Heteroaryl amides useful as KIF18A inhibitors

Abstract

The present invention relates to a compound of general formula (I) as defined herein, which can regulate KIF18A protein, thereby affecting the processes of cell cycle and cell proliferation, to treat cancer and cancer-related diseases: The present invention relates to a compound having the formula (I) TIFF2022542394000094.tif59170, and synthetic intermediates thereof. The present invention also includes pharmaceutical compositions containing the compounds, and methods for treating conditions associated with KIF18A activity.

Description

[Technical field]

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

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

[0003] Cancer is often characterized by deregulated cell proliferation. Damage to one or more genes that govern cellular pathways that control the progression of proliferation through the cell cycle and the centrosome cycle can lead to a loss of normal regulation of cell proliferation. These deregulated genes may code for various tumor suppressor or oncogene proteins that are involved in a cascade of events, resulting in unrestrained cell cycle progression and cell proliferation. Various kinase and kinesin proteins have been identified that play important roles in cell cycle and mitosis regulation, as well as the progression of normal dividing and cancerous cells.

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

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end directed motor. KIF18A is thought to affect the dynamics at the plus end of kinetochore microtubules, which control correct chromosome positioning and spindle tension. Depletion of human KIF18A leads to longer spindles, increased chromosome oscillations 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 various types of cancer, including but not limited to colon, breast, pancreatic, prostate, bladder, head, neck, cervical, and ovarian cancer. Furthermore, genetic deletion or knockdown or inhibition of KIF18A results in the mitotic spindle apparatus in cancer cell lines. Specifically, it has been found that the inhibition of KIF18A induces mitotic cell arrest, known vulnerability that can promote cell death during mitosis via apoptosis, mitotic catastrophe, or multipolarity-driven lethality or death after mitotic slippage in interphase.Therefore, there is strong interest in discovering inhibitors of KIF18A protein.

[0006] Therefore, inhibition of the ATPase activity of KIF18A is a promising approach for developing novel anticancer drugs. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] O. Rath and F. Kozielski,Nature Review Cancer,12:527-39,2012 [Non-Patent Document 2] MI Mayr et al,Current Biology 17,488-98,2007 Summary of the Invention [Means for solving the problem]

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

[0009] The compounds provided by the present invention have MT-based KIF18A regulating 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 medicaments for the therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders, including but not limited to cancer.Therefore, the compounds of the present invention are useful in the manufacture of anti-cancer drugs.The present invention also provides the process for the manufacture of the compound of formula I, and intermediates useful in such process.

[0010] In embodiment 1, the present invention provides a compound of formula (I), a compound of formula I: [ka] or any pharma- ceutically acceptable salt thereof, wherein: X 1 is N or CR 6 and X 2 is N or CR 3a and X 3 is N or CR 3b and X 4 is N or CR 3c and X 5 is N or CR 3d and X 6 is N or CR 3e and X 7 is N or CR 3f and where X 3 , X 4 , X 5 and X 6 3 or less of are N, R 1 is -CN or a group -ZR 8 where Z is -C 0-4 alk-, -NR 7 -, -NR 7 SO 2 -, -SO 2 NR 7 -, -N=S(=O)-(R 7 ) 2 (Here, alternatively, two R 7 can combine with the sulfur atom to which each is 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), -NR 7 -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, C 0-4 alk-O-, -(C=O)-, -(C=O)NR 7 -, -C=N(OH)-, or -NR 7 (C=O), R 2 is a halo or a group -YR 9 where Y is -C 0-4 alk-, -NR a -, -N(C 1-4 alk)-, -NH-(CH 2 ) 0-4 -, -NR a R a (C 1-4 alk), -O-(CH 2 ) 0-4 , C 0-4 alk-S-, C 0-4 alk-S=O,C 0-4 alk-S(=O) 2 , -SO 2 NR a -C 0-4 alk-, -C 0-4 alk-S(=O)(=NH)-, -OC0-4 alk-, -C 0-4 alk-(C=O)-, -C 0-4 alk-(C=O)-O- or -N=S(=O)< L is -NR 3 , -O-, -S-, S=O, or S(=O) 2 and R 3 , H, C 1-4 alk or C 1-4 Helloalk, R 3a H, halo, C 1-8 alk or C 1-4 Helloalk, R 3b H, halo, C 1-8 alk or C 1-4 Helloalk, R 3c H, halo, C 1-8 alk or C 1-4 Helloalk, R 3d H, halo, C 1-8 alk or C 1-4 Helloalk, R 3e H, halo, C 1-8 alk or C 1-4 Helloalk, R 3f H, halo, C 1-8 alk or C 1-4 Helloalk, R 4 H, halo, R 4a , or R 4b and R 5 H, halo, C 1-8 alk or C 1-4 Helloalk, R 6 H, halo, C 1-8 alk, C 1-4 Helloalk, -OC 1-8 alk, or -OR 6a where R 6ais 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 X H, [ka] is selected from R Xa , R Xb , R Xc , R Xd , R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk and R Xl Each of the following is H, halo, R Xm , or R Xn and Or, R Xa and R Xb vs. R Xc and R Xd vs. R Xe and R Xf vs. R Xg and R Xh vs. R Xi and R Xj Pairs of and R Xk and R Xl can independently combine with the carbon atom to which each is bonded to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or azepanyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further wherein said 3-, 4-, 5-, or 6-membered monocyclic ring contains zero F, Cl, Br, C, 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -NR a R a or oxo; R 7 , H, R 7a , or R7b and R 8 , H, R 8a , or R 8b and R 9 is R 9a , or R 9b and R 4a , R Xm , R 7a , R 8a , and R 9a independently, at each occurrence, contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2-6 alkNR a R a , -OC 2-6 alkOR a , -SR a , -S(=O)R b , -S(=O) 2 R b , -S(=O) 2 NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C(=O)OR b ,-N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a, -N(R a )S(=O) 2 R b , -N(R a )S(=O) 2 NR a R a , -NR a C 2-6 alkNR a R a , -NR a C 2-6 alkOR a , -C 1-6 alkNR a R a , -C 1-6 alkOR a , -C 1-6 alkN(R a )C(=O)R b , -C 1-6 alkOC(=O)R b , -C 1-6 alkC(=O)NR a R a , -C 1-6 alkC(=O)OR a , R 10 and oxo, R 4b , R Xn , R 8b , R 8b , and R 9b is independently, at each occurrence, F, Cl, Br, -OR a , -OC 1-4 C substituted with 0, 1, 2, 3, 4, or 5 groups selected from halo, alk, or CN 1-6 alk is selected from the group consisting of R 10 independently, at each occurrence, contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4ハロalk、CN、-C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a ,-OC(=O)R b 、-OC(=O)NR a R a 、-OC 2-6 alkNR a R a 、-OC 2-6 alkOR a 、-SR a 、-S(=O)R b 、-S(=O) 2 R b 、-S(=O) 2 NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b ,-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O) 2 R b 、-N(R a )S(=O) 2 NR a R a 、-NR a C 2-6 alkNR a R a 、-NR a C 2-6 alkOR a 、-C 1-6 alkNR a R a 、-C 1-6 alkOR a 、-C 1-6 alkN(R a )C(=O)R b 、-C1-6 alkOC(=O)R b , -C 1-6 alkC(=O)NR a R a , -C 1-6 alkC(=O)OR a and oxo; R a is independently, at each occurrence, H or R b and R b is, independently, in each instance, C 1-6 alk, phenyl, or benzyl, where C 1-6 Alk is halo, -OH, -OC 1-4 alk, -NH 2 , -NHC 1-4 alk, -OC(=O)C 1-4 alk, or -N(C 1-4 alk)C 1-4 alkoxy; phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from halo, C 1-4 alk, C 1-3 Haloalk, -OH, -OC 1-4 alk, -NH 2 , -NHC 1-4 alk, -OC(=O)C 1-4 alk, or -N(C 1-4 alk)C 1-4 alk is substituted with 0, 1, 2 or 3 substituents selected from

[0011] In embodiment 2, the present invention provides a method for producing a compound comprising: 1 is CR 6 and X 2 is CR 3a and X 3 is N and X 4 is CR 3c and X 5 is N and X 6 is CR 3e and X 7 is CR3f and providing a compound having the formula (Ia): [ka] In the formula, R Xa and R Xb can combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the piperidinyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -NR a R a or oxo.

[0012] In embodiment 3, the present invention provides a method for the preparation of a compound comprising: 1 is N and X 2 is CR 3a and X 3 is N and X 4 is CR 3c and X 5 is N and X 6 is CR 3e and X 7 is CR 3f and providing a compound having the formula (Ib): [ka] In the formula, R Xa and R Xb can combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the piperidinyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4Haloalk, CN, -NR a R a or oxo.

