is similar to the coupling reaction as described above in step 3a.

[0285] Protocol C

[0286] Scheme C provides another alternative method for forming the compounds of formula (I) disclosed herein. According to Scheme C, step 1a can be carried out as described in Scheme A, followed by step 2b as described in Scheme B.

[0287] Step 3c: Couple the ring Ar 1 compound with the ring Ar 2 compound

[0288]

[0289] In step 3c, compound A-1a (which is compound A-1 of Scheme A, where X 1 is N and W 1 is a halogen, such as fluorine or chlorine) can be reacted with compound B-5 obtained from step 2b of Scheme B in the presence of an activator under conditions similar to those of steps 3a and 3b above to form compound C-1, where W 1 is as defined in compound A-1a, and then it can be reacted with a reagent containing an R 2 group in the presence of a suitable base (such as diisopropylethylamine, potassium carbonate or sodium hydride) in a suitable organic solvent (such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) to form the compound of formula (I), and the reagent containing an R 2 group is, for example, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride or (4) 3,3,3-trifluoropropan-1-ol.

[0290] Protocol D

[0291] Scheme D provides another alternative method for forming the compounds of formula (I) disclosed herein. According to Scheme D, step 1a or 1b can be carried out as described in Scheme A, followed by step 2b as described in Scheme B.

[0292] Step 3d: Couple the ring Ar 1 compound with the ring Ar 2 compound

[0293]

[0294] In step 3d, compound A-1a (which is compound A-1 of Scheme A, where X 1 is N and W 1 is a halogen, such as fluorine or chlorine) can be reacted with compound A-4 obtained from step 2a of Scheme A to form compound D-1, where W 1 is as defined in compound A-1a and W 3as defined in Compound B-5, and then it can optionally be reacted with a reagent containing an R group (e.g., (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol) in the presence of a suitable base (e.g., diisopropylethylamine, potassium carbonate, or sodium hydride) in a suitable organic solvent (e.g., NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, dichloromethane, etc.) to form Compound A-5a, i.e., Compound A-5, where X 2 is N and W 1 is as defined in Compound B-5, and then it can be reacted with a reagent containing an R group in a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, etc.) in the presence of a metal catalyst by a transformation reaction (e.g., metal-catalyzed sulfonamidation, sulfidation, or sulfonylation) to form the compound of formula (I). 3 is as defined in Compound B-5, and then it can be reacted with a reagent containing an R group in a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, etc.) in the presence of a metal catalyst by a transformation reaction (e.g., metal-catalyzed sulfonamidation, sulfidation, or sulfonylation) to form the compound of formula (I). 1 is as defined in Compound B-5, and then it can be reacted with a reagent containing an R group in a suitable organic solvent (e.g., DMSO, acetonitrile, tetrahydrofuran, DMF, etc.) in the presence of a metal catalyst by a transformation reaction (e.g., metal-catalyzed sulfonamidation, sulfidation, or sulfonylation) to form the compound of formula (I).

[0295] Protocol E

[0296] Scheme E provides another alternative method for forming the compounds of formula (I) disclosed herein. According to Scheme E, Step 1a or 1b can be carried out as described in Scheme A to prepare Compound A-2. Compound E-1 (where W 6 is a halogen, such as fluorine or chlorine, which includes but is not limited to 2-fluoro-4-nitrobenzoic acid, 2,5-difluoro-4-nitrobenzoic acid, or 2,6-difluoro-4-nitrobenzoic acid) is commercially available or can be synthesized by those skilled in the art according to known methods.

[0297] Step 3e: Couple the ring Ar1 compound with the ring Ar 2 compound

[0298]

[0299] In Step 3e, Compound A-2 can be reacted with Compound E-1 in the presence of an activator under conditions similar to those in Steps 3a and 3b above to form Compound E-2, which can then be reacted with an R x reagent in a manner similar to that described in Step 2a to form Compound E-3. Then, the nitro group on Compound E-3 can be converted to an amino group by reaction with a reducing agent (which includes but is not limited to palladium on carbon and hydrogen) to form Compound E-4, which can then be reacted with an R 1 reagent in a suitable organic solvent (such as DMSO, acetonitrile, tetrahydrofuran, DMF, etc.) in the presence of a metal catalyst by a transformation reaction (e.g., metal-catalyzed sulfonamidation, sulfidation, or sulfonylation) to form Compound (I), and this R 1Reagents such as (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.

[0300] Example

[0301] Preparation of Synthetic Intermediates

[0302] Ring AR 1 Intermediate:

[0303] Intermediate 1: (R)-2-(2-Methylmorpholino)pyrimidin-4-amine

[0304]

[0305] 2-Chloropyrimidin-4-amine (60.0 g, 463 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine (65.6 g, 648 mmol, Wuxi Apptec), and DIPEA (243 mL, 1389 mmol) in NMP (600 mL) were placed in an autoclave and heated at 150 °C for 36 h. The reaction mixture was cooled to room temperature, quenched with water (1 L) and extracted with ethyl acetate (3 x 500 mL). The organic layer was washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude material as a brownish-yellow oil. The crude material was adsorbed onto a silica plug and purified by column chromatography on silica (60-120 mesh) eluting with a gradient of 50% to 100% ethyl acetate in hexane to give a yellow solid. The solid was further triturated with hexane (300 mL), filtered and dried in vacuo to give the title compound as a pale yellow solid (70 g, 78% yield). 11H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (d, J = 5.6 Hz, 1H), 6.42 (s, 2H), 5.75 (d, J = 5.6 Hz, 1H), 4.26 - 4.49 (m, 2H), 3.83 (ddd, J = 11.4, 3.6, 1.4 Hz, 1H), 3.31 - 3.50 (m, 2H), 2.78 (ddd, J = 13.2, 11.8, 3.5 Hz, 1H), 2.42 - 2.48 (m, 1H), 1.11 (d, J = 6.2 Hz, 3H). m / z (ESI): 195.2 (M+H) + 。

[0306] Intermediate 2: (R)-6-Methyl-2-(2-methylmorpholino)pyrimidin-4-amine

[0307]

[0308] 2-Chloro-6-methylpyrimidin-4-amine (30.0 g, 209 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine (40.3 g, 293 mmol, Wuxi Apptec, PR China), and DIPEA (109 mL, 627 mmol) were placed in a autoclave (600 mL) and heated at 150 °C for 12 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 x 1500 mL). The organic layer was washed with brine solution (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60 - 120 mesh) using 50% ethyl acetate in hexane as the eluent to afford the title compound as a yellow solid (25.0 g, 57% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 6.28 (s, 2H), 5.62 (s, 1H), 4.45 - 4.31 (m, 2H), 3.83 (ddd, J = 11.4, 3.5, 1.3 Hz, 1H), 3.42 (ddt, J = 14.4, 9.7, 2.8 Hz, 2H), 2.78 - 2.70 (m, 1H), 2.43 (dd, J = 13.0, 10.3 Hz, 1H), 2.05 (s, 3H), 1.11 (d, J = 6.2 Hz, 3H). m / z (ESI): 209.2 (M+H) + 。

[0309] Intermediate 3: 2-(4,4-Difluoropiperidin-1-yl)pyrimidin-4-amine

[0310]

[0311] In a glass microwave reaction vessel, 2-chloro-4-aminopyrimidine (1.0 g, 7.7 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (1.82 g, 11.58 mmol, Combi-Blocks, San Diego, CA), and DIPEA (4.04 mL, 23.2 mmol) were successively charged in NMP (12 mL). The reaction mixture was stirred and microwave-heated at 200 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 x 2 mL). The organic extract was washed with brine (30 x mL), dried over Na2SO4, and concentrated in vacuo to give the crude material as a brown viscous liquid. The crude material was adsorbed onto a silica gel plug and purified by flash chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with 0% to 100% ethyl acetate in heptane to give the title compound as an off-white solid (6.02 g, 91%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 7.21 (d, J = 5.6 Hz, 1H), 6.46 (br s, 2H), 5.77 (d, J = 5.6 Hz, 1H), 3.80 (t, J = 5.6 Hz, 4H), 1.85 - 1.90 (m, 4H). m / z (ESI): 215.2 (M+H) + 。

[0312] Intermediate 4: 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine

[0313]

[0314] 2-Chloro-6-methylpyrimidin-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 481 mmol, Combi-Blocks, San Diego, CA), and DIPEA (166 mL, 961 mmol) in NMP (460 mL, 10.00 mL / g) were placed in an autoclave (1 L) and heated at 180 °C for 30 h. The reaction mixture was cooled to room temperature and quenched with water (500 mL), and extracted with ethyl acetate (2 x 1000 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto silica gel plugs and purified by column chromatography on silica gel (60 - 120 mesh) eluting with 50% to 100% ethyl acetate in hexane as the eluent to afford the product. It was redissolved in ethyl acetate (500 mL) and washed with water (2 x 500 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The yellow solid was resuspended in hexane (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexane (100 mL), and dried in vacuo to afford the title compound as a pale yellow solid (58 g, 79% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80 - 3.78 (dd, J = 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95 - 1.85 (tt, J = 14.2, 5.7 Hz, 4H). m / z (ESI): 229.2 (M+H) + 。

[0315] Intermediate 5: 2-(3,3-Difluoroazetidin-1-yl)pyrimidin-4-amine

[0316]

[0317] 2-Chloro-4-aminopyrimidine (5.0 g, 38.6 mmol, Combi-Blocks, San Diego, CA), 3,3-difluoroazetidine hydrochloride (7.50 g, 57.9 mmol, Combi-Blocks, San Diego, CA) and potassium carbonate (5.33 g, 38.6 mmol) in dioxane (25 mL) were heated at 95 °C for 16 h. The reaction mixture was cooled to room temperature and the suspension was filtered. The crude material was adsorbed onto silica plugs and purified by flash chromatography through a Redi-Sep prepacked silica column (40 g), eluting with 10% MeOH in DCM to afford the title compound as a light brown solid (6.1 g, 85%). 1 H NMR (300 MHz, DMSO-d6) δ ppm 8.29 - 8.66 (m, 2H), 7.81 (d, J = 7.05 Hz, 1H), 6.22 (d, J = 7.26 Hz, 1H), 4.61 (t, J = 12.23 Hz, 4H). m / z (ESI): 187.2 (M+H) + 。

[0318] Intermediate 6: 2-(4,4-Difluorocyclohexyl)-6-methylpyrimidin-4-amine

[0319]

[0320] Step 1: To a solution of 2-chloro-6-methylpyrimidin-4-amine (70.0 g, 488 mmol, Combi-Blocks, San Diego, CA) in 1,4-dioxane (560 mL) and water (210 mL) was added 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (119 g, 488 mmol, Combi-Blocks, San Diego, CA) and tripotassium phosphate (310 g, 1463 mmol). The reaction mixture was degassed and purged with nitrogen for 5 min. To this reaction mixture was added PdCl2(dppf)-DCM adduct (39.8 g, 48.8 mmol), and the mixture was stirred at 100 °C for 16 h. By The bed was filtered with a dark and inhomogeneous mixture, and the filter cake was washed with ethyl acetate (2 x 1000 mL). The filtrate was washed with 1N NaOH solution (300 mL), followed by water (500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was adsorbed onto a silica plug and purified by column chromatography on silica gel (60 - 120 mesh), eluting with a gradient of 50% to 60% ethyl acetate in hexane to afford 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine as a pale yellow solid (70 g, 64% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 6.85 (br s, 1H), 6.59 (br s, 2H), 6.13 (s, 1H), 2.62 - 2.80 (m, 4H), 2.19 (s, 3H), 2.04 - 2.17 (m, 2H). m / z (ESI): 226.2 (M + H) + 。

[0321] Step 2: To a solution of 2-(4,4-difluorocyclohex-1-en-1-yl)-6-methylpyrimidin-4-amine (70.0 g, 311 mmol) in EtOH (700 mL) was added 10% Pd on carbon (33.1 g, 155 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h under a hydrogen pressure of 1 atm. The reaction mixture was filtered through a bed and washed with a mixture of ethyl acetate and ethanol (1:1, 500 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (60 - 120 mesh) using 50% ethyl acetate in hexane to afford the title compound as an off-white solid (58.5 g, 83% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (s, 2H), 6.09 (s, 1H), 2.56 - 2.67 (m, 1H), 2.16 (s, 3H), 1.72 - 2.10 (m, 8H). m / z (ESI): 228.1 (M + H) + 。

[0322] Intermediate 7: 2-Methyl-6-(3,3,3-trifluoropropoxy)pyridin-4-amine

[0323]

[0324] At 0 °C, sodium hydride (60 wt% in mineral oil, 0.79 g, 19.82 mmol) was added to a solution of 3,3,3-trifluoropropan-1-ol (1.99 g, 17.44 mmol, Combi-Blocks) in 30 mL of THF. The mixture was stirred at room temperature for 30 min and then treated with 2-fluoro-6-methylpyridin-4-amine (1.00 g, 7.93 mmol, AstaTech Inc). The mixture was heated at 65 °C in an oil bath for 5 h. It was cooled to room temperature, quenched with water (10 mL) and extracted with EtOAc (2 x 50 mL). The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was adsorbed onto a silica plug and purified on a silica column (15% to 30% EtOAc in heptane) to give 2-methyl-6-(3,3,3-trifluoropropoxy)pyridin-4-amine as a pale yellow oil (0.47 g, 2.13 mmol, 27% yield). m / z (ESI): 221.1 (M+H) + 。

[0325] Table 1: The following intermediates were prepared according to a similar procedure to that of Intermediate 7:

[0326]

[0327] Intermediate 8: 2-(4,4-Difluoropiperidin-1-yl)pyridin-4-amine

[0328]

[0329] A mixture of 2-chloropyridin-4-amine (2.00 g, 15.56 mmol, Combi-Blocks), DIPEA (6.03 g, 46.70 mmol, Sigma-Aldrich) and 4,4-difluoropiperidine (2.45 g, 20.22 mmol, Enamine) in NMP (6 mL) was microwave heated at 200 °C for 6 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The organic extract was concentrated. The residue was purified by silica chromatography (20% to 70% EtOAc in heptane) to afford 2-(4,4-difluoropiperidin-1-yl)pyridin-4-amine as a pale yellow solid (2.91 g, 13.65 mmol, 88% yield). m / z (ESI): (M+H) + 214.1。