[0013] In embodiment 4, the present invention provides a method for the preparation of a compound comprising: 1 is CR 6 and X 2 is N and X 3 is N and X 4 is CR 3c and X 5 is N and X 6 is CR 3e and X 7 is CR 3f and providing a compound having the formula (Ic): [ka] In the formula, R Xa and R Xb can combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the piperidinyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -NR a R a or oxo.

[0014] In embodiment 5, the present invention provides a method for the preparation of a compound comprising: 1 is N and X 2 is N and X 3 is N and X 4 is CR 3c and X 5 is N and X 6 is CR 3e and X 7 is CR 3f and providing a compound having the formula (Id): [ka] Here, the R Xa and R Xb can combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the piperidinyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -NR a R a or oxo.

[0015] In embodiment 6, the present invention provides a method for the preparation of a compound comprising: 1 is CR 6 and X 2 is CR 3a and X 3 is N and X 4 is N and X 5 is CR 3d and X 6 is CR 3e and X 7 is CR 3f and providing a compound having the formula (Ie): [ka] In the formula, R Xa and R Xb can combine with the carbon atom to which each is attached to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring that is spiro to the piperidinyl ring, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero N, O, and S atoms, and further, said 3-, 4-, 5-, or 6-membered monocyclic ring containing zero F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -NR a R aor oxo.

[0016] In embodiment 7, the present invention provides a compound according to any of embodiments 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R 3 is H or methyl.

[0017] In embodiment 8, the present invention provides a compound according to any of embodiments 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R Xc , R Xd , R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk , and R Xl Each of the following is H, halo, C 1-6 alk or C 1-4 Haloalk is R Xa and R Xb each of the pairs combine with the carbon atom to which they are each attached to form a saturated 3-, 4- or 5-membered monocyclic ring that is spiro to the piperidinyl ring, said ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S.

[0018] In embodiment 9, the present invention provides a compound according to any of embodiments 1 to 8, or a pharma- ceutically acceptable salt thereof, wherein R Xc , R Xd , R Xe , R Xf , R Xg , R Xh , R Xi , R Xj , R Xk , and R Xl is H, methyl, or ethyl; Xa and R Xb each of the pairs combine with the carbon atom to which they are each attached to form a cyclopropyl, cyclobutyl, or cyclopentyl ring which is spiro to the piperidinyl ring.

[0019] In embodiment 10, the present invention provides a compound according to any one of embodiments 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein: [ka] teeth, [ka] is selected from.

[0020] In embodiment 11, the present invention provides a compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof, comprising the group [ka] teeth, [ka] It is.

[0021] In embodiment 12, the present invention provides a compound according to any one of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein R 1 is -CN or a group -ZR 8 and Z is absent, -NH-, -NHSO 2 -, -SO 2 NH-, -N=S(=O)-(R 11 ) 2 (Here, alternatively, two R 7 can combine with the sulfur atom to which each is bonded 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), -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, R 8 is the following: (a) H, (b) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydrofuranyl, azetidinyl, imidazolyl, morpholinyl, pyrrolidinyl, piperazinyl, [ka] wherein each of said rings is selected from the group consisting of OH, F, methyl, -CH 2 OH, -C(=O)OCH 3 , -C(=O)OC(CH 3 ) 3 , N.H. 2 , CN, and oxo; or (c) 0, 1, 2 or 3 OH, F, -C(=O)OCH 3 , -NH 2 , -NH(CH 3 ), or -N(CH 3 ) 2 C replaced with 1-6 alk is selected from.

[0022] In embodiment 13, the present invention provides a compound according to any one of embodiments 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein R 1 is -CN or a group -ZR 8 and Z is absent, -NH-, -NHSO 2 -, -SO 2 NH-, -N=S(=O)-(R 7 ) 2 (Here, alternatively, two R 7 can combine with the sulfur atom to which each is bonded 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), -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, (a)R 8 is H, (b)R 8is oxetanyl, cyclopropyl, or (c)R 8 is C substituted with 0, 1, 2 or 3 OH groups 1-6 It is alk.

[0023] In embodiment 14, the present invention provides a compound according to any one of embodiments 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein R 1 is the group -ZR 8 and Z is -N=S(=O)-(R 7 ) 2 And each R 7 are independently selected from the group consisting of H, methyl, or isopropyl; or two R 7 In combination with the sulfur atom bonded to each of them, [ka] and 0, 1, or 2 atoms selected from O and S.

[0024] In embodiment 15, the present invention provides a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein R 1 is the group -ZR 8 and Z is -SO 2 , -NHSO 2 -, -SO 2 NH- or -S(=O)(=NH)-, R 8 is H, oxetanyl, cyclopropyl, or R 8 is C substituted with 0, 1, 2 or 3 OH groups 1-6 It is alk.

[0025] In embodiment 16, the present invention provides a compound according to any of embodiments 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein R 1 is the group -ZR 8 and Z is -NHSO 2 - and R8 is -CH 2 -CH 2 -OH.

[0026] In embodiment 17, the present invention provides a compound according to any of embodiments 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein R 1 is the group -ZR 8 and Z is -SO 2 and R 8 is methyl.

[0027] In embodiment 18, the present invention provides a compound according to any of embodiments 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein R 1 is the group -ZR 8 Z is -S(=O)(=NH)-, R 8 is cyclopropyl.

[0028] In embodiment 19, the present invention provides a compound according to any of embodiments 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein R 1 is H.

[0029] In embodiment 20, the present invention provides a compound according to any of embodiments 1 to 19, or a pharma- ceutically acceptable salt thereof, wherein R 2 is a halo or a group -YR 9 and Y is absent, -NH-, -NH-(CH 2 ) 0-4 - or -O-(CH 2 ) 0-4 and R 9 contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and is selected from F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OH, -OC 1-4 Haloalk, CN, R 10and oxo; or R 9 are F, Cl, Br, -OH, -OC 1-4 C substituted with 0, 1, 2, 3, 4, or 5 groups selected from halo, alk, or CN 1-6 It is alk.

[0030] In embodiment 21, the present invention provides a compound according to embodiments 1-17, or a pharma- ceutically acceptable salt thereof, wherein R 2 is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1, or 2 N atoms and 0 or 1 O atom, and each of said rings is selected from the group consisting of F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OH, -OC 1-4 Haloalk, CN, R 10 and oxo.

[0031] In embodiment 22, the present invention provides a compound according to any of embodiments 1 to 21, or a pharma- ceutically acceptable salt thereof, wherein R 2 is (a) a halo, (b) a group -YR 9 (where Y is absent and R 9 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, [ka] and each of said rings is selected from F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 , CN, and oxo), or (c) a group -YR 9 (wherein Y is NH, -O-, -O-(CH 2 )-, -O-(CH 2)-(CH 2 )- or -O-(CH 2 )-(CH 2 )-(CH 2 )- and R 9 teeth, [ka] or R 9 is F, Cl, Br, methyl, CF 3、 C substituted with 0, 1, 2, 3, 4, or 5 groups selected from -OH or CN 1-6 alk).

[0032] In embodiment 23, the present invention provides a compound according to any of embodiments 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein R 2 is F, Cl, Br, methyl, CF 3 , -OH, -OCHF 2 , CN, or oxo.

[0033] In embodiment 24, the present invention provides a compound according to any of embodiments 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein R 2 is morpholinyl substituted by one, two or three methyl groups.

[0034] In embodiment 25, the present invention provides a compound according to any of embodiments 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein R 2 is piperidinyl substituted by 1, 2, or 3 fluoro groups.

[0035] In embodiment 26, the present invention provides a compound according to any of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein R 2 teeth [ka] It is.

[0036] In embodiment 27, the present invention provides a compound according to any of embodiments 1 to 26, or a pharma- ceutically acceptable salt thereof, wherein R 2 is methyl or -O-(CH 2 )-(CH 2 )-CF 3 It is.

[0037] In embodiment 28, the present invention provides a compound according to any of embodiments 1 to 27, or a pharma- ceutically acceptable salt thereof, wherein Z is absent, -NH-, -NHSO. 2 -, -SO 2 NH-, -N=S(=O)<(R a ) 2 (Here, each R 7 are independently selected from the group consisting of H, methyl, or isopropyl), -S(=O)(=NH)-, -S-, -S(=O)-, -SO 2 -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-.