[0330] Table 2: The following intermediates were prepared according to a similar procedure to that described for Intermediate 8:

[0331]

[0332] Intermediate 9: 2-(4,4-Difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-amine

[0333]

[0334] Step 1: At -60 °C, n-butyllithium (2 M in hexanes, 20.52 mL, 41.0 mmol) was added dropwise to a solution of diisopropylamine (5.85 mL, 41.0 mmol) in tetrahydrofuran (50 mL). The reaction mixture was slowly warmed to 0 °C and stirred at the same temperature for 45 min. In another round-bottom flask, the LDA solution prepared above was added dropwise to a solution of 2-bromo-3-fluoro-6-methylpyridine (3.9 g, 20.52 mmol) in tetrahydrofuran (50 mL) at -78 °C. The resulting reaction mixture was stirred at the same temperature for 45 min, and then iodine (10.42 g, 41.0 mmol) in THF (40 mL) was added dropwise. The reaction mixture was stirred at the same temperature for 1 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with sodium thiosulfate solution, water, and brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-3-fluoro-4-iodo-6-methylpyridine as a yellow solid (6 g, 18.99 mmol, 93% yield). The product was used in the next step without further purification. 1 1H NMR (400 MHz, chloroform-d) δ ppm 7.53 (d, J = 3.8 Hz, 1H), 2.52 (s, 3H). m / z (ESI): 315.8, 317.8 (M+H) + 。

[0335] Step 2: A mixture of 2-bromo-3-fluoro-4-iodo-6-methylpyridine (1.5 g, 4.75 mmol), (4-methoxyphenyl)methanamine (0.782 g, 5.70 mmol), cesium carbonate (4.64 g, 14.24 mmol), Xantphos (0.549 g, 0.950 mmol), and Pd2(dba)3 (0.065 g, 0.071 mmol) in 1,4-dioxane (30 mL) was stirred at ambient temperature for 16 h. Then the reaction mixture was filtered through a plug and the filtrate was diluted with EtOAc. The resulting solution was washed with water, brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 18% ethyl acetate in petroleum ether to give 2-bromo-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine as a pale yellow solid (0.7 g, 2.15 mmol, 45% yield). 1HNMR (300 MHz, DMSO-d6) δ ppm 7.38 (s, 1H), 7.21 - 7.31 (m, 2H), 6.84 - 6.95 (m, 2H), 6.52 (d, J = 6.0 Hz, 1H), 4.32 (d, J = 6.3 Hz, 2H), 3.72 (s, 3H), 2.20 (s, 3H). m / z (ESI): 325.0, 327.0 (M + H) + 。

[0336] Step 3: A mixture of 2-bromo-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.7 g, 2.153 mmol), 4,4-difluoropiperidine hydrochloride (0.407 g, 2.58 mmol), cesium carbonate (2.81 g, 8.61 mmol), Xantphos (0.249 g, 0.431 mmol) and Pd2(dba)3 (0.030 g, 0.032 mmol) in 1,4-dioxane (15 mL) was stirred in a sealed tube at 100 °C for 16 h. Then the reaction mixture was filtered through a plug, and the filtrate was diluted with EtOAc. The resulting solution was washed with water, brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 6% ethyl acetate in petroleum ether to afford 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine as a pale yellow solid (0.67 g, 1.83 mmol, 85% yield). 1 HNMR (300 MHz, DMSO-d6) δ ppm 7.19 - 7.29 (m, 2H), 6.83 - 6.93 (m, 2H), 6.75 (m, 1H), 6.13 (d, J = 5.4 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H), 3.72 (s, 3H), 3.40 (d, J = 11.5 Hz, 4H), 1.92 - 2.14 (m, 7H). m / z (ESI): 366.1 (M + H) + 。

[0337] Step 4: At ambient temperature, anisole (0.179 mL, 1.642 mmol) and TFA (1.5 mL, 19.47 mmol) were added to a solution of 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-N-(4-methoxybenzyl)-6-methylpyridin-4-amine (0.3 g, 0.821 mmol) in dichloromethane (3 mL), and the reaction mixture was stirred at 50 °C for 2.5 h. The reaction mixture was then quenched with water, the pH was adjusted to 8 with 10% sodium bicarbonate solution, and then it was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 20% ethyl acetate in petroleum ether to afford 2-(4,4-difluoropiperidin-1-yl)-3-fluoro-6-methylpyridin-4-amine as a yellow oil (0.17 g, 0.69 mmol, 84% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 6.15 (d, J = 5.5 Hz, 1H), 5.79 (s, 2H), 3.40 (t, J = 5.6 Hz, 4H), 2.13 (s, 3H), 2.02 (tt, J = 14.2, 5.6 Hz, 4H). m / z (ESI): 246.2 (M+H) + 。

[0338] Intermediate 10: 2-(6-Amino-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)propan-2-ol

[0339]

[0340] Step 1: At 0 °C, (3,5-dimethoxyphenyl)methanamine (19.39 g, 116 mmol) and DIPEA (33.7 mL, 193 mmol) were added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (20.00 g, 97 mmol) in tetrahydrofuran (200 mL). The reaction mixture was then stirred at ambient temperature for 16 h, then quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The concentrate was triturated with DCM and hexanes to afford methyl 2-chloro-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate as an off-white solid (19.5 g, 57.7 mmol, 59.8% yield). 11H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (t, J = 5.5 Hz, 1H), 7.16 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.4, 2.4 Hz, 1H), 4.40 (d, J = 5.4 Hz, 2H), 3.82 (d, J = 14.5 Hz, 6H), 3.75 (d, J = 5.8 Hz, 3H). m / z (ESI): 338.1 (M+H) + 。

[0341] Step 2: A solution of methyl 2-chloro-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (3 g, 8.88 mmol), 4,4-difluoropiperidine hydrochloride (2.10 g, 13.32 mmol) and DIPEA (3.44 g, 26.6 mmol) in DMF (30 mL) was stirred in a sealed tube at 90 °C for 16 h. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography using a gradient of 50% to 60% ethyl acetate in petroleum ether to afford methyl 2-(4,4-difluoropiperidin-1-yl)-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (2.6 g, 6.15 mmol, 69.3% yield) as a pale yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.3, 2.4 Hz, 2H), 4.39 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.33 (m, 4H), 1.85 - 2.00 (m, 4H).

[0342] Step 3: Sulfuric acid (0.126 mL, 2.37 mmol) was added dropwise to a solution of methyl 2-(4,4-difluoropiperidin-1-yl)-6-((3,5-dimethoxybenzyl)amino)pyrimidine-4-carboxylate (1 g, 2.367 mmol) in DCM (10 mL) at 0 °C. The mixture was then warmed to room temperature and the reaction progress was monitored by TLC. After the starting material was consumed, the reaction mixture was quenched with ice water and the pH was adjusted to 9 by using 10% NaHCO3 solution. Then, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-carboxylate (0.45 g, 1.653 mmol, 69.8% yield) as an off-white solid. 1 1H NMR (300 MHz, DMSO-d6) δ ppm 6.90 (br s, 2H), 6.39 (s, 1H), 3.85 - 3.83 (m, 4H), 3.79 (s, 3H), 1.99 - 1.35 (m, 4H). m / z (ESI): 273.1 (M+H) + 。

[0343] Step 4: Methylmagnesium bromide (2.0 M in diethyl ether) (2.07 mL, 4.13 mmol) was added to a solution of methyl 6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidine-4-carboxylate (0.45 g, 1.653 mmol) in tetrahydrofuran (5 mL) at 0 °C and the mixture was stirred at room temperature for 2 h. After the starting material was consumed, the reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0% to 90% ethyl acetate in petroleum ether to afford 2-(6-amino-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)propan-2-ol (0.35 g, 1.28 mmol, 78% yield) as a pale yellow solid. m / z (ESI): 273.1 (M+H) + 。

[0344] Table 3: The following intermediates were prepared according to a similar procedure as described for Intermediate 10

[0345]

[0346] Intermediate 11: 2-(4-Amino-6-methylpyrimidin-2-yl)propan-2-ol

[0347]

[0348] Step 1: A mixture of 2,4-dichloro-6-methylpyrimidine (3.0 g, 18.40 mmol, Aldrich, St. Louis, MO, USA), bis(4-methoxybenzyl)-amine (7.10 g, 27.6 mmol, Combi-Blocks Inc., San Diego, CA, USA), and potassium carbonate (7.63 g, 55.2 mmol, Aldrich, St. Louis, MO, USA) in tetrahydrofuran (100 mL) was stirred at room temperature for 72 h. The reaction mixture was diluted with water (50 mL) and then extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc / heptane) to afford 2-chloro-N,N-bis(4-methoxybenzyl)-6-methylpyrimidin-4-amine as an off-white solid (3.11 g, 8.10 mmol, 44.0%). 1 HNMR (DMSO-d6) δ ppm 7.16 (br d, J = 6.2 Hz, 4H), 6.89 (d, J = 8.7 Hz, 4H), 6.60 (s, 1H), 4.39 - 4.84 (m, 4H), 3.73 (s, 6H), 2.20 (s, 3H). m / z (ESI): 384.2 (M+H)+.

[0349] Step 2: 2-Chloro-N,N-bis(4-methoxybenzyl)-6-methylpyrimidin-4-amine (1.0 g, 2.61 mmol), 1,3-bis(diphenylphosphino)propane (64.5 mg, 0.156 mmol, Aldrich, St. Louis, MO, USA), diethyl oxalate (0.529 mL, 3.91 mmol, Aldrich, St. Louis, MO, USA), trans-dichlorobis(triphenylphosphine)palladium(ii) (54.9 mg, 0.078 mmol, Strem Chemicals Inc., Newburyport, MA, USA), and 4-(dimethylamino)pyridine (477 mg, 3.91 mmol, Aldrich, St. Louis, MO, USA) in ethanol (0.5 mL) were subjected to microwave irradiation at 140 °C for 20 min. The reaction mixture was then diluted with water (50 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) afforded ethyl 4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidine-2-carboxylate (274 g, 0.650 mmol, 24.95% yield) as a pale yellow solid. 1 HNMR (methanol-d4) δ ppm 7.29 (br s, 4H), 6.97 (d, J = 8.5 Hz, 4H), 6.68 (s, 1H), 4.78 - 4.93 (m, 4H), 4.54 (q, J = 7.2 Hz, 2H), 3.88 (s, 6H), 2.43 (s, 3H), 1.53 (t, J = 7.0 Hz, 3H). m / z (ESI): 422.1 (M+H)+.

[0350] Step 3: Under N2 and at 0 °C, a solution of ethyl 4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidine-2-carboxylate (396 mg, 0.940 mmol) in 2-methyltetrahydrofuran (7 mL) was added dropwise with methylmagnesium bromide (3.4 M in 2-methyltetrahydrofuran) (0.829 mL, 2.82 mmol, Aldrich, St. Louis, MO, USA). After addition, the mixture was then stirred at 0 °C for 3.5 h. The mixture was then quenched with saturated NH4Cl (10 mL) and then extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) afforded 2-(4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)propan-2-ol as a yellow solid (307 mg, 0.753 mmol, 80% yield). m / z (ESI): 408.2 (M+H)+.

[0351] Step 4: A solution of 2-(4-(bis(4-methoxybenzyl)amino)-6-methylpyrimidin-2-yl)propan-2-ol (300 mg, 0.736 mmol) in trifluoroacetic acid (10 mL, Aldrich, St. Louis, MO, USA) was subjected to microwave irradiation at 110 °C for 30 min. The mixture was then concentrated under reduced pressure. The crude product was then dissolved in DCM (10 mL) and then quenched with saturated Na2CO3 (15 mL). The mixture was then extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc:EtOH (3:1) / heptane) afforded 2-(4-amino-6-methylpyrimidin-2-yl)propan-2-ol as a pale yellow solid (123 mg). m / z (ESI): 168.2 (M+H)+.

[0352] Ring Ar 2 Preparation of Intermediate

[0353] Intermediate 12: 4-Iodo-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid

[0354]

[0355] To a solution of 2-fluoro-4-iodobenzoic acid (300 g, 1.13 mol, Combi-Blocks, San Diego, CA) 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 solution 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 (2.00 L x 3). The aqueous phase was separated and the pH was adjusted to 6 with HCl (2.00 mol / L, aqueous solution). 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, 68.9% 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).

[0356] Table 4: The following intermediates were prepared according to a procedure similar to that of Intermediate 12:

[0357]

[0358] Intermediate 13: 4-(Methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid

[0359]

[0360] 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 room temperature for 12 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 (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 0% to 30% ethyl acetate in hexane as the eluent to give 2-fluoro-4-(methylsulfonyl)benzoic acid benzyl ester as a white solid (100 g, 79% yield). 11H 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).

[0361] Step 2: To a solution of benzyl 2-fluoro-4-(methylsulfonyl)benzoate (55 g, 178 mmol) in dimethyl sulfoxide (550 mL) was added DIPEA (57.6 g, 446 mmol), followed by 6-azaspiro[2.5]octane (29.8 g, 268 mmol), and the reaction mixture was stirred at 100 °C for 24 h. The reaction mixture was quenched with water (1 L) and extracted with MTBE (3 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% to 10% ethyl acetate in hexane as the eluent 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) + 。

[0362] Step 3: To a solution of benzyl 4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoate (65 g, 163 mmol) in tetrahydrofuran (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 with hexane (200 mL), and dried in vacuo for 12 h to afford 4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (42 g, 83% yield) as an off-white solid. 11H 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 (bs, 4H), 1.55 (bs, 4H), 0.41 (s, 4H). m / z (ESI): 310.1 (M+H) + 。

[0363] Intermediate 14: 4-(((1-Methylcyclopropyl)-1-sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid

[0364]

[0365] Step 1: Sodium carbonate (31.5 g, 297 mmol) was added to a solution of 4-bromo-2-fluorobenzoic acid (50.0 g, 228 mmol, F Chemicals, China) in DMF (500 mL) at 0 °C, followed by the addition of benzyl bromide (43.0 g, 251 mmol), and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3 x 2000 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as the eluent to afford benzyl 4-bromo-2-fluorobenzoate as a colorless viscous oil (65 g, 92% yield). 1 1H NMR (400 MHz, chloroform-d) δ ppm 7.91 (t, J = 8.4 Hz, 1H), 7.47 (dt, J = 6.0, 1.5 Hz, 2H), 7.43 (dd, J = 6.8, 1.8 Hz, 1H), 7.41 (q, J = 1.5 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.02 (dd, J = 8.7, 2.1 Hz, 1H), 6.79 (s, 1H), 5.38 (s, 2H). m / z (ESI): 310.2 (MH) + 。

[0366] Step 2: To a solution of benzyl 4-bromo-2-fluorobenzoate (60.0 g, 194 mmol) in DMSO (200 mL) was added 6-azaspiro[2.5]octane (32.4, 291 mmol, Wuxi Apptec) in DMSO (200 mL) and DIPEA (30 g, 291 mmol), and the mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched with water (2000 mL) and extracted with ethyl acetate (3 x 2000 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 10% ethyl acetate in hexane to give benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate as a yellow oil (70 g, 90% yield). 1 HNMR (400 MHz, chloroform-d) δ ppm 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.49 - 7.28 (m, 3H), 7.20 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 8.3, 1.9 Hz, 1H), 5.36 (s, 2H), 3.12 - 3.02 (m, 4H), 1.47 (t, J = 5.3 Hz, 4H), 0.33 (d, J = 1.8 Hz, 4H). m / z (ESI): 398.1, 400.1 (M+H) + 。

[0367] Step 3: Add benzyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (9 g, 22.48 mmol), 1-methylcyclopropane-1-sulfonamide (3.95 g, 29.2 mmol, Combi-Blocks, San Diego, CA), and K2CO3 (6.21 g, 45.0 mmol) in 1,4-dioxane (90 mL) to a 250 mL sealed tube. Degas the reaction and purge with nitrogen for 5 min. Add Xantphos (1.301 g, 2.248 mmol) to the reaction mixture, followed by Pd2(dba)3 (1.03 g, 1.12 mmol). Close the sealed tube and stir at 110 °C for 18 h. Quench the reaction mixture with water (250 mL) and extract with ethyl acetate (2 x 150 mL). Wash the organic layer with water (100 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the crude residue by column chromatography on silica gel eluting with a gradient of 0% to 15% EtOAc in hexane to afford benzyl 4-((1-methylcyclopropane)-1-sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (6.1 g, 59% yield) as an orange oil. 1 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) + 。

[0368] Step 4: Add 10% Pd-C (1.05 g, 50% wt / wt) 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 methanol (20 mL) and ethyl acetate (10 mL) under a nitrogen atmosphere. Degas the reaction mixture and stir under a hydrogen pressure (1 atm, balloon pressure) for 4 h. By The reaction mixture was filtered through a bed and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford 4-((1-methylcyclopropyl)-1-sulfamoyl)-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) + 。

[0369] Intermediate 15: 4-(N-(3-Methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6- yl)benzoic acid

[0370]

[0371] Step 1: To a solution of 3-methyl-3-oxetanamine hydrochloride (5.50 g, 44.5 mmol) and N,N-diisopropylethylamine (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 room temperature for 1 h. The mixture was diluted with 1.0 N HCl (200 mL) and extracted with dichloromethane (150 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by Biotage SNAP 100 g column eluting with 0% to 30% 3:1 EtOAc-EtOH in heptane 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). 1 1H 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).

[0372] 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 1,4 - dioxane was stirred at 100 °C for 20 h. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The combined organic phases 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% to 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 HNMR(500MHz,DMSO - d6)δppm 8.42(s,1H),7.72(d,J=8.04Hz,1H),7.47(d,J=1.56Hz,1H),7.36(dd,J=1.82,8.04Hz,1H),4.55(d,J=5.97Hz,2H),4.14(d,J=6.49Hz,2H),3.85(s,3H),3.02 - 3.09(m,4H),1.44 - 1.50(m,4H),1.42(s,3H),0.35(s,4H).

[0373] Step 3: A mixture of methyl 4 - (N - (3 - methyloxetan - 3 - yl)sulfamoyl)-2-(6 - azaspiro[2.5]octan - 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 at room temperature overnight. The mixture was concentrated under reduced pressure to remove some of the organic solvents. 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, 72.8% yield) as a white solid. 11H 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), 0.36 - 0.46 (s, 4H).

[0374] Intermediate 16: 4-(((1-(tert-Butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5] oct-6-yl)benzoic acid

[0375]

[0376] Step 1: A mixture of methyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (10.50 g, 32.4 mmol, Intermediate 12-2), DIPEA (8.37 mL, 64.8 mmol), Xantphos (1.874 g, 3.24 mmol), and Pd2(dba)3 (2.97 g, 3.24 mmol) in 1,4-dioxane was bubbled with argon, and then tert-butyl 3-mercaptoazetidine-1-carboxylate (7.66 mL, 40.5 mmol) was added. The mixture was stirred at 100 °C for 18 h. The mixture was cooled to room temperature, concentrated, and purified by Biotage SNAP eluting with a gradient of 0% to 25% 3:1 EtOAc-EtOH in heptane to afford tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfanyl)azetidine-1-carboxylate (13.85 g, 32.0 mmol, 99% yield) as a pale yellow viscous solid. 1 1H NMR (500 MHz, DMSO-d6) δ ppm 7.55 (d, J = 8.04 Hz, 1H), 6.79 (s, 1H), 6.76 (d, J = 8.14 Hz, 1H), 4.34 - 4.43 (m, 2H), 4.27 - 4.34 (m, 1H), 3.79 (s, 3H), 3.70 (dd, J = 4.67, 8.56 Hz, 2H), 2.97 - 3.04 (m, 4H), 1.41 - 1.51 (m, 4H), 1.38 (s, 9H), 0.29 - 0.37 (m, 4H).

[0377] Step 2: To a solution of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfanyl)azetidine-1-carboxylate (13.85 g, 32.0 mmol) in 1,4-dioxane (300 mL) was added Oxone monopersulfate (39.4 g, 64.0 mmol) in 150 mL of water. The mixture was stirred at room temperature for 5 h, and 150 mL of ethyl acetate and 150 mL of water were added, and the mixture was stirred for 10 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic matters were washed with brine, dried, filtered and concentrated. The crude product was purified by Biotage SNAP 340 g column eluting with a gradient of 0% to 25% EtOAc-EtOH (3:1) in heptane to give tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (12.77 g, 27.5 mmol, 86% yield) as an off-white solid. 1 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 8.04 Hz, 1H), 7.44 - 7.50 (m, 2H), 4.48 - 4.55 (m, 1H), 4.09 (br s, 2H), 3.97 - 4.02 (m, 2H), 3.86 (s, 3H), 3.04 - 3.17 (m, 4H), 1.42 - 1.51 (m, 4H), 1.38 (s, 9H), 0.35 (s, 4H).

[0378] Step 3: A mixture of tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate (12.77 g, 27.5 mmol) and lithium hydroxide monohydrate (11.53 g, 275 mmol) in THF-water-MeOH (1:1:1, 230 mL) was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure to remove some organic solvents. The solution was acidified to pH < 3 with 2N HCl. The precipitated solid was filtered and dried to give 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (10.6 g, 23.53 mmol, 86% yield) as an off-white solid. 11H NMR (500 MHz, DMSO-d6) δ ppm 8.03 (d, J = 8.30 Hz, 1H), 7.93 (d, J = 1.82 Hz, 1H), 7.72 (dd, J = 1.69, 8.17 Hz, 1H), 4.48 - 4.60 (m, 1H), 4.10 (br.s., 2H), 3.99 - 4.06 (m, 3H), 3.14 - 3.22 (m, 4H), 1.49 - 1.59 (m, 4H), 1.38 (s, 9H), 0.41 (s, 4H).

[0379] With AR 1 and AR 2 Intermediate compounds with rings

[0380] Intermediate 17: N-(2-Chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]oct-6-yl)benzoyl amine

[0381]

[0382] 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphane 2,4,6-trioxide (50 wt% solution in EtOAc, 12.50 mL, 21.00 mmol) and triethylamine (2.93 mL, 21.00 mmol) were added to a suspension of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (3.0 g, 8.40 mmol, Intermediate 12) and 2-chloro-6-methylpyrimidin-4-amine (1.45 g, 10.08 mmol, Aurum Pharmtech Inc.) in DCE (20 mL). The mixture was heated at 85 °C for 24 h and then cooled to room temperature. Water (10 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (1 x 10 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a solid. The solid was suspended in 1:1 EtOAc / heptane and filtered to afford N-(2-chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.61 g, 7.48 mmol, 89% yield) as an off-white solid. 1 1H NMR (400 MHz, chloroform-d) δ ppm 13.53 (br s, 1H) 8.11 (s, 1H) 7.92 (d, J = 8.29 Hz, 1H) 7.70 (s, 1H) 7.65 - 7.69 (m, 1H) 3.05 (t, J = 5.39 Hz, 4H) 2.53 (s, 3H) 1.61 - 1.88 (m, 4H) 0.44 (s, 4H). m / z (ESI): 483.0 (M+H) + 。

[0383] Intermediate 18: (R)-4-Bromo-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0384]

[0385] Step 1: Add 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (0.9 g, 2.90 mmol, Intermediate 12-1), pyridine (0.657 mL, 8.12 mmol), and perfluorophenyl 2,2,2-trifluoroacetate (0.717 g, 3.77 mmol) in DCM (8 mL) to a 100 mL round-bottom flask. Stir the resulting mixture at room temperature for 16 h and remove the solvent in vacuo to obtain the crude product, which can be used in the next step without purification. m / z (ESI): 476 and 478 (M+1).

[0386] Step 2: Add (R)-6-methyl-2-(2-methylmorpholino)pyrimidin-4-amine (0.223 g, 1.15 mmol, Intermediate 2) dissolved in N,N-dimethylformamide (6 mL) to a 50 mL round-bottom flask, and then add sodium hydride (0.084 g, 2.1 mmol) at room temperature under a nitrogen atmosphere. Stir the reaction mixture for 10 min, and then treat it with perfluorophenyl 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoate (0.5 g, 1.050 mmol) at room temperature under a nitrogen atmosphere. Stir the resulting reaction mixture at room temperature for another 2 h. Extract the reaction mixture with DCM (2 x 30 mL), separate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude material. Then adsorb it onto a silica gel plug and purify it by flash column chromatography on silica gel eluting with 30% to 50% EtOAc / hexane to afford the title compound as a white solid (0.20 g, 0.40 mmol, 38% yield). 1 1H NMR (300 MHz, DMSO-d6) δ ppm 13.19 (bs, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 4.45 (t, J = 12 Hz, 2H), 3.88 (m, 1H), 3.52 - 3.48 (m, 2H) 3.10 - 2.90 (m, 6H), 2.30 (s, 3H), 1.71 - 1.62 (m, 4H), 1.14 (d, J = 6 Hz, 3H), 0.36 (s, 4H). m / z (ESI): 500 and 502 (M+1).

[0387] Intermediate 19: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro [2.5]oct-6-yl)benzamide

[0388]

[0389] 4-Iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (150.0 g, 420 mmol, Intermediate 12) was suspended in dichloromethane (1000 mL) under argon. Catalytic DMF (1.0 mL) was added, and then a solution of thionyl chloride (54.6 g, 28 mL, 459 mmol, Sigma-Aldrich Corporation) in dichloromethane (500 mL) was added dropwise over 10 min. After stirring for 30 min at ambient temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was azeotroped with toluene (2 x 300 mL) and then suspended in dichloromethane (300 mL) under argon. Tripotassium phosphate (267 g, 1.26 mol, Sigma-Aldrich Corporation) was added, followed by a solution of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (100 g, 438 mmol, Intermediate 4) and N,N-diisopropylethylamine (200 mL, 1.14 mol, Sigma-Aldrich Corporation) in DCM (300 mL, added over 5 min). The yellow mixture was stirred at ambient temperature for 3 h and then evaporated to dryness under reduced pressure. The crude solid was suspended in dichloromethane (1 L) and stirred for 10 min. The mixture was filtered through a frit, and the solid was washed with additional dichloromethane (2 x 100 mL). The solid was discarded, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was suspended in acetonitrile (750 mL) and stirred at ambient temperature for 15 min. The suspension was filtered through a frit, and the solid was washed with additional acetonitrile (75 mL). The solid was dried under a stream of nitrogen to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (186 g, 328 mmol, 78% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.38 (br s, 1H) 7.72 - 7.87 (m, 3H) 7.39 (s, 1H) 3.91 (br s, 4H) 2.99 - 3.06 (m, 4H) 2.32 (s, 3H) 1.92 - 2.07 (m, 4H) 1.62 - 1.85 (m, 4H) 0.38 (s, 4H). m / z (ESI): 568.0 (M + H) + 。

[0390] Intermediate 20: 4-Bromo-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-(6-aza spiro[2.5]oct-6-yl)benzamide

[0391]

[0392] Step 1: To a solution of 4-bromo-2,6-difluorobenzoic acid (3.0 g, 12.7 mmol, Apollo Scientific Ltd.) in THF (50 mL) was added oxalyl chloride (1.7 mL, 19.0 mmol), followed by 1 drop of DMF. The mixture was stirred for 1 h and then the solvent was removed in vacuo to give a solid which was used directly in the next stage without further characterization. The solid was dissolved in DCM (50 mL) and anhydrous pyridine (4.31 mL, 50.6 mmol), followed by the addition of 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (2.89 g, 12.7 mmol, Intermediate 4), and the mixture was stirred at room temperature for 16 h. EtOAc (200 mL) was added and the mixture was washed with saturated NH4Cl (1x), water (1x), brine (1x), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with 0% to 40% EtOAc / heptane to afford 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluorobenzamide as a white solid (1.36 g, 3.04 mmol, 24% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1H) 7.64 (d, J = 7.05 Hz, 2H) 7.19 - 7.37 (m, 1H) 3.86 (br s, 4H) 2.32 (s, 3H) 1.98 (br d, J = 11.40 Hz, 4H). m / z (ESI): 447.0, 449.0 (M+H) + 。

[0393] Step 2: 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,6-difluorobenzamide (0.65 g, 1.45 mmol) in DMSO (2.5 mL), 6-azaspiro[2.5]octane (0.18 g, 1.60 mmol, Wuxi App Tech), and DIPEA (0.31 mL, 1.74 mmol) were heated to 100 °C for 8 h and then cooled to room temperature. Water was added, the resulting suspension was filtered, and the obtained solid was dried. The solid was purified by silica gel chromatography, eluting with 0% to 15% EtOAc / heptane to afford 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-6-(6-azaspiro[2.5]oct-6-yl)benzamide as a white solid (0.23 g, 0.43 mmol, 28.2% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (br s, 1H) 7.30 (br s, 1H) 7.21 (br d, J = 9.12 Hz, 1H) 7.10 (br s, 1H) 3.88 (br s, 4H) 3.05 (br s, 4H) 2.32 (br s, 3H) 1.77 - 2.04 (m, 4H) 1.36 (br s, 4H) 0.27 (s, 4H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -94.88 (s, 1F) -113.60 (s, 1F). m / z (ESI): 538.2, 540.2 (M + H) + .