[0038] In embodiment 29, the present invention provides a compound according to any of embodiments 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein R 8 are (a) H, (b) F, Cl, Br, -OH, -OCH 3 or cyclopropyl; 1-6 alk, or (c) containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and containing F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -C 1-6 AlkOH, -OH, -OCH 3 , -NH 2 or oxo.

[0039] In embodiment 30, the present invention provides a compound according to any of embodiments 1 to 29, or a pharma- ceutically acceptable salt thereof, wherein R8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.

[0040] In embodiment 31, the present invention provides a compound according to any of embodiments 1 to 30, or a pharma- ceutically acceptable salt thereof, wherein R 3 is H.

[0041] In embodiment 32, the present invention provides a compound according to any of embodiments 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein R 4 is (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups; 1-6 or (c) cyclopropyl.

[0042] In embodiment 33, the present invention provides a compound according to any of embodiments 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein R 4 is methyl.

[0043] In embodiment 34, the present invention provides a compound according to any of embodiments 1 to 33, or a pharma- ceutically acceptable salt thereof, wherein R 5 is H.

[0044] In embodiment 35, the present invention provides a compound according to any of embodiments 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein R 6 is H or F.

[0045] In embodiment 36, the present invention provides a compound according to any of embodiments 1 to 35, or a pharma- ceutically acceptable salt thereof, wherein R 3a is H or F.

[0046] In embodiment 37, the present invention provides a compound according to any of embodiments 1 to 36, or a pharma- ceutically acceptable salt thereof, wherein R 3b is H.

[0047] In embodiment 38, the present invention provides a compound according to any of embodiments 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein R 3c is H.

[0048] In embodiment 39, the present invention provides a compound according to any of embodiments 1 to 38, or a pharma- ceutically acceptable salt thereof, wherein R 3d is H.

[0049] In embodiment 40, the present invention provides a compound according to any of embodiments 1 to 39, or a pharma- ceutically acceptable salt thereof, wherein R 3e is H.

[0050] In embodiment 41, the present invention provides a compound according to any of embodiments 1 to 40, or a pharma- ceutically acceptable salt thereof, wherein R 3f is H.

[0051] In embodiment 42, the present invention provides a compound selected from the following, or a pharma- ceutically acceptable salt thereof: N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-2-methyl-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine, N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine, (R)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone, (S)-Cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone, 2-hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, N-(4-((3,5-dimethylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(5-(6-azaspiro[2.5]octan-6-yl)-4-((3-(3,3,3-trifluoropropoxy)phenyl)amino)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenoxy)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(1-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide, (R)-2-hydroxy-N-(4-((3-methyl-5-(2-methylmorpholino)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, (R)-2-hydroxy-N-(4-((4-methyl-6-(2-methylmorpholino)pyridin-2-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, (R)-2-hydroxy-N-(4-((6-methyl-2-(2-methylmorpholino)pyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, 2-hydroxy-N-(4-((2-((1-hydroxy-2-methylpropan-2-yl)amino)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, N-(4-((2-fluoro-3-((1-hydroxy-2-methylpropan-2-yl)amino)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, 2-hydroxy-N-(4-((3-(2-hydroxy-2-methylpropoxy)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide, 4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-N-(3-methyloxetan-3-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide, (S)—N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfonamide, (R)—N-(4-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-1-hydroxypropane-2-sulfonamide, N-(4-((2-(3,3-difluoroazetidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-8-fluoro-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(7-azaspiro[3.5]nonan-7-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-5-(4,4-dimethylazepan-1-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, 2-((4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)sulfonyl)ethan-1-ol, N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)thio)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, 7-(azetidin-3-ylsulfonyl)-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine, N-(tert-butyl)-3-((7-((2-hydroxyethyl)sulfonamido)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-yl)amino)benzenesulfonamide, N-(4-((3-(cyclopentylsulfonyl)-4-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(tert-butyl)-4-((6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide, N-(tert-butyl)-4-(chroman-5-ylamino)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-sulfonamide, N-(1-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide, N-(1-((6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-yl)amino)-8-(6-azaspiro[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonamide, N-(1-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro[2.5]octan-6-yl)isoquinolin-6-yl)-2-hydroxyethane-1-sulfonamide, 2-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)isothiazolidine 1,1-dioxide, N-(4-((3-(3,3-difluoro-6-azabicyclo[3.1.1]heptan-6-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((3-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, N-(4-((3-(4,4-difluoropiperidin-1-yl)-4-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide, 4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-N-(2-hydroxyethyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazoline-7-carboxamide, 2-((8-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-1-(6-azaspiro[2.5]octan-6-yl)-2,7-naphthyridin-3-yl)amino)-2-methylpropan-1-ol, 2-((5-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspiro[2.5]octan-6-yl)-1,6-naphthyridin-2-yl)amino)-2-methylpropan-1-ol, 2-((5-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-4-(6-azaspiro[2.5]octan-6-yl)pyrido[4,3-d]pyrimidin-2-yl)amino)-2-methylpropan-1-ol, 2-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)propan-2-ol, or N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)pyrido[3,4-d]pyrimidin-4-amine.

[0052] In embodiment 43, the present invention provides a compound selected from the following, or a pharma- ceutically acceptable salt thereof:

[0053] [Table 1]

[0054] [Table 2] or any pharma- ceutically acceptable salt thereof.

[0055] Another aspect of the present invention is a pharmaceutical composition comprising a new class of compounds, or pharma- ceutically acceptable salts thereof, useful for modulating KIF18A protein, either alone or in a complex bound to microtubules.

[0056] In embodiment 44, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 43 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent or carrier.

[0057] Yet another aspect of the present invention is a method for treating a condition that can be treated with a KIF18a inhibitor, the method comprising administering to a patient in need thereof a therapeutically effective amount of a new class of compounds, or a pharma- ceutically acceptable salt thereof, useful for regulating KIF18A protein, alone or in a complex bound to microtubules.

[0058] In embodiment 45, the present invention provides a method for treating a condition that can be treated with a KIF18a inhibitor, the method comprising administering a therapeutically effective amount of a compound according to embodiments 1 to 43, or a composition according to embodiment 44, to a patient in need thereof.

[0059] In embodiment 46, the invention provides the method of embodiment 45, wherein the condition is (a) a solid or hematologically derived tumor selected from bladder cancer, endometrial cancer, lung squamous cell carcinoma, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer. (b) hematopoietic neoplasms of the lymphatic system selected from leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (c) hematopoietic neoplasms of the myeloid lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and neurilemmoma; or (f) cancer selected from the group consisting of melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, or Kaposi's sarcoma.

[0060] In subembodiment 46a, the present invention provides the method of embodiment 45, wherein the condition is a cancer selected from the group consisting of melanoma, prostate cancer, cervical cancer, breast cancer, colon cancer, sarcoma, or leukemia. See Zhang C.et.al., "Kif18A is involved in human breast carcinogenesis", Carcinogenesis, 2010 Sep;31(9):1676-84.doi:10.1093 / carcin / bgq134.Epub 2010 Jul 1. See also: (1) https: / / www.proteinatlas.org / ENSG00000121621-KIF18A / pathology; (2) Nagahara, M. et. al., “Kinesin 18A expression: clinical relevance to colorectal cancer progression” Int. J. Cancer: 129, 2543-2552 (2011) VC 2011 UIC; and (3) Yu, Y. et. al., “The Role of Kinesin Family Proteins in Tumorigenesis and Progression-Potential Biomarkers and Molecular Targets for Cancer Therapy” Cancer 2010; 116: 5150-60. VC 2010 American Cancer Society.

[0061] In embodiment 47, the present invention provides a method for reducing the size of a solid tumor in a subject, the method comprising administering a therapeutically effective amount of a compound described in embodiments 1-43, or a composition described in embodiment 44 to a subject in need thereof.

[0062] In embodiment 48, the present invention provides a method for treating a cell proliferation disorder in a subject, the method comprising administering a therapeutically effective amount of a compound described in embodiments 1-43, or a composition described in embodiment 44, to a subject in need thereof.

[0063] In embodiment 49, the present invention provides a method for inhibiting KIF18A in a cell, comprising contacting the cell with a compound described in embodiments 1 to 43, or a pharma- ceutically acceptable salt thereof, or a composition described in embodiment 44.

[0064] Yet another aspect of the present invention is a method for preparing a new class of compounds, or pharma- ceutically acceptable salts thereof, useful for modulating KIF18A protein, either alone or in a complex bound to microtubules.

[0065] In embodiment 50, the present invention provides a method of preparing a compound of formula (I) described herein.