[0394] Intermediate 21: 4-Amino-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6- azaspiro[2.5]oct-6-yl)benzamide

[0395]

[0396] Step 1: Triethylamine (3.11 mL, 22.2 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 wt% in EtOAc, 13.2 mL, 22.2 mmol) were added to a solution of 2,5-difluoro-4-nitrobenzoic acid (1.5 g, 7.39 mmol, Combi-Blocks Inc.) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.69 g, 7.39 mmol, Intermediate 4) in DCE (15 mL). The mixture was heated to 85 °C for 2 h and then cooled to room temperature. Water (15 mL) was added, and the resulting two-phase mixture was separated. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a solid. The solid was suspended in DCM (15 mL), filtered, and dried to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluoro-4-nitrobenzamide (3.05 g, 4.55 mmol, 62% yield) as a yellow solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (s, 1H) 8.27 (dd, J = 8.81, 5.91 Hz, 1H) 7.99 (dd, J = 10.57, 5.39 Hz, 1H) 7.23 (br s, 1H) 3.85 (br s, 3H) 2.33 (s, 4H) 1.89 - 2.05 (m, 4H). 19 19F NMR (376 MHz, DMSO-d6) δ ppm -95.11 (s, 1F) -123.35 (s, 1F) -123.40 (s, 1F). m / z (ESI): 414.2 (M+H) + .

[0397] Step 2: N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluoro-4-nitrobenzamide (1.0 g, 2.42 mmol) and palladium (10 wt% on activated carbon, 0.45 g, 0.42 mmol) were placed under an argon atmosphere. Then, EtOH (15 mL) was added, followed by ammonium formate (0.76 g, 12.1 mmol). The mixture was stirred at 75 °C for 10 min and then cooled to room temperature. Using Palladium was filtered out, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in EtOAc (10 mL), and the solution was washed with water (2 x 10 mL), brine (1 x 10 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluorobenzamide as a white solid (0.93 g, 2.19 mmol, 91% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 9.68 - 9.80 (m, 1H) 7.40 (dd, J = 11.61, 6.84 Hz, 1H) 7.28 (s, 1H) 6.54 (dd, J = 13.48, 7.26 Hz, 1H) 6.26 (s, 2H) 3.83 - 3.90 (m, 4H) 2.30 (s, 3H) 1.92 - 2.05 (m, 4H). 19 19F NMR (376 MHz, DMSO-d6) δ ppm -95.07 (s, 1F) -116.10 (s, 1F) -140.24 (s, 1F). m / z (ESI): 384.2 (M+H) + .

[0398] Step 3: 4-Amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2,5-difluorobenzamide (0.80 g, 2.09 mmol), 6-azaspiro[2.5]octane (0.70 g, 6.26 mmol, Wuxi App Tech), and DIPEA (1.1 mL, 6.26 mmol) in NMP (4 mL) were heated in a microwave reactor to 200 °C for 4 h. Water (4 mL) was added, and the resulting suspension was stirred for 30 min, filtered, and the collected solid was dried to give a white solid. The solid was dissolved in DCM, flash chromatographed on silica gel and purified by silica gel chromatography, eluting with 0% to 50% EtOAc / heptane to afford 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6-azaspiro[2.5]oct-6-yl)benzamide as a white solid (702 g, 1.48 mmol, 70.9% yield). 1HNMR (400 MHz, DMSO-d6) δ ppm 13.77 (s, 1H) 7.64 (d, J = 12.85 Hz, 1H) 7.38 (s, 1H) 6.83 (d, J = 8.09 Hz, 1H) 6.04 (s, 2H) 3.90 (br t, J = 5.39 Hz, 4H) 2.91 (br s, 4H) 2.29 (s, 3H) 1.88 - 2.04 (m, 4H) 0.37 (s, 4H). (Note: 4 protons not observed) 19 F NMR (376 MHz, DMSO-d6) δ ppm -94.73 (s, 1F) -138.31 (s, 1F). m / z (ESI): 475.2 (M + H) + 。

[0399] Table 5: Intermediates 21-1 to 21-20 were prepared according to a similar procedure to Intermediates 17 to 21:

[0400]

[0401]

[0402]

[0403] Intermediate 22: Ethyl 2-Sulfamoylpropionate

[0404]

[0405] 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 tetrahydrofuran (4000 mL) at -78 °C and stirred for 30 min. Ethyl chloroformate (92.0 mL, 973.0 mmol) in THF (50 mL) was added to the reaction mixture and stirred at -78 °C for 1 h. The reaction mixture was quenched with HCl (1.5 N, 3000 mL) and extracted with EtOAc (2 x 3000 mL). The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product of ethyl 2-(N,N-bis(4-methoxybenzyl)aminosulfonyl)propionate (250.0 g, 60% purity) as a yellow oil. 1 1H-NMR showed the desired peaks and the next step could be carried out without any purification.

[0406] 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 room temperature 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 organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel using 25% ethyl acetate in hexane to afford a pale yellow solid (168 g), which was dissolved in DCM (1 L) and precipitated by the addition of hexane (3000 mL). The solid was filtered and dried in vacuo to afford 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) + 。

[0407] Intermediate 23: 2-Hydroxypropane-1-sulfonamide

[0408]

[0409] Step 1: Methanesulfonyl chloride (1.73 mL, 22.3 mmol) was added dropwise to a 0 °C solution of bis(4-methoxybenzyl)amine (5.0 g, 19.4 mmol, Combi-Blocks Inc.) and triethylamine (8.12 mL, 58.3 mmol) in DCM (40 mL) over 5 min. The mixture was then stirred at room temperature for 2 h, then 1N HCl (50 mL) was added. The layers were separated and the organic layer was washed with brine (1 x 50 mL), dried over anhydrous MgSO4, filtered and then concentrated in vacuo to afford a brown oil. The oil was dissolved in MeOH (50 mL) and partially concentrated in vacuo until a thick suspension formed. The suspension was stirred for 30 min, filtered and the collected solid was dried in vacuo to afford N,N-bis(4-methoxybenzyl)methanesulfonamide as a white solid (5.11 g, 15.2 mmol, 78% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.19 (d, J = 8.50 Hz, 4H) 6.90 (d, J = 8.50 Hz, 4H) 4.19 (s, 4H) 3.75 (s, 6H) 2.89 (s, 3H).

[0410] Step 2: n-Butyllithium (4.10 mL, 6.56 mmol) was added dropwise to a solution of N,N-bis(4-methoxybenzyl)methanesulfonamide (2.0 g, 5.96 mmol) in THF (15 mL) at -78 °C. The mixture was stirred for 10 min, after which acetaldehyde (0.37 mL, 6.56 mmol) was added dropwise. The mixture was stirred at -78 °C for 5 min and then the -78 °C bath was replaced with a 0 °C bath. The mixture was stirred for 15 min and then the reaction was quenched with saturated NH4Cl. EtOAc was added, the resulting two-phase mixture was separated, the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with a 0% to 70% EtOAc / heptane gradient to afford 2-hydroxy-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide as an oil (1.84 g, 4.85 mmol, 81% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 7.16 (d, J = 8.50 Hz, 4H) 6.80 - 6.92 (m, 4H) 4.99 (d, J = 5.18 Hz, 1H) 4.15 - 4.28 (m, 4H) 4.01 - 4.13 (m, 1H) 3.74 (s, 6H) 3.16 (dd, J = 13.99, 6.53 Hz, 1H) 3.04 (dd, J = 13.89, 5.39 Hz, 1H) 1.12 - 1.27 (m, 3H). m / z (ESI): 402.2 (M+Na) + 。

[0411] Step 3: A mixture of 2-hydroxy-N,N-bis(4-methoxybenzyl)propane-1-sulfonamide (1.84 g, 4.85 mmol) and anisole (1.06 mL, 9.70 mmol) in TFA (10 mL) was stirred at room temperature for 2 h and then the volatiles were removed in vacuo. The resulting oil was purified by silica gel chromatography, eluting with a 0% to 100% EtOAc / heptane gradient to afford 2-hydroxypropane-1-sulfonamide as a colorless oil (592 g, 4.25 mmol, 88% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 6.70 (s, 2H) 4.02 - 4.13 (m, 1H) 3.50 - 3.25 (br s, 1H) 3.07 - 3.15 (m, 1H) 2.98 - 3.06 (m, 1H) 1.20 (d, J = 6.22 Hz, 3H).

[0412] Example 1: N-(2-((1-Hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide Example 2: N-(2-(2-Hydroxypropan-2-yl)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3-yl)aminosulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0413]

[0414] A mixture of N-(2-chloro-6-methylpyrimidin-4-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (200 mg, 0.46 mmol, Intermediate 21-19), 2-amino-2-methyl-1-propanol (180 μL, 1.80 mmol, Aldrich, St. Louis, MO), and DIPEA (200 μL, 1.14 mmol) in NMP (1 mL) was heated at 130 °C for 60 h. The reaction mixture was cooled to room temperature and quenched with water (10 mL), then extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a silica plug and purified by column chromatography on silica (60-120 mesh), eluting with 0% to 70% ethyl acetate in hexane to afford the title compound as an off-white solid (111 mg, 49%). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 - 11.96 (m, 1H), 8.07 - 8.25 (m, 1H), 7.82 - 7.87 (m, 1H), 7.75 - 7.81 (m, 1H), 7.32 - 7.41 (m, 1H), 6.13 - 6.24 (m, 1H), 4.73 - 4.91 (m, 1H), 3.42 - 3.54 (m, 2H), 3.30 - 3.33 (m, 3H), 3.01 - 3.16 (m, 4H), 2.18 - 2.28 (m, 3H), 1.55 - 1.75 (m, 4H), 1.25 - 1.42 (m, 6H), 0.27 - 0.40 (m, 4H). m / z (ESI): 487.4 (M+H) + 。

[0415] Table 6: Examples 1-1 to 1-7 were prepared according to a similar procedure as described for Example 1:

[0416]

[0417]

[0418] Example 3: (R)-4-((2-Hydroxyethyl)sulfamoyl)-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide Example 4: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0419]

[0420] At 0 °C, 1-propane phosphonic anhydride (50% in ethyl acetate, 0.469 mL, 0.789 mmol, Aldrich) was added to a solution of 4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoic acid (150 mg, 0.394 mmol, Intermediate 15) and 2-(4-aminopyrimidin-2-yl)propan-2-ol (91 mg, 0.591 mmol, AstaTech, Bristol, PA, USA) in dichloromethane (2.6 mL), followed by the addition of DIPEA (0.207 mL, 1.18 mmol, Aldrich). The resulting mixture was then stirred overnight at room temperature. The mixture was then diluted with saturated aqueous NaHCO3 (2 mL), followed by dilution with saturated NH4Cl (7 mL). The mixture was then extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc / heptane) to afford N-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-4-(N-(3-methyloxetan-3-yl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (45 mg, 0.087 mmol) as a pale yellow solid. 1 1H NMR (DMSO-d6) δ ppm 13.52 (brs, 1H), 8.76 (d, J = 5.6 Hz, 1H), 8.54 (br d, J = 3.5 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.08 (brd, J = 5.4 Hz, 1H), 7.86 (d, J = 1.0 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 4.96 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.13 (d, J = 6.4 Hz, 2H), 3.08 (br t, J = 5.2 Hz, 4H), 1.70 (br s, 4H), 1.51 (s, 6H), 1.41 (s, 3H), 0.38 (s, 4H). m / z (ESI): 516.2 (M+H)+.

[0421] Table 7: Examples 2-1 to 2-8 were prepared according to a similar procedure as described for Example 2:

[0422]

[0423]

[0424] Examples 5-1 and 5-2: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamideExample 5-1: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide.

[0425]

[0426] Potassium phosphate tribasic (9.89 g, 46.6 mmol, Sigma-Aldrich), copper(I) iodide (0.710 g, 3.73 mmol, Sigma-Aldrich), 2-hydroxyethane-1-sulfonamide (1.166 g, 9.32 mmol, Wuxi Apptec, China), sarcosine (0.830 g, 9.32 mmol) and (R)-4-iodo-N-(6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (5.1 g, 9.32 mmol, Intermediate 21-2) were combined in a three-necked flask under argon. Dry degassed DMF (20 mL) was added and the mixture was heated to 110 °C for 45 min with overhead stirring. The reaction mixture was cooled to ambient temperature and saturated ammonium chloride (75 mL), water (200 mL) and ethyl acetate (200 mL) were added. The phases were mixed and separated, and the organic layer was dried over brine (75 mL) and then evaporated to dryness under reduced pressure. The crude solid was stirred in boiling ethanol (15 mL) for 10 m, then cooled to ambient temperature and filtered through a sintered glass frit. The solid was dried on the frit, then suspended in water (75 mL) and heated to 80 °C. After 10 min, the mixture was cooled to ambient temperature and filtered through a sintered glass frit. The solid was dried under a stream of nitrogen to afford the title compound as an off-white solid (3.3 g, 6.06 mmol, 65.0% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (bs, 1H), 10.26 (bs, 1H), 8.05 (m, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 4.95 (bs, 1H), 4.50 - 4.42 (m, 2H), 3.84 (m, 1H), 3.76 - 3.74 (m, 2H), 3.51 - 3.45 (m, 2H), 3.00 - 2.82 (m, 6H), 2.61 - 2.58 (m, 2H), 2.31 (s, 3H), 1.91 - 1.65 (m, 4H), 1.17 (d, J = 6.0 Hz, 3H), 0.39 (s, 4H). m / z (ESI): 545.2 (M + H)+.

[0427] Example 5-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. Table 8: Examples 6-1 to 6-40 were prepared according to a similar procedure to Examples 3 to 5-2:

[0428]

[0429] A mixture of 2-hydroxyethane-1-sulfonamide (1.28 g, 10.3 mmol, Wuxi AppTec), copper(I) iodide (0.49 g, 2.56 mmol), tripotassium phosphate (5.44 g, 25.6 mmol) and sarcosine (0.48 g, 5.13 mmol) in a 100 mL round-bottomed flask was placed under an argon atmosphere. Anhydrous DMF (20 mL) was added and the mixture was warmed to 50 °C for 5 min. Solid N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (2.91 g, 5.13 mmol, Intermediate 19) was added and the mixture was heated to 100 °C and stirred for 2 h, then cooled to room temperature. EtOAc (20 mL) and water (20 mL) were added, the resulting two-phase mixture was separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were then washed with water (2x), 9:1 NH4Cl / NH4OH (aqueous solution), brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography, eluting with a 0% to 50% EtOAc / heptane gradient, then isocratically with 50% EtOAc / heptane to afford an off-white solid. The solid was suspended in methanol, filtered, and dried to give a white solid. The solid was then suspended in water, stirred for 24 h, filtered and dried in vacuo to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.55 g, 2.75 mmol, 54% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d⁶) δ ppm 13.37 (s, 1H) 10.03 - 10.52 (m, 1H) 8.06 (d, J = 8.71 Hz, 1H) 7.41 (s, 1H) 7.28 (d, J = 1.87 Hz, 1H) 7.15 (dd, J = 8.71, 1.87 Hz, 1H) 4.73 - 5.14 (m, 1H) 3.92 (brt, J = 5.39 Hz, 4H) 3.77 (t, J = 6.43 Hz, 2H) 3.34 - 3.40 (m, 2H) 2.98 (brt, J = 4.56 Hz, 4H) 2.32 (s, 3H) 1.93 - 2.07 (m, 4H) 1.58 - 1.85 (m, 4H) 0.40 (s, 4H). 1919F NMR (376 MHz, DMSO-d6) δ ppm -94.74 (s, 1F). m / z (ESI): 565.2 (M+H) + .

[0430] Example 7: N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide Examples 8-1 and 8-2: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide Example 8-1: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy-1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide ​

[0431]

[0432] Step 1: A mixture of ethyl 2-sulfamoylpropionate (1.44 g, 7.93 mmol, Intermediate 22), copper(I) iodide (0.503 g, 2.64 mmol, Strem), sarcosine (0.47 g, 5.29 mmol, Sigma-Aldrich Corporation), and potassium phosphate (4.49 g, 21.2 mmol) in DMF (15 mL) was placed under an argon atmosphere and warmed to 50 °C for 5 min. N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.0 g, 5.29 mmol, Intermediate 19) was added and the mixture was heated to 100 °C for 3 h and then cooled to room temperature. EtOAc (50 mL), IPA (5 mL), and water (50 mL) were added and the mixture was stirred vigorously for 5 min. The resulting two-phase mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined extracts were washed with water (2 x 50 mL), 9:1 NH4Cl / NH4OH (1 x 50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give an oil. The crude oil was purified by silica gel chromatography using a Redi-Sep pre-packed silica gel column (80 g) eluting with a 0% to 50% EtOAc / heptane gradient to afford ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propionate (2.76 g, 4.45 mmol, 84% yield) as a white solid. 11H NMR (400 MHz, DMSO-d6) δ ppm 13.35 (s, 1H) 10.69 (brs, 1H) 8.07 (d, J = 8.71 Hz, 1H) 7.40 (s, 1H) 7.31 (d, J = 1.87 Hz, 1H) 7.17 (dd, J = 8.60, 1.97 Hz, 1H) 4.06 (qd, J = 7.08, 4.87 Hz, 2H) 3.92 (br t, J = 5.49 Hz, 4H) 2.98 (br t, J = 4.77 Hz, 4H) 2.32 (s, 3H) 1.85 - 2.06 (m, 5H) 1.73 (br s, 4H) 1.48 (d, J = 6.84 Hz, 3H) 1.14 (t, J = 7.05 Hz, 3H) 0.39 (s, 4H). 19 19F NMR (376 MHz, DMSO-d6) δ ppm -94.75 (s, 1F). m / z (ESI): 621.2 (M+H) + .

[0433] Step 2: Add ethyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propionate (10.39 g, 16.74 mmol) in THF (100 mL) and lithium borohydride solution (2.0 M in THF, 16.7 mL, 33.5 mmol, Sigma-Aldrich Corporation) to a 250 mL round bottom flask. Methanol (4.29 mL, 134 mmol) was added slowly within 5 min and the resulting solution was stirred at room temperature for 30 min. 1N HCl (20 mL) was added slowly, followed by EtOAc (20 mL), and the resulting two-phase mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was extracted with EtOAc (1 x 25 mL) and the combined extracts were washed with saturated NaHCO3 (1 x 50 mL), brine (1 x 50 mL), dried over anhydrous MgSO4, filtered and concentrated to give 8.9 g of a racemic mixture. The material was separated by preparative SFC using a Chiral Tech AD column (250X 30 mm, 5 mm) with a mobile phase of 85% liquid CO2 at a flow rate of 150 mL / min and 15% MeOH with 0.2% TEA to give:

[0434] ​ ​ The first elution peak (3.50 g, 6.05 mmol, 36.1% yield, >99% ee). 11H NMR (400 MHz, DMSO-d6) δ ppm 13.36 (s, 1H), 8.05 (d, J = 8.50 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J = 1.87 Hz, 1H), 7.17 (dd, J = 8.71, 2.07 Hz, 1H), 3.88 - 3.97 (m, 4H), 3.84 (dd, J = 10.99, 4.35 Hz, 1H), 3.37 - 3.54 (m, 1H), 3.25 - 3.30 (m, 1H), 2.97 (br t, J = 4.77 Hz, 4H), 2.32 (s, 3H), 1.84 - 2.06 (m, 4H), 1.57 - 1.84 (br s, 4H), 1.30 (d, J = 6.84 Hz, 3H), 0.39 (s, 4H). Two exchangeable protons were not observed. 19 19F NMR (376 MHz, DMSO-d6) δ ppm -94.74 (s, 1F). m / z (ESI): 579.2 (M+H) + 。

[0435] ​ ​ The second elution peak (2.66 g, 4.60 mmol, 27.5% yield, 98.9% ee). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.35 (s, 1H), 8.05 (d, J = 8.50 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J = 2.07 Hz, 1H), 7.17 (dd, J = 8.60, 1.97 Hz, 1H), 3.88 - 3.97 (m, 4H), 3.84 (dd, J = 10.99, 4.35 Hz, 1H), 3.50 (dd, J = 10.99, 7.46 Hz, 1H), 3.25 - 3.32 (m, 1H), 2.97 (br t, J = 4.77 Hz, 4H), 2.31 (s, 3H), 1.83 - 2.06 (m, 4H), 1.73 (br s, 4H), 1.30 (d, J = 6.84 Hz, 3H), 0.39 (s, 4H). Two exchangeable protons were not observed. 19 19F NMR (376 MHz, DMSO-d6) δ ppm -94.75 (s, 1F). m / z (ESI): 579.2 (M+H) + The stereochemistry was arbitrarily determined.

[0436] ​

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445] ​ ​

[0446]

[0447] Step 1: A solution of N-(2-chloro-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.3 mg, 0.747 mmol, Intermediate 21-18), 3,3-difluoroazetidine hydrochloride (0.145 g, 1.120 mmol, Combi-Blocks), and DIPEA (0.261 mL, 1.49 mmol) in DMF (0.5 mL) and ethanol (1 mL) was heated at 80 °C for 4 h. The reaction mixture was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with 30% to 50% ethyl acetate in petroleum ether to afford N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (180 g, 0.393 mmol, 52.6% yield) as a yellow solid. 1 HNMR (400 MHz, chloroform-d) δ ppm 8.47 (d, J = 8.7 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.17 (dd, J = 8.7, 2.2 Hz, 1H), 7.68 (s, 1H), 3.79 - 3.66 (m, 4H), 3.17 (t, J = 5.4 Hz, 4H), 2.60 (s, 3H), 1.28 (s, 4H), 0.50 (s, 4H). m / z (ESI): 459.2 (M+H) + 。

[0448] Step 2: To a solution of N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.18 g, 0.39 mmol) in ethanol (8 mL) and water (8 mL) was added iron powder (0.066 g, 1.18 mmol) and ammonium chloride (0.063 g, 1.18 mmol). The mixture was then heated at 90 °C for 3 h and then filtered through a bed and washed with ethyl acetate (3 × 100 mL). The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated to afford 4-amino-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a pale yellow solid (0.12 g, 0.280 mmol, 71.3% yield). It was used directly in the next step without further purification. m / z (ESI): 429.2 (M+H) + .

[0449] Step 3: To a solution of 4-amino-N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.120 g, 0.280 mmol) in DCM (5 mL) at 0 °C was added Et3N (0.078 mL, 0.560 mmol) and methyl 2-(chlorosulfonyl)acetate (0.058 g, 0.336 mmol, Combi-Blocks). The mixture was stirred at room temperature for 4 h and then quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give methyl 2-(N-(4-((2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate as a pale yellow solid (140 g, 0.25 mmol, 89% yield). It was used in the next step without further purification. m / z (ESI): 565.2 (M+H) + .

[0450] Step 4: A solution of methyl 2-(N-(4-((2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)acetate (130 mg, 0.230 mmol) in THF (5 mL) was treated with LiBH4 (230 μl, 0.460 mmol) at -30 °C. The reaction mixture was stirred at 0 °C for 30 min and then quenched at 0 °C with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 20% to 100% EtOAc in hexanes to afford N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.112 mmol, 48.6% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.55 (s, 1H), 10.28 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.51 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.6, 2.2 Hz, 1H), 4.95 (s, 1H), 4.45 (d, J = 12.3 Hz, 4H), 3.76 (t, J = 6.4 Hz, 2H), 3.64 (s, 1H), 3.57 (s, 1H), 2.97 (t, J = 5.4 Hz, 4H), 2.34 (s, 3H), 1.74 (br s, 4H), 0.40 (s, 4H). m / z (ESI): 537.2 (M+H) + 。

[0451] ​ ​ ​ ​

[0452]

[0453] Step 1: At 0 °C, 2-(chlorosulfonyl)propionic acid methyl ester (177 mg, 0.95 mmol, Enamine) was added to a solution of 4-amino-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.41 g, 0.86 mmol, Intermediate 21) and triethylamine (0.18 mL, 1.30 mmol) in DCM (3 mL). The mixture was stirred for 1 h and then concentrated in vacuo. Purification was carried out by silica gel chromatography using a Redi-Sep pre-packed silica gel column (12 g) with a gradient elution of 25% EtOAc / heptane to afford methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-2-fluoro-5-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)propionate (0.54 g, 0.48 mmol, 54.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.71 (s, 1H) 10.66 (br s, 1H) 7.88 (d, J = 11.61 Hz, 1H) 7.60 (d, J = 7.26 Hz, 1H) 7.39 (s, 1H) 4.38 (d, J = 7.05 Hz, 1H) 3.88 - 3.96 (m, 4H) 3.57 (s, 3H) 2.98 (br t, J = 4.56 Hz, 4H) 2.33 (s, 3H) 1.92 - 2.07 (m, 4H) 1.57 - 1.91 (m, 4H) 1.52 (d, J = 6.84 Hz, 3H) 0.40 (s, 4H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -94.77 (s, 1F) -126.39 (s, 1F). m / z (ESI): 625.2 (M + H) + 。

[0454] Step 2: Methanol (0.10 mL, 2.52 mmol) was added dropwise to a solution of methyl 2-(N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-2-fluoro-5-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)propionate (192 mg, 0.31 mmol) and lithium borohydride (2.0 M in THF, 0.35 mL, 0.69 mmol) in THF (2.5 mL). The mixture was stirred for 30 min and then aqueous NH4Cl was added. The product was extracted into EtOAc (2x), and the combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the racemic product as a solid. The material was separated by preparative SFC using an OD column (250X 21 mm, 5 mm) and an OD column (150X 21 mm, 5 mm) with a mobile phase of 90% liquid CO2 and 10% EtOH / 0.2% triethylamine at a flow rate of 80 mL / min to give:

[0455] ​ ((1-Methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The first elution peak (94 mg, 0.16 mmol, 33.2% yield, >99% ee). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.74 (s, 1H) 7.82 (d, J = 11.82 Hz, 1H) 7.58 (d, J = 7.26 Hz, 1H) 7.39 (s, 1H) 3.77 - 3.96 (m, 6H) 3.37 - 3.54 (m, 1H) 3.22 - 3.30 (m, 1H) 2.88 - 3.05 (m, 4H) 2.32 (s, 3H) 1.92 - 2.05 (m, 4H) 1.73 (br s, 4H) 1.31 (d, J = 6.84 Hz, 3H) 0.40 (s, 4H). 19 19F NMR (376 MHz, DMSO-d6) δ ppm -94.77 (s, 1F) -127.36 (s, 1F). m / z (ESI): 597.2 (M+H) + .