[0066] In embodiment 51, the present invention provides intermediate compounds used in the processes for preparing compounds of formula (I) described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0068] Examples of isotopes suitable for inclusion in the compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C and 14 Carbon, such as C 38 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O and 18 Oxygen, such as O 32 Phosphorus such as P 35 and isotopes of sulfur such as, but not limited to, S.

[0069] Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and ready means of detection.

[0070] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances because it may confer certain therapeutic advantages, such as increased metabolic stability, increased in vivo half-life or reduced dosage requirements.

[0071] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0072] Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described in the accompanying Examples and Preparations, substituting an appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0073] Pharmaceutically acceptable solvates according to the invention include those in which the solvent of crystallization may be isotopically substituted, e.g. 2 O, d 6 -Acetone, d 6 -DMSO.

[0074] Specific embodiments of the present invention include the compounds exemplified in the Examples below, as well as pharma- ceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives thereof.

[0075] Unless otherwise stated, the following definitions apply to terms found in the specification and claims.

[0076] "C α-β "Alk" means an alkyl group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, or any combination thereof, where α and β represent integers. The alkyl groups described in this section may also contain one or two double or triple bonds. 0 The notation alk refers to a direct bond. 1-6 Examples of alkyl include, but are not limited to, the following: [ka]

[0077] The "benzo group", alone or in combination, is the divalent radical C 4 H 4 one representation is -CH=CH-CH=CH- which, when attached adjacent to another ring, forms a benzene-like ring, e.g., tetrahydronaphthylene, indole, etc.

[0078] The terms "oxo" and "thioxo" refer to the groups =O (as in carbonyl) and =S (as in thiocarbonyl), respectively.

[0079] "Halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0080] "C α-β "Haloalk" refers to an alk group as defined above in which any number (at least one) of the hydrogen atoms attached to the alk chain has been replaced by F, Cl, Br, or I.

[0081] Group N(R a )R a For example, two R a Included are substituents where the groups together form a ring which optionally contains an N, O, or S atom, such as: [ka] Examples of such groups include:

[0082] Group N(C α-β alk)C α-β As alk (wherein α and β are as defined above), two C α-β Included are substituents where the alk groups together form a ring which optionally contains an N, O, or S atom, such as: [ka] Examples of such groups include:

[0083] "Bicyclic ring" means a group characterized by two joined rings. The bicyclic ring may be carbocyclic (all ring atoms are carbon) or heterocyclic (ring atoms consist of, in addition to carbon atoms, e.g., one, two, or three heteroatoms, e.g., N, O, or S). The two rings may both be aliphatic (e.g., decalin and norbornane) or aromatic (e.g., naphthalene) or a combination of aliphatic and aromatic (e.g., tetralin).

[0084] Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom, a spiroatom, which is usually a quaternary carbon. Examples of spirocyclic compounds include: [ka] (b) Fused bicyclic compounds include, but are not limited to, compounds in which two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic compounds include: [ka] and (c) bridged bicyclic compounds in which two rings share three or more atoms and a bridge containing at least one atom separates the two bridgehead atoms. For example, norbornane, also known as bicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane rings each sharing three of the five carbon atoms. Examples of bridged bicyclic compounds include: [ka] These include, but are not limited to:

[0085] The term "carbocycle" or "carbocyclic", by itself or in combination with other terms, means "C α-β Examples of carbocycles include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene, and the like.

[0086] "Heterocycle" or "heterocyclic" means a ring containing at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles that may be found in the claims include: [ka] These may include, but are not limited to:

[0087] "Pharmaceutically acceptable salt" refers to salts prepared by conventional means, which are well known to those skilled in the art. "Pharmaceutically acceptable salt" includes base salts of inorganic and organic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid, etc. When the compound of the present invention contains an acidic functional group, such as a carboxy group, suitable pharma- ceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art, and include alkali, alkaline earth, ammonium, quaternary ammonium cations, etc. For additional examples of "pharmacologically acceptable salts", see below and Berge et al., J.Pharm.Sci.66:1(1977).

[0088] "Saturated, partially saturated, or unsaturated" includes substituents that are saturated with hydrogens, substituents that are not saturated with hydrogens at all, and substituents that are partially saturated with hydrogens.

[0089] "Leaving group" generally refers to a group that is readily displaceable by a nucleophile, such as an amine, thiol, or alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferred leaving groups are indicated herein where appropriate.

[0090] "Protecting group" generally refers to groups well known in the art that are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto, and the like, from undergoing undesired reactions, such as nucleophilic reactions, electrophilic reactions, oxidation reactions, reduction reactions, and the like. Preferred protecting groups are indicated herein as necessary. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyls include, but are not limited to, benzyl, orthomethylbenzyl, trityl, and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl, and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl, and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably having 6-10 carbon atoms, include, but are not limited to, cyclohexenylmethyl. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. The amino protecting groups, together with the nitrogen to which they are attached, can also form heterocyclic rings, such as, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl, and the like, which can further include adjacent aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di-, or tri-substituted, such as nitrophthalimidyl. Amino groups can also be protected against undesired reactions, such as oxidation, by forming an addition salt with hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, and the like.Many of the amino acid protecting groups are also suitable for protecting carboxy, hydroxy, and mercapto groups, for example aralkyl groups. Alkyl groups such as tert-butyl are also suitable for protecting hydroxy and mercapto groups.

[0091] Silyl protecting groups are silicon atoms optionally substituted with one or more alkyl, aryl, and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane, and diphenylmethylsilyl. Silylation of amino groups can provide mono- or disilylamino groups. Silylation of amino alcohol compounds can provide N,N,O-trisilyl derivatives. Removal of silyl functions from silyl ether functions is easily accomplished by treatment with, for example, metal hydroxide or ammonium fluoride reagents, either as a separate reaction step or in situ during reaction with alcohol groups. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Also, methods for preparing these amine derivatives from the corresponding amino acids, amino acid amides, or amino acid esters are well known to those skilled in the art of organic chemistry, including amino acid / amino acid ester, or amino alcohol chemistry.

[0092] Protecting groups are removed under conditions that do not affect the remainder of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis, and the like. A preferred method involves the removal of a protecting group such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like, or a mixture thereof. A t-butoxycarbonyl protecting group can be removed using an inorganic or organic acid such as HCl or trifluoroacetic acid in a suitable solvent system such as dioxane or methylene chloride. The resulting amino salt can be easily neutralized to give the free amine. Carboxy protecting groups such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl, and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.

[0093] The compounds of the invention may contain groups that may exist in tautomeric form, such as cyclic and acyclic amidine and guanidine groups, heteroatom-substituted heteroaryl groups (Y' = O, S, NR), as illustrated in the following examples: [ka] It should be noted that although one form may be named, described, represented, and / or claimed herein, all tautomeric forms are intended to be inherently included in such naming, description, representation, and / or claim.

[0094] Prodrugs of the compounds of the present invention are also contemplated by the present invention. Prodrugs are active or inactive compounds that are chemically modified to the compounds of the present invention by in vivo physiological action, such as hydrolysis, metabolism, etc., after the prodrug is administered to a patient. The suitability and techniques involved in the manufacture and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masked carboxylate anions include various esters such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives that are cleaved in vivo by esterases to release the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing acidic NH groups such as imidazoles, imides, and indoles have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy 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 use.

[0095] The present specification and claims include lists of chemical species (sometimes referred to as Markush groups) using the phrases "selected from and" and "or." When this term is used in this application, unless otherwise specified, it is intended to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this phrase is merely for shorthand purposes and in no way limits the exclusion of individual elements or subgroups, where appropriate.

[0096] Pharmaceutical Compositions, Dosages, and Routes of Administration Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, together with a pharma- ceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. Administration of the compounds is described in more detail below.

[0097] Suitable pharmaceutical formulations can be determined by those skilled in the art depending on the route of administration and the desired dosage. For example, see Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). Formulations can affect the physical state, stability, in vivo release rate and in vivo clearance rate of the administered drug. Depending on the route of administration, suitable doses can be calculated according to body weight, body surface area or organ size. Further refinement of calculations required to determine appropriate therapeutic doses can be routinely performed by those skilled in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein and pharmacokinetic data obtained in animal or human clinical trials.

[0098] The phrases "pharmacologically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse allergic or other untoward reactions when administered to animals or humans. As used herein, "pharmacologically acceptable excipients" include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such excipients for pharma- ceutical active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the therapeutic composition, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In an exemplary embodiment, the formulation comprises corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride. , L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, mixed tocopherols, calcium pantothenate, copper sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0099] The compound may be present in the pharmaceutical composition as a pharma- ceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" includes, for example, base addition salts and acid addition salts.

[0100] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds can also be prepared with pharma- ceutically acceptable cations. Suitable pharma-ceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations include sodium, potassium, magnesium, ammonium, calcium or iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

[0101] Pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids. Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate. Other suitable pharma- ceutically acceptable salts are well known to those skilled in the art, and include, for example, formate, acetate, citric acid, oxalic acid, tartaric acid, or mandelic acid, hydrochloride, hydrobromic acid, sulfuric acid, or phosphoric acid; organic carboxylic acid, sulfonic acid, sulfoacid, or phosphoric acid, or N-substituted sulfamic acid, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and with the 20 alpha amino acids involved in the synthesis of natural proteins, such as glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamate) or with other acid organic compounds, such as ascorbic acid.

[0102] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation depends on the route of administration chosen.

[0103] For oral administration, suitable compositions can be easily formulated by combining the compounds disclosed herein with pharma- ceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds disclosed herein with solid excipients, optionally grinding the resulting mixture, and processing the granular mixture, after adding suitable auxiliaries as necessary, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can be added as necessary. Pharmaceutically acceptable ingredients are well known for various types of formulations and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavoring agents, coatings, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various formulation types.

[0104] When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is typically in the form of a solid (e.g., a tablet, capsule, pill, powder or lozenge) or a liquid preparation (e.g., an aqueous suspension, solution, elixir or syrup).

[0105] When administered in tablet form, the composition may further contain a functional solid, such as gelatin or an adjuvant, and / or a functional solid carrier. The tablet, capsule, and powder may contain about 1 to about 95% of the compound, preferably about 15 to about 90% of the compound.

[0106] When administered in the form of a solution or suspension, a functional liquid and / or a functional liquid carrier, such as water, petroleum, or oil of animal or plant origin, can be added. The liquid form of the composition can further include a saline solution, a sugar alcohol solution, a dextrose or other sugar solution, or a glycol. When administered in the form of a solution or suspension, the composition can contain about 0.5 to about 90% by weight of the compound disclosed herein, preferably about 1 to about 50% of the compound disclosed herein. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition can be provided as a rapidly dissolving solid formulation that is dissolved or suspended immediately prior to administration.

[0107] When a therapeutically effective amount of the compounds disclosed herein is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. Preparation of such parenterally acceptable solutions, with due consideration of pH, isotonicity, stability, and the like, is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection typically contains an isotonic vehicle in addition to the compounds disclosed herein. Such compositions can be prepared for administration as a solution of a free base or a pharmacologically acceptable salt in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, as well as in oils. Under ordinary conditions of storage and use, these preparations can optionally contain a preservative to prevent the growth of microorganisms.

[0108] Injectable compositions can include sterile aqueous solutions, suspensions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions or dispersions. In all embodiments, the form must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must resist the contaminating action of microorganisms such as bacteria and fungi, optionally by including preservatives. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one possible embodiment, the carrier is non-aqueous or substantially non-aqueous. The proper fluidity can be maintained, for example, by the use of a coating agent such as lecithin, by maintaining the particle size of the compound required in the embodiment of the dispersion, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many embodiments, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0109] Sterile injection is prepared by incorporating the active compound in the required amount in a suitable solvent together with various other necessary ingredients listed above, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other desired ingredients from the ingredients listed above.In the embodiment of sterile powder for preparing sterile injection, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient plus any other desired ingredients from the solution that has been previously sterilized and filtered.

[0110] Slow or sustained release formulations can also be prepared to provide a controlled release of active compound in contact with body fluids in the gastrointestinal tract and to provide a substantially constant and effective level of active compound in plasma. For example, release can be controlled by one or more of dissolution, diffusion and ion exchange. Furthermore, the slow release approach can enhance absorption via saturable or restricted pathways in the gastrointestinal tract. For example, the compound can be embedded for this purpose in a polymer matrix of a biodegradable polymer, a water-soluble polymer or a mixture of both, and optionally a suitable surfactant. Embedding in this context can mean incorporating microparticles in a polymer matrix. Controlled release formulations can also be obtained by encapsulation of dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0111] For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of aerosol spray dispensed from pressurized packs or nebulizers using a suitable propellant.In pressurized aerosol embodiments, the dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0112] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion).The preparation for injection can be provided in unit dosage form (e.g., in ampoules or multi-dose containers) with added preservative.The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0113] Pharmaceutical preparations for parenteral administration include aqueous solutions of the compound in water-soluble form. Furthermore, suspensions of the compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0114] The compounds disclosed herein can also be formulated in rectal compositions such as suppositories or retention enemas (e.g., containing conventional suppository bases). In addition to the formulations described above, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by injection (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or can be formulated as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0115] In particular, the compounds disclosed herein may be administered orally, bucally or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or ovoids, alone or in mixture with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid preparations may be prepared with pharma- ceutically acceptable additives, such as suspending agents. The compounds may also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compounds are most often used in the form of a sterile aqueous solution, which may contain other substances, such as salts or sugar alcohols, such as mannitol or glucose, to make the solution isotonic with blood.

[0116] For veterinary use, the compounds disclosed herein are administered in an appropriately acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0117] In some embodiments, all components necessary for the treatment of KIF18A-associated disorders, using the compounds disclosed herein alone or in combination with another drug or intervention conventionally used for the treatment of such diseases, can be packaged into a kit.Specifically, the present invention provides a kit for use in the treatment of disease, comprising a compound disclosed herein and a drug, including buffers and other components for preparing a deliverable form of said drug, and / or an apparatus for delivering such a drug, and / or any drug used in combination therapy with the compound disclosed herein, and / or a packaged set of instructions for the treatment of the disease packaged with the drug.The instructions can be fixed on any tangible medium, such as printed paper or computer-readable magnetic or optical medium, or can be instructions that refer to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0118] "Therapeutically effective amount" refers to an amount effective to treat, prevent progression, or alleviate existing symptoms of the subject being treated. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. In general, "therapeutically effective dose" refers to the amount of a compound that produces a desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KIF18A activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0119] The amount of compound administered may depend on the subject being treated, the subject's age, health, sex and weight, type of concurrent treatment (if any), severity of disease, nature of the desired effect, mode and frequency of treatment, and the prescribing physician's judgment.Frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen pressure.Although individual needs vary, determining the optimal range of effective amounts of the compound is within the skill of the art.Such doses may be administered in a single dose or divided into multiple doses.

[0120] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a mammal that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, sarcoma, blastoma, and leukemia. More specific examples of such cancer include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, and head and neck cancer, ovarian cancer, and endometrial cancer. The term "cancer" as used herein is not limited to any one specific form of disease, but the method of the present invention is believed to be particularly effective for cancers that are found to involve unregulated levels of KIF18A or to be dependent on KIF18A for proper chromosome segregation and survival in mammals.

[0121] As used herein, the terms "treat," "treating," and "treatment" refer to therapies, including but not limited to curative, prophylactic, and preventative therapies. Prophylactic treatment generally consists of either preventing the onset of a disorder altogether or delaying the onset of a pre-clinical stage of the disorder in an individual.

[0122] As used herein, the term "patient," "subject," or "mammal" refers to any "patient," "subject," or "mammal," including humans, cows, horses, dogs, and cats. In one embodiment of the invention, the mammal is a human.

[0123] The term "comprising" is meant to be open-ended, including the indicated components, but not excluding other elements.

[0124] The term "Formula I" includes any subformulas.

[0125] How to use KIF18A inhibitors The present disclosure provides compounds with MT-based KIF18A regulating activity in general, and inhibiting activity in particular. In one embodiment of the present invention, a method for regulating KIF18A protein in a subject is provided, comprising administering to the subject an effective dosage of a compound of formula I. Thus, the compounds of the present invention can be used to treat cell proliferation disorders, including uncontrolled cell growth, abnormal cell cycle regulation, and centrosome abnormalities (structural and / or numerical, fragmentation). Other diseases or disorders involving the accumulation of extra centrosomes (>2) include human papillomavirus (HPV) infection, including HPV-associated neoplasia. The compounds are also useful for cilia-related disorders, and for ablating haploid germ cell populations, which can be used as male contraceptives.

[0126] In addition, the compounds of the present invention are useful for preventing or treating cancer and other KIF18A-mediated diseases or disorders, but are not limited thereto. For example, the compounds of the present invention are useful for preventing or treating various solid and blood-borne 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 lymphatic system (leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and the like); and Burkitt's lymphoma); hematopoietic tumors of myeloid lineage (including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and neurilemmoma); and other tumors (including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, and Kaposi's sarcoma).