[0456] Example 8-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-fluoro-4-((2-hydroxy ((1-methylethyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The second elution peak (102 mg, 0.17 mmol, 36.1% yield, >98.4% ee). 1HNMR (400 MHz, DMSO-d6) δ ppm 13.74 (s, 1H) 7.82 (d, J = 11.82 Hz, 1H) 7.58 (d, J = 7.26 Hz, 1H) 7.39 (s, 1H) 3.77 - 3.96 (m, 6H) 3.37 - 3.54 (m, 1H) 3.22 - 3.30 (m, 1H) 2.88 - 3.05 (m, 4H) 2.32 (s, 3H) 1.92 - 2.05 (m, 4H) 1.73 (br s, 4H) 1.31 (d, J = 6.84 Hz, 3H) 0.40 (s, 4H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -94.76 (s, 1F) -127.73 (s, 1F). m / z (ESI): 597.2 (M+H) + . The stereochemistry is arbitrarily determined.

[0457] Table 9: Examples 9-1 to 9-2 were prepared according to a similar procedure to Examples 8-1 and 8-2:

[0458]

[0459] Examples 10-1 and 10-2: (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4- ((2-hydroxypropyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (S)-N-(2-(3,3-difluoroazetidin-1- yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxypropyl)sulfamoyl)-2-(6-azaspiro[2.5]oct- 6-yl)benzamide

[0460]

[0461] Step 1: A solution of N-(2-chloro-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (2.0 mg, 4.14 mmol, Intermediate 17), 3,3-difluoroazetidine hydrochloride (1.07 g, 8.29 mmol, Combi-Blocks Inc.), and potassium carbonate (1.72 g, 12.4 mmol, Combi-Blocks Inc.) in NMP (10 mL) was heated to 90 °C for 24 h. The mixture was cooled to room temperature, EtOAc (10 mL) was added, and then the mixture was washed with water (1 x 10 mL), 1 N HCl (1 x 10 mL), and brine (1 x 10 mL). The mixture was then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a solid. The solid was then suspended in MeOH, filtered, and dried in vacuo to afford N-(2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a light brown solid (1.16 g, 2.15 mmol, 51.9% yield). 1HNMR (400 MHz, DMSO-d6) δ ppm 13.53 (br s, 1H) 7.79 - 7.86 (m, 2H) 7.73 - 7.77 (m, 1H) 7.49 (s, 1H) 4.43 (t, J = 12.44 Hz, 4H) 3.02 (br t, J = 5.08 Hz, 4H) 2.31 - 2.38 (m, 3H) 1.65 - 1.82 (m, 4H) 0.39 (s, 4H). 19 F NMR (376 MHz, DMSO-d6) δ ppm -99.09 (s, 1F). m / z (ESI): 540.0 (M + H) + .

[0462] Step 2: 2-Hydroxypropane-1-sulfonamide (206 mg, 1.48 mmol, Intermediate 23), copper(I) iodide (71 mg, 0.37 mmol), sarcosine (66 mg, 0.74 mmol) and potassium phosphate (787 mg, 3.71 mmol) were placed under an argon atmosphere, dissolved in anhydrous DMF (3 mL), and warmed to 50 °C for 5 min. N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.40 g, 0.74 mmol) was added in one portion, and the mixture was heated to 100 °C for 2.5 h and then cooled to room temperature. Water was added and the product was extracted into EtOAc (2x). The combined extracts were then washed with water (2x), 9:1 saturated NH4Cl / NH4OH (1x), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the racemic product as an oil. The material was separated by preparative SFC using an IF column (250X 301 mm, 5 mm) with a mobile phase of 75% liquid CO2 and 25% MeOH at a flow rate of 130 mL / min to give:

[0463] Example 10-1: (R)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy propyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The first elution peak (88 mg, 0.16 mmol, 21.6% yield, >99% ee). 11H NMR (400 MHz, DMSO-d6) δ ppm 13.54 (s, 1H), 8.05 (d, J = 8.71 Hz, 1H), 7.51 (s, 1H), 7.27 (d, J = 1.87 Hz, 1H), 7.14 (dd, J = 8.71, 1.87 Hz, 1H), 4.44 (t, J = 12.44 Hz, 4H), 4.07 - 4.15 (m, 1H), 3.22 - 3.29 (m, 2H), 2.97 (br t, J = 4.87 Hz, 4H), 2.34 (s, 3H), 1.74 (br s, 4H), 1.19 (d, J = 6.22 Hz, 3H), 0.40 (s, 4H). Two exchangeable protons were not observed. 19 19F NMR (376 MHz, DMSO-d6) δ ppm -99.08 (s, 1F). m / z (ESI): 551 (M + H) + 。

[0464] Example 10-2: (S)-N-(2-(3,3-Difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxy propyl)sulfamoyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The second elution peak (89 mg, 0.162 mmol, 21.8% yield, >99% ee). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.55 (s, 1H), 8.05 (d, J = 8.71 Hz, 1H), 7.51 (s, 1H), 7.26 (d, J = 1.87 Hz, 1H), 7.14 (dd, J = 8.71, 1.87 Hz, 1H), 4.43 (t, J = 12.44 Hz, 4H), 4.11 (d, J = 6.01 Hz, 1H), 3.21 - 3.31 (m, 2H), 2.97 (br t, J = 4.87 Hz, 4H), 2.34 (s, 3H), 1.53 - 2.01 (m, 4H), 1.19 (d, J = 6.43 Hz, 3H), 0.40 (s, 4H). Two exchangeable protons were not observed. 19 19F NMR (376 MHz, DMSO-d6) δ ppm -99.09 (s, 1F). m / z (ESI): 551 (M + H) + 。The stereochemistry was arbitrarily determined.

[0465] Table 10: Examples 11-1 to 11-83 were prepared according to a similar procedure to Example 10:

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] Example 12: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0480]

[0481] Step 1: A mixture of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg, 0.881 mmol, Intermediate 19), triphenylphosphine (34.7 mg, 0.132 mmol, Aldrich, St. Louis, MO, USA), 1,10-phenanthroline (23.82 mg, 0.132 mmol, Aldrich, St. Louis, MO, USA), palladium(II) acetate (9.89 mg, 0.044 mmol, Strem Chemicals Inc., Newburyport, MA, USA), sodium formate (132 mg, 1.939 mmol, Thermo Fisher Scientific, Grand Island, NY, USA) and tetrabutylammonium bromide (426 mg, 1.322 mmol, Aldrich, St. Louis, MO, USA) in dimethyl sulfoxide (3 mL) was stirred at 70 °C under N2 for 45 min. Then, the mixture was cooled to room temperature and ethyl iodoacetate (0.157 mL, 1.322 mmol, Aldrich, St. Louis, MO, USA) was added. Then the mixture was stirred at room temperature for 10 min. Then the reaction mixture was diluted with water (20 mL) and then extracted with EtOAc (2 x 40 mL). Then the combined organic extracts were dried over MgSO4 and concentrated. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc / heptane) afforded ethyl 2-((4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (330 mg, 0.558 mmol) as a pale yellow solid. 11H NMR (DMSO-d6) δ 13.14 (br s, 1H), 8.27 (br d, J = 8.1 Hz, 1H), 7.97 (s, 1H), 7.84 (br d, J = 7.7 Hz, 1H), 7.40 (s, 1H), 4.80 (s, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.92 (br s, 4H), 3.03 - 3.13 (m, 4H), 2.34 (s, 3H), 1.90 - 2.07 (m, 4H), 1.71 (br s, 4H), 1.07 (t, J = 7.0 Hz, 3H), 0.39 (s, 4H). m / z (ESI): 592.3 (M + H)+.

[0482] Step 2: Under N2 at 0 °C, a solution of ethyl 2-((4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)acetate (320 mg, 0.541 mmol) in 2-methyltetrahydrofuran (3.5 mL) was added dropwise to a solution of lithium borohydride (2.0 M in tetrahydrofuran, 0.541 mL, 1.082 mmol, Aldrich, St. Louis, MO USA). After addition, the mixture was stirred overnight at room temperature. Then, the mixture was quenched with saturated NH4Cl (18 mL) and stirred for 15 min at room temperature. Then the mixture was extracted with EtOAc (2 x 30 mL). Then the combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by chromatography (silica gel, 0% to 100% EtOAc / heptane) to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.109 mmol, 20% yield), N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (60 mg, 0.109 mmol) as a white solid. 11H NMR (DMSO-d6) δ ppm 13.17 (br s, 1H), 8.25 (br d, J = 8.3 Hz, 1H), 7.93 (br s, 1H), 7.82 (br d, J = 8.3 Hz, 1H), 7.40 (br s, 1H), 4.91 (br t, J = 5.0 Hz, 1H), 3.92 (br s, 4H), 3.68 - 3.77 (m, 2H), 3.52 - 3.60 (m, 2H), 3.09 (br s, 4H), 2.34 (s, 3H), 1.87 - 2.08 (m, 4H), 1.70 (br d, J = 1.0 Hz, 4H), 0.39 (s, 4H). 19 19F NMR (DMSO-d6) δ ppm -94.76 (s, 2F). m / z (ESI): 550.1 (M + H)+.

[0483] Examples 13-1 and 13-2: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy propan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (R)-N-(2-(4,4-difluoropiperidin-1- yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzoyl amine

[0484]

[0485] Step 1: A solution of N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.08 g, 1.90 mmol, Intermediate 19), 2-mercaptopropan-1-ol (0.48 g, 5.21 mmol, Enamine), and potassium carbonate (0.237 mL, 3.91 mmol) in 4 mL of DMSO was heated in a sealed bottle at 90 °C for 4 h. The mixture was cooled to room temperature, 50 mL of ethyl acetate and 10 mL of brine were added. The organic layer was separated, washed with brine, dried, and evaporated. The resulting product was adsorbed onto a silica plug and purified by silica chromatography (0% to 30% EtOAc in heptane) to afford N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as a yellow solid. 1HNMR (400 MHz, chloroform-d) δ ppm 0.39 - 0.44 (m, 4H) 1.37 - 1.43 (m, 3H) 1.55 - 1.60 (m, 4H) 1.96 - 2.04 (m, 4H) 2.35 - 2.41 (m, 3H) 3.01 - 3.11 (m, 4H) 3.46 - 3.78 (m, 3H) 3.96 - 4.05 (m, 4H) 7.28 - 7.36 (m, 2H) 7.48 - 7.53 (m, 1H) 8.12 - 8.32 (m, 1H) 13.01 - 13.37 (m, 1H). m / z (ESI): 531.4 (M + H) + 。

[0486] Step 2: To N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)thio)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.62 g, 1.17 mmol) in 15 mL of THF was added oxone(r) monopersulfate compound (0.72 g, 1.17 mmol) in 5 mL of water. After stirring for 1.5 h, LCMS showed the formation of a mixture of sulfone and sulfoxide. An additional 0.4 g of oxone in 3 mL of water was added. After stirring for another 2 h, EtOAc (50 mL) and brine (20 mL) were added to the reaction mixture, and the organic layer was collected, washed with brine, dried, and evaporated. The crude product was purified by preparative SFC using a (S,S)Whelk-01 (250X 21 mm, 5 mm) column with a mobile phase of 60% liquid CO2 and 40% MeOH at a flow rate of 80 mL / min to give N-2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (337 mg, 0.58 mmol, 50% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 0.30 - 0.57 (m, 4H) 1.27 - 1.37 (m, 3H) 1.59 - 1.72 (m, 4H) 1.94 - 2.10 (m, 4H) 2.40 - 2.54 (m, 3H) 2.55 - 2.97 (m, 1H) 3.05 - 3.23 (m, 4H) 3.28 - 3.41 (m, 1H) 3.84 - 4.06 (m, 6H) 7.63 - 7.86 (m, 2H) 8.13 - 8.37 (m, 1H) 11.08 - 11.59 (m, 1H). m / z (ESI): 598.3 (M + H) +。The racemic mixture was separated using preparative SFC with an OD (250X 21mm, 5mm) column and a mobile phase of 85% liquid CO2 and 15% iPrOH at a flow rate of 90 mL / min to yield:

[0487] Example 13-1: (S)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan -2-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The first elution peak (85 mg, >99% ee). 1 HNMR (400 MHz, chloroform-d) δ ppm 12.74 - 13.01 (m, 1H), 8.36 - 8.54 (m, 1H), 7.69 - 8.03 (m, 2H), 7.41 - 7.58 (m, 1H), 3.83 - 4.06 (m, 6H), 3.25 - 3.43 (m, 1H), 3.03 - 3.17 (m, 4H), 2.50 - 2.81 (m, 1H), 2.31 - 2.42 (m, 3H), 1.93 - 2.10 (m, 4H), 1.61 - 1.90 (m, 4H), 1.28 - 1.36 (m, 3H), 0.35 - 0.50 (m, 4H). m / z (ESI): 563.2 (M + H) + 。

[0488] Example 13-2: (R)-N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxypropan -2-yl)sulfonyl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide. The second elution peak (84 mg, 97% ee). 1 HNMR (400 MHz, chloroform-d) δ ppm 12.71 - 13.05 (m, 1H), 8.39 - 8.56 (m, 1H), 7.74 - 8.03 (m, 2H), 7.38 - 7.54 (m, 1H), 3.81 - 4.04 (m, 6H), 3.26 - 3.39 (m, 1H), 3.03 - 3.19 (m, 4H), 2.48 - 2.83 (m, 1H), 2.33 - 2.41 (m, 3H), 1.92 - 2.10 (m, 4H), 1.60 - 1.90 (m, 4H), 1.28 - 1.33 (m, 3H), 0.36 - 0.46 (m, 4H). m / z (ESI): 563.2 (M + H) + 。The stereochemistry is arbitrarily assigned.

[0489] Example 14: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan 2-(6-azaspiro[2.5]octan-6-yl)-N-(2-methylpropyl)sulfonylbenzamide

[0490]

[0491] Step 1: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.55 g, 0.967 mmol, Intermediate 19), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.034 g, 0.058 mmol), Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.035 g, 0.034 mmol), DIPEA (0.4 mL, 2.29 mmol) and 2-Mercapto-2-methylpropan-1-ol (0.134 g, 1.29 mmol) in 3 mL of dioxane were purged with N2 for 5 min in a sealed tube. The mixture was heated at 90 °C for 3 h and cooled to room temperature. The resulting crude product was adsorbed onto a silica plug and purified by silica gel chromatography (0% to 7% EtOAc in DCM) to afford N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. 1 1H NMR (400 MHz, chloroform-d) δ ppm 0.38 - 0.47 (m, 4H) 1.25 - 1.31 (m, 6H) 1.56 - 1.56 (m, 4H) 1.94 - 2.04 (m, 4H) 2.35 - 2.41 (m, 3H) 3.03 - 3.12 (m, 4H) 3.31 - 3.38 (m, 2H) 3.95 - 4.04 (m, 4H) 7.41 - 7.47 (m, 2H) 7.48 - 7.52 (m, 1H) 8.14 - 8.32 (m, 1H) 12.96 - 13.41 (m, 1H). 4H overlapped with water peak. m / z (ESI): 546.2 (M+H) + 。

[0492] Step 2: To N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan-2-yl)thio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.36 g, 0.66 mmol) in THF (15 mL) cooled to 0 °C was added oxone® monopersulfate compound (0.52 g, 0.85 mmol) in water (5 mL). The mixture was stirred from 0 °C to room temperature for 2.5 h. An additional 0.35 g of oxone was added. After 1 h, Icms showed that the sulfoxide was almost consumed. Ethyl acetate (40 mL) and brine (20 mL) were added, the organic layer was separated, dried and evaporated. The crude mixture was purified by preparative SFC using (S,S)Whelk-01 (250 x 21 mm, 5 mm) with a mobile phase of 60% liquid CO2 and 40% MeOH at a flow rate of 80 mL / min to give N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.15 - 8.73 (m, 1H), 7.64 - 7.90 (m, 2H), 7.41 - 7.52 (m, 1H), 3.94 - 4.07 (m, 4H), 3.70 - 3.83 (m, 2H), 3.04 - 3.20 (m, 4H), 2.34 - 2.47 (m, 3H), 1.96 - 2.12 (m, 4H), 1.47 - 1.95 (m, 4H), 1.30 - 1.41 (m, 6H), 0.37 - 0.52 (m, 4H). 19 F NMR (376 MHz, chloroform-d) δ ppm -96.68 (br s, 1F). m / z (ESI): 578.2 (M+H) + .

[0493] Table 11: Examples 14-1 to 14-9 were prepared according to a similar procedure to Examples 12 to 14:

[0494]

[0495]

[0496] Example 15: N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide Examples 16-1 and 16-2: (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and (R)-N-(2-(4,

[0497]

[0498] A mixture of 4-bromo-N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.055 g, 0.106 mmol, Intermediate 21-13), 2-hydroxyethane-1-sulfonamide (0.020 g, 0.159 mmol, Wuxi), tripotassium phosphate (0.045 g, 0.212 mmol), copper(I) iodide (0.020 g, 0.106 mmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7.53 mg, 0.053 mmol, Combi-Blocks) in DMF (1.5 mL) was heated at 90 °C for 16 h. Then the reaction mixture was filtered through the pad of the pad, and the filtrate was diluted with EtOAc. The resulting solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase HPLC using a 60% ACN gradient in water (0.1% TFA) to give N-(2-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.025 g, 0.044 mmol, 42% yield) as a white solid. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.70 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.16 - 7.08 (m, 1H), 3.75 (t, J = 6.3 Hz, 2H), 3.03 - 2.85 (m, 6H), 2.44 (d, J = 4.5 Hz, 5H), 2.05 (s, 5H), 1.92 (d, J = 11.7 Hz, 4H), 1.72 (s, 4H), 0.38 (s, 4H). m / z (ESI): 564.1 (M + H)+.

[0499] 4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide Example 16-1: (S)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Example 16-2: (R)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((2-fluoro-1-(hydroxymethyl)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. Example 17: N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0500]

[0501]

[0502] Step 1: To a solution of 1-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)propane-2-sulfonamide (0.803 g, 2.23 mmol) in THF at room temperature was added tetrabutylammonium fluoride solution (2.75 mL, 2.75 mmol, 1 M in THF). The reaction was stirred for 1 h and then concentrated under reduced pressure. The resulting material was used immediately in the next step.

[0503] Step 2: To a pressure release bottle containing the sulfonamide from the previous step was added copper(I) iodide (0.196 g, 1.03 mmol), methylglycine (0.128 g, 1.440 mmol), tripotassium phosphate (0.934 g, 4.40 mmol) and N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.975 g, 1.72 mmol, Intermediate 19). The bottle was sealed and evacuated / backfilled with nitrogen, then DMF (7 mL) was added. The lid was placed on and the reaction was stirred in a preheated oil bath at 100 °C for 16 h. The reaction mixture was partitioned between saturated NH4Cl:NH4OH (9:1) and EtOAc. The organic phase was separated, washed with brine and concentrated in vacuo. The material was purified by silica gel chromatography (20% to 100% EtOAc in heptane) to give 4-((2-(benzyloxy)-1-(hydroxymethyl)ethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.635 g, 0.927 mmol, 54.0% yield). 1 H NMR (400 MHz, chloroform-d) δ ppm 13.11 (br dd, J = 4.66, 2.38 Hz, 1H) 8.14 (d, J = 8.50 Hz, 1H) 7.49 (br s, 1H) 7.31 - 7.44 (m, 5H) 7.13 (d, J = 1.87 Hz, 1H) 6.83 (dd, J = 8.60, 2.18 Hz, 2H) 4.49 - 4.62 (m, 2H) 4.08 (dt, J = 11.77, 5.83 Hz, 1H) 3.94 - 4.03 (m, 5H) 3.88 - 3.93 (m, 1H) 3.95 (br s, 1H) 3.45 - 3.55 (m, 1H) 2.96 (br t, J = 4.98 Hz, 4H) 2.29 - 2.49 (m, 4H) 1.95 - 2.07 (m, 4H) 1.57 (br s, 4H) 1.18 - 1.35 (m, 2H) 0.85 - 0.91 (m, 1H) 0.40 (s, 4H). m / z (ESI, +ve ion): 683.8 (M + H) + .

[0504] Step 3: Triethylamine trihydrofluoride (0.262 mL, 1.61 mmol) was added dropwise via an addition funnel to a solution of xtalfluor-m (0.351 g, 1.446 mmol) in DCM (6 mL) in a brine / ice bath, followed by the addition of 4-((2-(benzyloxy)-1-(hydroxymethyl)ethyl)sulfamoyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (0.55 g, 0.803 mmol) in DCM (10 mL). The reaction was gradually warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated sodium bicarbonate (aqueous solution) and diluted with water and DCM. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by silica gel chromatography (20% to 100% EtOAc in heptane) to afford a 1:0.8 mixture (265 mg) of racemic-4-((2-(benzyloxy)-1-(fluoromethyl)ethyl)sulfamoyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and 4-((1-((benzyloxymethyl)vinyl)sulfamoyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide. This mixture was used without further purification.

[0505] Step 4: AcOH (0.033 mL, 0.579 mmol) was added to a suspension of 265 mg of the product mixture from the previous step and palladium hydroxide on carbon (0.135 g, 0.193 mmol) in EtOH (20 mL). The reaction was hydrogenated at room temperature under 55 psi of hydrogen for 24 h. After flushing the reaction with nitrogen, an additional portion of palladium hydroxide on carbon (0.135 mL, 0.193 mmol) was added, followed by an additional amount of AcOH (0.033 mL, 0.579 mmol). The reaction vessel was flushed with N2 and then the atmosphere was replaced with 55 psi of hydrogen. The reaction was continued at room temperature for an additional 48 h. The reaction was flushed with nitrogen and then filtered and the filtrate was concentrated in vacuo. The racemic mixture was separated by preparative SFC using IE (250 x 21 mm, 5 mm) with a mobile phase of 80% liquid CO2 and 20% MeOH (flow rate of 80 mL / min) to afford: The first elution peak

[0506] Examples 18-1 and 18-2: 2-(6-azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfinyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide and 2-(6-azaspiro[2.5]octan-6-yl)-4-(S- cyclopropylsulfinyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide The first elution peak 11H NMR (400 MHz, DMSO-d6) δ ppm 13.35 (s, 1H), 10.21 - 10.84 (m, 1H), 8.06 (d, J = 8.50 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 2.07 Hz, 1H), 7.16 (dd, J = 8.50, 2.07 Hz, 1H), 5.12 - 5.38 (m, 1H), 4.88 - 4.97 (m, 1H), 4.71 - 4.84 (m, 1H), 3.85 - 4.01 (m, 5H), 3.74 (dd, J = 11.30, 7.98 Hz, 1H), 3.51 - 3.63 (m, 1H), 2.98 (br t, J = 4.77 Hz, 4H), 2.32 (s, 3H), 1.93 - 2.07 (m, 4H), 1.51 - 1.91 (m, 4H), 0.40 (s, 4H). m / z (ESI, +ve ion): 597.2 (M + H) + 。

[0507] Example 18-1: 2-(6-azaspiro[2.5]octan-6-yl)-4-(R-cyclopropylsulfinyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide. Example 18-2: 2-(6-azaspiro[2.5]octan-6-yl)-4-(S-cyclopropylsulfinyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)benzamide. The second elution peak. 1 1H NMR (400 MHz, DMSO-d6) δ ppm 13.35 (s, 1H), 10.32 - 10.70 (m, 1H), 8.05 (d, J = 8.71 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 2.07 Hz, 1H), 7.16 (dd, J = 8.71, 2.07 Hz, 1H), 5.14 - 5.40 (m, 1H), 4.85 - 4.97 (m, 1H), 4.73 - 4.84 (m, 1H), 3.87 - 3.98 (m, 5H), 3.74 (dd, J = 11.09, 7.98 Hz, 1H), 3.48. m / z (ESI, +ve ion): 597.2 (M + H) + The stereochemistry is arbitrarily determined.

[0508] 2-(6-azaspiro[2.5]octan-6-yl)terephthalamide Example 21: 4-(azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0509]

[0510] In a glass tube, a mixture of N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (212 mg, 0.384 mmol, Intermediate 21-14), 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO) (55 mg, 0.23 mmol, Sigma-Aldrich Corporation), palladium diacetate (13 mg, 0.06 mmol, Strem), ((3R,5R,7R)-adamantan-1-yl)((3S,5S,7S)adamantan-1-yl)(butyl)phosphine (28 mg, 0.08 mmol, Strem) and triethylamine (107 μL, 0.77 mmol) was degassed for 3 min. The tube was sealed and then heated at 85 °C in an oil bath for 3 h. The heterogeneous mixture was cooled to room temperature, treated with 2-aminoethan-1-ol (47 mg, 0.77 mmol, Sigma-Aldrich), followed by treatment with sodium hypochlorite solution (10 wt%, 571 mg, 0.77 mmol, Sigma-Aldrich), and stirred at room temperature for 18 h. The mixture was treated with 2-aminoethan-1-ol (23 mg), followed by treatment with sodium hypochlorite solution (10 wt%, 275 mg), and then stirred at room temperature for 5 h. EtOAc (20 mL) and water (5 mL) were added to the heterogeneous mixture, and the insoluble solid was filtered off. The filter cake was washed with water (2 x 2 mL), followed by washing with EtOAc (2 x 4 mL). The organic solution was taken and concentrated in vacuo. The residue was purified by silica gel chromatography (10% to 60% EtOAc in heptane) to afford N-(2-(4,4-difluoropiperidin-1-yl)pyridin-4-yl)-4-(N-(2-hydroxyethyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as an off-white solid (100 mg, 0.18 mmol, 47% yield). 11H NMR (400 MHz, methanol-d4) δ ppm 7.99 - 8.14 (m, 2H), 7.79 (s, 1H), 7.68 (d, J = 7.88 Hz, 1H), 7.47 (s, 1H), 7.01 (d, J = 4.77 Hz, 1H), 3.76 (t, J = 5.29 Hz, 4H), 3.58 (t, J = 5.91 Hz, 2H), 3.16 (t, J = 5.08 Hz, 4H), 3.02 (t, J = 5.80 Hz, 2H), 1.98 - 2.11 (m, 4H), 1.62 (s, 4H), 0.42 (s, 4H). m / z (ESI): (M + H) + 550.1。

[0511] Table 12: Examples 17-1 to 17-8 were prepared according to a similar procedure to Example 17:

[0512]

[0513]

[0514] Example 22: 4-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-((1-methylazetidin- ​ ​

[0515]

[0516] Step 1: N-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.00 g, 1.762 mmol, Intermediate 19), tris(dibenzylideneacetone)dipalladium(0) (0.161 g, 0.176 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.102 g, 0.176 mmol) were placed in a 20 mL microwave vessel, followed by 1,4-dioxane (10 mL). The resulting mixture was stirred and purged with nitrogen for 5 min, then 1,1'-dimethylethylamine (0.616 mL, 3.52 mmol) was added under nitrogen, followed by cyclopropanethiol (0.142 mL, 1.939 mmol). The vessel was sealed and again subjected to microwave conditions (10 h, 90 °C). The crude mixture was directly loaded onto a silica pre-column and subjected to combi-fast column chromatography on a 40-g ISCO gold column, eluting twice with MeOH / DCM (5 min at 0%, 25 min from 0% to 6%) to afford 4-(cyclopropylthio)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as an off-white solid (0.92 g, 1.791 mmol, 102% yield).1 HNMR (400 MHz, dichloromethane-d2) δ ppm 13.33 (s, 1H), 8.15 (d, J = 8.29 Hz, 1H), 7.48 (s, 1H), 7.22 - 7.35 (m, 2H), 3.91 - 4.09 (m, 4H), 3.06 (br t, J = 5.18 Hz, 4H), 2.35 (s, 3H), 2.17 - 2.28 (m, 1H), 1.62 - 2.10 (m, 6H), 1.52 (s, 2H), 1.13 - 1.21 (m, 2H), 0.68 - 0.76 (m, 2H), 0.40 (s, 4H). m / z (ESI): 514.1 (M+H) + 。