[0127] The compounds of the invention are also useful in the treatment of cancer-related indications such as solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), hematopoietic malignancies including retinoblastoma, rhabdomyosarcoma, neuroblastoma, leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.

[0128] Based on their ability to modulate kinesin, which affects angiogenesis, the compounds of the present invention are also useful for the treatment and therapy of proliferative diseases.Specifically, these compounds can be used to treat inflammatory diseases such as various inflammatory rheumatoid diseases, especially conditions in the locomotor system, especially chronic polyarthritis, including rheumatoid arthritis, juvenile arthritis, or arthropathic psoriasis; paraneoplastic syndromes or tumor-induced inflammatory diseases, cloudy effusions, collagen diseases, such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma, or mixed collagen diseases; post-infectious arthritis (no pathogens found living in or within the affected body part), seronegative spondyloarthritis, such as ankylosing spondylitis; vasculitis, sarcoidosis, or arthropathy; or any further combination thereof.

[0129] The compounds of the present invention can also be used as active agents against pathologies such as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collateral arteries, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter-associated disease, bone fractures, cat scratch fever, rubeosis, neovascular glaucoma, and retinopathies such as those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers, and hyperproliferative disorders, such as thyroid hyperplasia (particularly Graves' disease), and cysts (e.g. hypervascularization of the ovarian stroma, a feature of polycystic ovary syndrome (Stein-Leventhal syndrome)), since these diseases require proliferation of vascular cells for growth and / or metastasis.

[0130] In addition to being useful for human treatment, these compounds are useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs and cats can be treated with the compounds provided by the present invention.

[0131] Use in combination The compounds of the invention can be taken or administered as the sole active pharmaceutical agent, but they can also be used in combination with one or more compounds of the invention or in combination with other drugs. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.

[0132] The phrase "co-therapy" (or "combination-therapy") in defining the use of a compound of the invention and another pharmaceutical agent includes the administration of each agent sequentially in a dosing regimen that provides the beneficial effect of the drug combination, and also includes the administration of these agents in a substantially simultaneous combination, such as in a single capsule having a fixed ratio of the active agents or in separate capsules for each agent.

[0133] In particular, administration of the compounds of the invention may be combined with additional therapies known to those skilled in the art of cancer prevention or treatment, such as with radiation therapy, small molecule targeted agents (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies (e.g., naked and drug conjugated), immunotherapeutic antibodies (checkpoint inhibitors, bispecific T cell engagers), and anti-neoplastic or cytotoxic agents.

[0134] When formulated as a fixed dose, such combination products use the compounds of the present invention within the acceptable dosage range. When combination formulation is inappropriate, the compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents. The present invention is not limited in the order of administration, and the compounds of the present invention may be administered before, simultaneously with, or after the administration of known anticancer or cytotoxic agents.

[0135] There are many anti-cancer drugs available in commercial use, in clinical evaluation, and in preclinical development that are selected for the treatment of neoplasia by combination drug chemotherapy. These drugs fall into several major categories, including antibiotic-type agents, alkylating and alkylating-like agents, antimitotic agents, targeted small molecule agents, antimetabolites, hormonal agents, immunological agents, antiangiogenic agents, interferon-type agents, and other classes of agents.

[0136] The present disclosure also provides a method of combination therapy, in which an overlapping set of drugs or even target enzymes known to regulate other pathways or other components of the same pathway are used in combination with the compounds of the present disclosure or their pharma- ceutically acceptable salts.In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, targeted small molecule agents, and radiation therapy to provide synergistic or additive therapeutic effects.

[0137] Currently, many chemotherapeutic agents are known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib) and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylameramines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, Actinomycin, Ausramycin, Azaserine, Bleomycin, Cactinomycin, Calicheamicin, Carabicin, Carminomycin, Carzinophilin, Casodex™, Chromomycin, Dactinomycin, Daunorubicin, Detorubicin, 6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epirubicin, Esorubicin, Idarubicin, Marcellomycin, Mitomycin, Mycophenolic acid, Nogalamycin, Olivomycin, Peplomycin, Potofilomycin, Puromycin Antibiotics such as keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and enocitabine. Pyrimidine analogues such as tabine and floxiridine; androgens such as calcineurone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxy Urea;Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Fenameth;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triaziquone;2,2',2''-Trichlorotriethylamine;Urethane;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pipobroman;Gacytosine;Arabinoside ("Ara-C");Cyclophosphamide;Thiotepa;Taxanes such as paclitaxel and docetaxel, Nab-paclitaxel; retinoic acid; esperamycin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0138] Also included as suitable chemotherapy cell conditioners are antihormonal agents that act to modulate or inhibit hormone action on tumors, such as antiestrogens, including, for example, tamoxifen, (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens, such as flutamide, nilutamide, bicalutamide, luprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin, oxaliplatin, carboplatin; etoposide (VP-16); ifosfamide; mitomycin. C; mitoxantrone; vinblastine; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; topotecan; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0139] Optionally, the compounds or pharmaceutical compositions of the present disclosure are selected from the group consisting of Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Abraxane, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aminopyridine-2-carboxylate, cyclosporine ... Carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderm, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exateca , exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lutecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, talazoparib, niraparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-3 8. It can be used in combination with commonly prescribed anticancer drugs such as salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126 or zosuquidar, CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, Kisqali; abemaciclib, Verzenio).

[0140] The present disclosure further relates to a method of combining the compounds or pharmaceutical compositions provided herein with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in a mammal.Methods for administering radiation therapy are known in the art, and these methods can be used in the combination therapy described herein.The administration of the compounds disclosed herein in this combination therapy can be determined as described herein.

[0141] Radiation therapy can be administered by one of several methods, or a combination of these methods, including, but not limited to, external beam therapy, internal radiation therapy, interstitial irradiation, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially restricted radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell conditioners of the present disclosure include both solid and liquid. As non-limiting examples, the radiation source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material can be a fluid made from any solution of the radionuclide, for example a solution of I-125 or I-131, or the radioactive fluid can be produced using a slurry of a suitable fluid containing microparticles of a solid radionuclide such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied as a gel or radioactive microspheres.

[0142] The compounds or pharmaceutical compositions of the present disclosure can be used in combination with an amount of one or more substances selected from an anti-angiogenic agent, a signal transduction inhibitor, an anti-proliferative agent, an antiglycolytic agent, or an autophagy inhibitor.

[0143] Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used with the disclosed compounds and pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172, WO 96 / 27583, EP 0818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 606046, EP 931788, and the like. No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 0,780,386, all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferably, they selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0144] The compounds of the present invention include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin, diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, f Rudarabine phosphate, Formestane, Fotemustine, Gallium nitrate, Gemcitabine, Gemtuzumabzogamicin, Gimeracil / oteracil / tegafur combination, Glycopin, Goserelin, Heptaplatin, Human chorionic gonadotropin, Human fetal alpha fetoprotein, Ibandronate, Idarubicin, (Imiquimod, Interferon alfa, Interferon alfa, Natural, Interferon alfa-2, Interferon alfa-2a, Interferon alfa-2b, Interferon alfa-N1, Interferon alfa Lon alfa-n3, interferon alfacon-1, interferon alfa, natural, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, natural interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leucocyte alpha interferon, leuprorelin,Levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, millimostim, mismatched double-stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis-stimulating protein, NSC 631570 Octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronate, pegaspargase, peginterferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, raltitrexed, rasbu Liembodiment, rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topote Can, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, barbicine, verteporfin, vinorelbine, Virulizin, zinostatin stimalamer or zoledronic acid; abarelix; AE941 (Aet erna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen,HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), idiotypic 105AD7MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafine gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl ethiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering It may also be used in combination therapy with other antineoplastic agents such as valspodar, melanoma oncolysate vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle Hospital) or valspodar.

[0145] The compounds of the present invention may further be used in combination with VEGFR inhibitors. Other compounds described in the following patents and patent applications may be used in combination therapy: U.S. Pat. No. 6,258,812, U.S. Patent Application Publication No. 2003 / 0105091, WO 01 / 37820, U.S. Pat. No. 6,235,764, WO 01 / 32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat. No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, WO 02 / 02 / 01, and the like. / 68406, 02 / 66470, 02 / 55501, 04 / 05279, 04 / 07481, 04 / 07458, 04 / 09784, 02 / 59110, 99 / 45009, 00 / 59509, 99 / 61422, U.S. Patent No. 5,990,141, WO 00 / 12089 and WO 00 / 02871.

[0146] In some embodiments, the combination comprises the composition of the present invention in combination with at least one antiangiogenic agent.Agents include, but are not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof.Agents may be agonists, antagonists, allosteric regulators, toxins, or more generally act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or halting cell growth.

[0147] Exemplary anti-angiogenesis agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents such as AVASTIN™ or VEGF-TRAP™ (e.g., antibodies or antigen binding regions that specifically bind to VEGF or a soluble VEGF receptor or its ligand binding region), and anti-VEGF receptor drugs (e.g., antibodies or antigen binding regions that specifically bind to), EGFR inhibitors such as Vectibix (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib) (e.g., antibodies or antigen binding regions that specifically bind to), anti-Ang1 and anti-Ang2 agents (e.g., to or against their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind to). The pharmaceutical compositions of the invention can also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind and inhibit the activity of a growth factor, such as antagonists and antibodies or antigen-binding regions of hepatocyte growth factor (HGF, also known as scatter factor) that specifically bind to the receptor "c-met."

[0148] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind, or soluble TWEAK receptor antagonists; Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (Fanslow et al., U.S. Patent Application Publication No. 2002 / 0042368), anti-ep h-receptor and / or anti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124, and members of those patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen binding regions that specifically bind), as well as antibodies or antigen binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto).

[0149] Further anti-angiogenic / anti-tumor agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 770622); pegabutanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat (Arriva, USA, U.S. Pat. No. 5,892,112); emaxanib (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (Alcon, USA); α-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands); DAC: Anti-angiogenic agent (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, European Patent No. 970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen E-fragment (BioActa, UK); Angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); metastatin (EntreMed, USA); angiogenesis inhibitors (Tripep, Sweden); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Benefin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda Pharmaceutical, Japan); FR-111142 (Fujisawa Pharmaceutical, Japan, Japanese Patent No. 02233610);Platelet factor 4 (RepliGen, USA, EP407122); Vascular endothelial growth factor antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, α5β3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); Gene therapy, retinopathy (Oxford BioMedica, UK); Enzastaurin hydrochloride (USAN), (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research,Italy);angiogenesis inhibitors (Alchemia,Australia);VEGF antagonists (Regeneron,USA);rBPI21 and BPI-derived antiangiogenic agents (XOMA,USA);PI88 (Progen,Australia);,cilengitide (pINN), (Merck KGaA,;Munich Technical University,Scripps Clinic and Research Foundation,USA);cetuximab (INN), (Aventis,France);AVE8062 (Ajinomoto,Japan);AS1404 (Cancer Research Laboratory,New Zealand);SG292 (Telios,USA);endostatin (Boston Children's Hospital,USA);ATN161 (Attenuon,USA);angiostatin (Boston Children's Hospital,USA);2-methoxyestradiol (Boston Children's Hospital,USA);ZD6474 (AstraZeneca,UK);ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK);Vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor (EntreMed, USA); pegaptanib (Pinn) (Gilead Sciences, USA); xanthrizol (Yonsei University, South Korea); gene-based vaccine, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California, San Diego, USA); PX478 (ProlX, USA); metastatin (EntreMed, USA); troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI4503 (OXiGENE, USA); o-guanidine (Dimensional Pharmaceuticals, USA); motuporamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai, Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccines, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1 alpha inhibitors (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, South Korea); GW2286 (GlaxoSmithKline, UK); EHT0101 (ExonHit, France); CP868596 (Pfizer, USA); CP564959 (OSI, USA);CP547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN633 (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol (EntreMed, USA); Anginex (Maastricht University, Netherlands and University of Minnesota, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-α inhibitor (National Institute on Aging, USA); SU11248 (Pfizer, USA and SUGEN, USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, α5β1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB116 (South Florida University, USA and Yale University, USA); CS706 (Sankyo, Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda, Japan and TAP, USA); AG13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA) CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, South Korea); MAb, vascular endothelial growth factor (Xenova, UK); Irsogladine (INN) (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany);Squalamine (pINN) (Genaera, USA); RPI4610 (Sirna, USA); Cancer therapy (Marinova, Australia); Heparanase inhibitors (InSight, Israel); KL3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho Pharmaceutical, Japan); VEGF receptor modulators (Pharmacopeia, USA); VE-cadherin-2 antagonists (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Vaccines, Flk-1 (ImClone Systems, USA); TZ93 (Tsumura, Japan); tumstatin (Beth Israel Hospital, USA); cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0150] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4 imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA that inhibit the expression of proteins, including, but not limited to, ATG5 (involved in autophagy), may also be used.

[0151] Additional pharma- ceutically active compounds / drugs that may be used in the treatment of cancer and may be used in combination with one or more compounds of the present invention include epoetin alfa; darbepoetin alfa; panitumumab; pegfilblastim; palifermin; filgrastim; denosumab; ancestim; AMG102; AMG386; AMG479; AMG655; AMG745; AMG951; and AMG706, or pharma- ceutically acceptable salts thereof.

[0152] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin A), and cyclosporine (cyclosporine). D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and removes cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, nitrogen mustards (e.g., antiproliferative / antimitotic alkylating agents such as, mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkylsulfonates (e.g., busulfan, nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozocin), trazene-dacarbazine (DTIC), folic acid analogs (e.g., antiproliferative / antimitotic antimetabolites such as methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroamic acid, vorinostat, LBH589, romidepsin, ACY-1215 and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaforolimus and sirolimus), KSP (Eg5) inhibitors (e.g., Array 520), DNA binders (e.g., Zalipsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multikinase inhibitors (e.g., TG02 and sorafenib), hormone (e.g., estrogen) and hormonal agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN163L), Aurora kinase inhibitors (e.g., MLN8237, AMG 900, AZD-1152), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torc1 / 2 specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., AR RY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib, talazoparib, niraparib, veliparib (ABT-888)), natural products such as BCL-2 antagonists. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or analogs or derived variants of any of the above.

[0153] The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy, all of which are well known to those skilled in the art.

[0154] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandre The therapeutically active agents may include, but are not limited to, cyclosporine ... Examples of drugs that can be used to treat nausea include the following: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharma- ceutically acceptable salts thereof.

[0155] The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more agents selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and anti-immunotherapies (including PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents), GITR agonists, CAR-T cells, and BiTEs.

[0156] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently lapatinib (TykerB). See, e.g., Yan L, et.al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005;39(4):565-8 and Paez JG, et.al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004;304(5676):1497-500.

[0157] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharma- ceutically acceptable salts and solvates of said EGFR inhibitors: EP 520722, published December 30, 1992; EP 566226, published October 20, 1993; WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, issued May 5, 1998; WO 96 / 33980, published October 3, 1996; / 30347;EP 787772 published August 6, 1997;WO 97 / 30034 published August 21, 1997;WO 97 / 30044 published August 21, 1997;WO 97 / 38994 published October 23, 1997;WO 97 / 49688 published December 31, 1997;EP 837063 published April 22, 1998;WO 98 / 02434 published January 22, 1998;October 1997 German Patent Application Publication No. 97 / 38983 published on 23rd of September 1997; German Patent Application Publication No. 95 / 19774 published on 27th of July 1995; German Patent Application Publication No. 95 / 19970 published on 27th of July 1995; German Patent Application Publication No. 97 / 13771 published on 17th of April 1997; German Patent Application Publication No. 98 / 02437 published on 22nd of January 1998; German Patent Application Publication No. 98 / 02438 published on 22nd of January 1998; German Patent Application Publication No. 97 / 32881 published on 12th of September 1997; German Patent Application Publication No. 19629652 published on 29th of January 1998; WO 98 / 33798 published August 6; WO 97 / 32880 published September 12, 1997; WO 97 / 32880 published September 12, 1997; EP 682027 published November 15, 1995; WO 97 / 02266 published January 23, 1997; WO 97 / 27199 published July 31, 1997; WO 98 / 07726 published February 26, 1998; WO 97 / 34895 published September 25, 1997;No. 96 / 31510 published on October 10, 1996; No. 98 / 14449 published on April 9, 1998; No. 98 / 14450 published on April 9, 1998; No. 98 / 14451 published on April 9, 1998; No. 95 / 09847 published on April 13, 1995; No. 97 / 19065 published on May 29, 1997; No. 98 / 17662 published on April 30, 1998; No. 100 / 100 / 100 published on August 4, 1998 No. 5,789,427 issued; No. 5,650,415 issued July 22, 1997; No. 5,656,643 issued August 12, 1997; WO 99 / 35146 published July 15, 1999; WO 99 / 35132 published July 15, 1999; WO 99 / 07701 published February 18, 1999, and WO 92 / 20642 published November 26, 1992. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.;

[0158] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand.Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, SM, et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0159] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0160] PI3K inhibitors include wortmannin, the 17-hydroxywortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941, described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ 235, described in WO 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, described in WO 2008 / 070740, LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, available from Axon Medchem), PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (Axon N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride available from Medchem), PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide available from Axon Medchem), GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include 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.