[0517] Step 2: To a stirred solution of 4-(cyclopropylthio)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.89 g, 1.733 mmol) and ammonium carbonate (0.250 g, 2.60 mmol) in MeOH (4.5 mL) and dichloromethane (9.0 mL) was added all at once solid (acetoxy)(phenyl)-iodonium acetate (1.284 g, 3.99 mmol). The resulting mixture was stirred at room temperature for 18 h under open air. The resulting mixture was directly loaded onto a silica pre-column (25 g) and subjected to combi-rapid column chromatography on a 40-g ISCO gold column, eluting with MeOH / DCM (3 min at 0%, 25 min from 0% to 14%) to afford the racemic mixture of 4-(cyclopropanesulfinyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide as an off-white solid (0.95 g, 1.744 mmol, 101% yield). The enantiomers were separated by preparative SFC using Regis (S,S) Whelk-01 (250 X 21 mm, 5 mm) with a mobile phase of 50% liquid CO2 and 50% MeOH at a flow rate of 60 mL / min to give:

[0518] ​ ​ The first elution peak, 11H NMR (400 MHz, chloroform-d) δ ppm 13.20 (br d, J = 3.73 Hz, 1H), 8.44 (d, J = 8.29 Hz, 1H), 7.96 (d, J = 1.45 Hz, 1H), 7.87 (dd, J = 1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J = 5.29 Hz, 4H), 2.53 - 2.63 (m, 1H), 2.44 (br s, 3H), 1.95 - 2.10 (m, 4H), 1.53 - 1.89 (m, 5H), 1.45 (tdd, J = 5.08, 6.92, 10.29 Hz, 1H), 1.20 - 1.30 (m, 1H), 1.07 - 1.17 (m, 1H), 0.93 - 1.03 (m, 1H), 0.44 (s, 4H). m / z (ESI): 545.2 (M+H) + 。

[0519] ​ ​ The second elution peak. 1 1H NMR (400 MHz, chloroform-d) δ ppm 13.20 (br d, J = 3.73 Hz, 1H), 8.44 (d, J = 8.29 Hz, 1H), 7.96 (d, J = 1.45 Hz, 1H), 7.87 (dd, J = 1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J = 5.29 Hz, 4H), 2.53 - 2.63 (m, 1H), 2.44 (br s, 3H), 1.95 - 2.10 (m, 4H), 1.53 - 1.89 (m, 5H), 1.45 (tdd, J = 5.08, 6.92, 10.29 Hz, 1H), 1.20 - 1.30 (m, 1H), 1.07 - 1.17 (m, 1H), 0.93 - 1.03 (m, 1H), 0.44 (s, 4H). m / z (ESI): 545.2 (M+H) + The stereochemistry determination is arbitrary.

[0520] Table 13: Examples 19-1 to 19-9 were prepared according to the procedure described for Examples 18-1 and 18-2:

[0521]

[0522]

[0523]

[0524] Example 20: (N 1 -(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]​

[0525]

[0526] Step 1: To a solution of 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (250 mg, 0.48 mmol, Intermediate 21-3) in DMF (2.5 mL) was added Pd(PPh3)4 (6 mg, 4.8 μmol) and Zn(CN)2 (113 mg, 0.961 mmol), and the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was then diluted with EtOAc and filtered through a bed. The filtrate was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography using a 30% EtOAc gradient in petroleum ether to afford 4-cyano-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide as an off-white solid (160 mg, 0.343 mmol, 71.4% yield). 1 HNMR (400 MHz, DMSO-d6) δ ppm 13.20 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.03 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 4.00 - 3.80 (m, 4H), 3.07 (t, J = 5.2 Hz, 4H), 2.34 (s, 3H), 1.99 (tt, J = 13.3, 5.7 Hz, 4H), 1.69 (s, 4H), 0.38 (s, 4H). m / z (ESI): 467.2 (M+H) + 。

[0527] Step 2: At 0 °C, to a solution of 4-cyano-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (110 mg, 0.236 mmol) in dimethyl sulfoxide (2 mL) was added K2CO3 (6.52 mg, 0.047 mmol) and H2O2 (103 μL, 1.179 mmol), and the reaction mixture was stirred for 1 h, then quenched with water and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography using a 10% methanol gradient in dichloromethane to afford N 1-(2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)terephthalamide (108 mg, 0.223 mmol, 95% yield). 1 HNMR (400 MHz, DMSO-d6) δ ppm 13.75 (s, 1H), 8.26 (m, 1H), 8.17 (m, 1H), 8.00 (s, 1H), 7.89 - 7.78 (m, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 3.94 (d, J = 5.8 Hz, 4H), 3.06 (d, J = 6.0 Hz, 4H), 2.34 (d, J = 2.3 Hz, 3H), 2.01 (q, J = 8.5, 8.1 Hz, 4H), 1.74 (s, 4H), 0.41 (d, J = 2.3 Hz, 4H). m / z (ESI): 485.2 (M+H) + 。

[0528] ​ ​

[0529]

[0530] To a solution of 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (2.54 g, 5.64 mmol, Intermediate 16) and HATU (3.22 g, 8.46 mmol, ChemPep) in DMF (35 mL) was added 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.93 g, 8.46 mmol, Intermediate 4) and DIPEA (2.46 mL, 14.09 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with saturated Na2CO3 and EtOAc. The organic layer was separated and washed with Na2CO3, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography: 0% to 30% to 60% EtOAc in heptane. m / z (ESI): 661.3 (M+H) + 。The residue was treated with DCM (8 mL) and TFA (4 mL) at room temperature for 30 min and concentrated in vacuo. The resulting solid was suspended in EtOAc and washed with 1N NaOH solution. The mixture was extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography: 0% to 20% MeOH in DCM with 2% NH4OH to give the title compound as a white solid. 1HNMR (400 MHz, methanol-d4) δ ppm 8.35 (d, J = 8.09 Hz, 1H), 7.90 (d, J = 1.24 Hz, 1H), 7.81 (dd, J = 1.66, 8.09 Hz, 1H), 7.46 (s, 1H), 4.46 - 4.60 (m, 1H), 3.97 - 4.06 (m, 6H), 3.76 - 3.86 (m, 2H), 3.10 - 3.21 (m, 4H), 2.37 (s, 3H), 1.93 - 2.01 (m, 4H), 1.73 - 1.88 (m, 4H), 0.45 (s, 4H). m / z (ESI): 561.2 (M + H) + 。

[0531] ​ (Alkane-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0532]

[0533] To a mixture of 4-(azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (0.045 g, 0.080 mmol, Example 21), MeOH (1 mL), and formaldehyde with 10% to 15% MeOH (0.016 g, 0.482 mmol, Fisher) was added AcOH (0.037 mL, 0.642 mmol, Aldrich), followed by sodium triacetoxyborohydride (0.204 g, 0.963 mmol, Aldrich). The mixture was stirred at room temperature for 18 h and concentrated in vacuo. The acid was neutralized with 1 N NaOH solution and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification by silica gel chromatography: 0% to 100% EtOAc / EtOH (3 / 1) in heptane to afford the title compound as a white solid. 1 HNMR (400 MHz, chloroform-d) δ ppm 12.82 (br s, 1H), 8.44 (d, J = 8.29 Hz, 1H), 7.82 (d, J = 1.66 Hz, 1H), 7.73 (dd, J = 1.76, 8.19 Hz, 1H), 7.46 (s, 1H), 3.97 - 4.11 (m, 5H), 3.60 - 3.90 (m, 4H), 3.12 (t, J = 5.29 Hz, 4H), 2.44 - 2.57 (m, 3H), 2.39 (s, 3H), 1.68 - 2.06 (m, 8H), 0.43 (s, 4H). m / z (ESI): 575.3 (M + H)+ 。

[0534] Biological Examples

[0535] The following assays were used to test exemplary compounds of the present invention. Data for those examples tested according to the procedures described below are shown in Table A below.

[0536] KIF18A enzyme assay: KIF18A enzyme activity after treatment with a 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 using an ADP-Glo TM Kinase / ATPase assay kit (Promega Inc) for a standardized homogeneous enzyme assay. This 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 for 15 min at room temperature. Next, ATP (K m , 75 μM) was added to the reaction mixture and incubated for an additional 15 min at room temperature. 5 μl of ADP-Glo TM reagent and 2.5 μl of the reaction mixture were mixed and incubated for 40 min at room temperature. 10 μl of ADP-Glo TM detection reagent was added and incubated for 40 min at room temperature. 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.

[0537] Table A provides data for the compounds exemplified in the present application and its priority documents. As representative compounds of the present invention, the following are provided: compound names and biological data. (IC 50 in μM. Example # refers to the example number)

[0538] Table A: Biological Data

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551] 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 by reference to the above description, but rather by reference to the appended claims below and the full scope of equivalents to which such claims are entitled.

[0552] 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 set forth.

Claims

1. A compound of formula I: or any pharmaceutically acceptable salt thereof, wherein: X 1 is N or -CR 6 ; R 1 is -CN or the group -Z-R 12 , where Z is -C 0-4 alkyl-, -NR 11 -, -NR 11 SO2-, -SO2NR 11 -, -NR 11 -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, C 0-4 alkyl-O-, -(C=O)-, -(C=O)NR 11 -, -C=N(OH)- or -NR 11 (C=O); or The group -Z-R 12 is -N=S(=O)-(R 12 )2, where the two R 12 may alternatively combine with the sulfur atoms to which they are respectively attached to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 2 is a halogen or the group -Y-R 13 , where Y is -C 0-4 alkyl-, -N(C 0-1 alkyl)-C 0-4 alkyl-, -C(=O)NR a R a (C 1-4 alkyl), -O-C 0-4 alkyl-, S, S=O, S(=O)2, -SO2NR 13 or -S(=O)(=NH)-; R 3 is H, C 1-4 alkyl or C 1-4 haloalkyl; R 4 is H, halogen, R 4a or R 4b ; R 5 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl; R 6 is H, halogen, C 1-8 alkyl, C 1-4 haloalkyl, -O-C 1-8 alkyl or -O-R 6a , where R 6a is a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; R 7 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl; R 8 is H, halogen, C 1-8 alkyl, C 1-4 haloalkyl, -OH, -O-R 8a or -O-R 8b ; R 9 is H, halogen, C 1-8 alkyl or C 1-4 haloalkyl; R x selected from the group consisting of: R 10a 、R 10b 、R 10c 、R 10d 、R 10e 、R 10f 、R 10g 、R 10h 、R 10i and R 10j Each of which is H, a halogen, R 10k or R 10l ; Alternatively, R 10a and R 10b pair, R 10c and R 10d pair, R 10e and R 10f pair, R 10g and R 10h pair or R 10i and R 10j For each of the pairs, R x and R 1-6 can independently combine with their respective attached carbon atoms to form a saturated or partially saturated 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring that is spiro-fused to the R 1-4 ring; wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and further wherein the 3-membered, 4-membered, 5-membered, 6-membered monocyclic ring is substituted with 0, 1, 2 or 3 groups selected from: F, Cl, Br, C a alkyl, C 1-4 haloalkyl, -OR a R a or oxo; R 11 is H, R 11a or R 11b ; R 12 is H, R 12a or R 12b ; R 13 is R 13a or R 13b ; R 4a 、R 8a 、R 10k 、R 11a 、R 12a and R 13a are each independently selected from the group consisting of: saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic rings containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which are 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, -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 alkylNR a R a 、-OC 2-6 alkylOR 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 、 R 14 and oxo; R 4b 、R 8b 、R 10l 、R 11b 、R 12b and R 13b are each independently selected from the group consisting of: C a alkyl, -OC 1-4 alkyl, or CN, which is substituted with 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, -OR 1-6 alkyl; R 14 Independently selected in each case from the group consisting of: saturated, partially saturated or unsaturated 3-membered, 4-membered, 5-membered, 6-membered or 7-membered monocycles or 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered 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 by 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, -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 alkylNR a R a , -OC 2-6 alkylOR 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 alkylNR 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 and oxo; R a independently H or R in each case b ; and R b independently C in each case 1-6 alkyl, phenyl or benzyl, wherein said 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.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is N; having the formula (Ia):

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is -CR 6 ; having the formula (Ib):

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 is H or methyl.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j each independently is H, halogen, C 1-6 alkyl or C 1-4 haloalkyl; and each pair of R 10a and R 10b together with the carbon atom to which they are attached forms a saturated 3-, 4- or 5-membered monocyclic ring spiro-fused to the R x ring; wherein the ring contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein each of R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i and R 10j is H, methyl or ethyl; and each of the pairs of R 10a and R 10b combines with the respective carbon atoms to which they are attached to form a cyclopropyl, cyclobutyl or cyclopentyl ring that is spiro-fused to the R x ring.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the group is selected from:

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the group is 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CN or the group -Z-R 12 , wherein Z is a bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-; and R 12 Selected from: (a) H; (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, Each of said rings is substituted with 0, 1, 2 or 3 groups selected from the following: each ring is substituted with 0, 1, 2 or 3 OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN and oxo; or (c) C alkyl substituted by 0, 1, 2 or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3) or -N(CH3)2 1-6 alkyl 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CN or the group -Z-R 12 , wherein Z is a bond, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH- or -NH(C=O)-; and (a)R 12 is H; (b)R 12 is oxetanyl, cyclopropyl; or (c)R 12 C alkyl substituted with 0, 1, 2 or 3 OH groups 1-6 alkyl

Images