[0161] AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J Nutr. 134 (12 Suppl), 3493S-3498S); perifosine (e.g., interferes with membrane localization of Akt; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64:4394-9).

[0162] TOR inhibitors include, but are not limited to, inhibitors including AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30 and torin 1). Other TOR inhibitors at the FKBP12 enhancer; rapamycin and its derivatives including: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010) and AP23573; rapalogs such as those disclosed in WO 98 / 02441 and WO 01 / 14387, such as AP23573, AP23464 or AP23841; 40-(2-hydroxyethyl) Rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapanycin and other derivatives disclosed in WO 05005434; U.S. Pat. No. 5,258,389; International Publication No. 94 / 090101, International Publication No. 92 / 05179, U.S. Patent No. 5,118,677, U.S. Patent No. 5,118,678, U.S. Patent No. 5,100,883, U.S. Patent No. 5,151,413, U.S. Patent No. 5,120,842, International Publication No. 93 / 111130, International Publication No. 94 / 02136, International Publication No. 94 / 02485, International Publication No. 95 / 140 23, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and derivatives disclosed in U.S. Pat. No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0163] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 110(1):186-192(2007), Thompson et al., Clin.Cancer Res.13(6):1757-1761(2007), and Korman et al., International Application No. PCT / JP2006 / 309606 (International Publication No. WO 2006 / 121168A1), each of which is expressly incorporated herein by reference. These include: Yervoy™ (ipilimumab) or tremelimumab (to CTLA-4), galiximab (to B7.1), BMS-936558 (to PD-1), MK-3475 (to PD-1), AMP224 (to B7DC), BMS-936559 (to B7-H1), MPDL3280A (to B7-H1), MEDI-570 (to ICOS), AMG557 (to B7H2), MGA271 (to B7H3), IMP321 (to LAG-3), BMS-663513 (to CD137), PF-05082566 (to CD137), CDX-1127 (to CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to OX40L), atacicept (to TACI), CP-870893 (to CD40), lucatumumab (to CD40), dacetuzumab (to CD40), muromonab-CD3 (to CD3), ipilimumab (to CTLA-4). Immunotherapies also include engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0164] GITR agonists include GITR fusion proteins described in U.S. Pat. No. 6,111,090box.c, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, WO 2010 / 003118 and WO 2011 / 090754, or GITR fusion proteins described in, for example, U.S. Pat. No. 7,025,962, European Patent No. 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, European Patent No. 1866339, WO 2011 / 028683, WO 2013 / 03995, and the like. Nos. 4, 2005 / 007190, 2007 / 133822, 2005 / 055808, 99 / 40196, 2001 / 03720, 99 / 20758, 2006 / 083289, 2005 / 115451, U.S. Pat. No. 7,618,632, and WO 2011 / 051726, and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies).

[0165] The compounds described herein may be used in combination with the agents disclosed herein or other suitable agents depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present disclosure will be co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration of separate dosage forms, and separate administration. That is, the compounds described herein and any of the agents described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compounds of the present disclosure and any of the agents described above may be administered simultaneously, where both agents are in separate formulations. In another alternative, the compounds of the present disclosure may be administered followed by any of the agents described above, or in the reverse order. In some embodiments of the separate administration protocol, the compounds of the present disclosure and any of the agents described above are administered within minutes, or within hours, or within days.

[0166] As one aspect of the present invention contemplates treating a disease / condition with a combination of pharma- ceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of the present invention, and a second pharmaceutical compound. The kit comprises a container for housing the separate compositions, such as a divided bottle or a divided foil pouch. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing medical professional.

[0167] experiment Abbreviations: The following abbreviations may be used herein:

[0168] [Table 3]

[0169] [Table 4]

[0170] Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. All parts are by weight and temperatures are in degrees Celsius unless otherwise indicated. All microwave assisted reactions were carried out using a Smith Synthesizer™ from Biotage™. All compounds exhibited NMR spectra consistent with their assigned structures. Melting points were determined on a Buchi instrument and are uncorrected. Mass spectral data were measured by electrospray ionization technique. All examples were purified to >90% as determined by high performance liquid chromatography. Reactions were carried out at room temperature unless otherwise noted.

[0171] In synthesizing the compounds of the present invention, the use of certain leaving groups may be desirable. The term "leaving group" ("LG") generally refers to a group that is displaceable by a nucleophile. Such leaving groups are well known in the art. Examples of leaving groups include halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylates, tosylates), sulfides (e.g., SCH 3 ), 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.

[0172] The following examples illustrate specific embodiments of the present invention, and are meant to be representative and are not intended to limit the scope of the claims in any way.

[0173] Note that when percentages (%) are used for liquids, this is the volume percent of the solution. When used for solids, this is the solid composition percent. Materials obtained from commercial sources were typically used without further purification. Reactions involving air or moisture sensitive reagents were typically performed under a nitrogen or argon atmosphere. Purity was determined using a high performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6×150 mm, 5 μm, 100% H2O with 0.1% TFA). 2 5-100% CH in O 3 CN, 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6 × 75 mm, HO with 0.1% formic acid 2 10-90% CH in O 3 CN, 1.0 mL / min for 12 min) (Agilent Technologies, Santa Clara, Calif.). Silica gel chromatography was typically performed using prepacked silica gel cartridges (Biotage, Uppsala, Sweden or Teledyne-Isco, Lincoln, Nebr.). 1 H NMR was recorded at ambient temperature on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, WI) or a Varian (Agilent Technologies, Santa Clara, CA) 400 MHz spectrometer. All observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) or other internal standard in the appropriate solvent specified. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data was determined on an Agilent 1100 Series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm and low-resonance electrospray mode (ESI).

[0174] General synthesis scheme Unless otherwise indicated, the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or are prepared by methods known to those skilled in the art following procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which the compounds of the present invention may be synthesized, and various modifications to these schemes are possible and will be suggested to one of ordinary skill in the art having reference to this disclosure. The starting materials and intermediates of the reactions, as well as the final products, may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0175] Unless otherwise indicated, reactions described herein occur at atmospheric pressure over a temperature range of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably room temperature (or ambient temperature), for example about 20°C.

[0176] For the sake of clarity, in this General Synthesis section, compounds of formula (I) as defined in the Summary of the Invention are prepared by reacting the ring Ar 1 and Ar 2 It can be depicted diagrammatically as including: [ka] In the formula, the group L is -NR 3 , -O-, -S-, S=O, or S(=O) 2 ;X 1 is N or -CR 6 and X 2 is N or -CR 3a and X 3 is N or -CR 3a and X 4 is N or -CR 3c and X 5 is N or -CR 3d and X 6 is N or -CR 3e and X 7 is N or -CR 3f and the ring Ar 1 is located to the left of the linker and is the ring Ar 2 is located to the right of the linker and is a group X 3 ;X 4 ; and X 5 is fused to a ring containing

[0177] In general, compounds of formula (I) can be synthesized via three general steps: Step 1: Ring Ar 1 Preparation of compounds. Step 2: Ring Ar 2 Preparation of compounds. Step 3: Ring Ar 1 Compound ring Ar 2 Combination of compounds.

[0178] The following general Schemes A-C are intended to provide guidance to a synthetic chemist of ordinary skill who will readily appreciate that modifications such as solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like, can be made as necessary and well within the skill and judgment of one of ordinary skill in the art.

[0179] In one embodiment, Schemes A-B below provide a general preparation of compounds of formula (I) having the formula: [ka] which embody compounds of formula (Ia), (Ib), (Ic), and (Id) as described herein: [ka]

[0180] Scheme A: Preparation of compounds (Ia), (Ib), (Ic), and (Id): According to Scheme A, in one embodiment, compounds of formula (Ia), (Ib), (Ic), and (Id) disclosed herein can be synthesized as follows: Step A-1-a: Ring Ar 1 Compound (X 1 is N or -CR 6 and X 2 is N or -CR 3a Preparation of: [ka] Compound A-1(W 1 is a halogen, e.g., fluoro, chloro, bromo) in the presence of a suitable base in a suitable organic solvent, such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, toluene, etc., via metal catalyzed amination using a suitable palladium or copper catalyst and base to give R 2Compound A-1 may be commercially available or may be synthesized by methods known to those skilled in the art. Examples of Compound A-1 include, but are not limited to, 1-bromo-3-methyl-5-nitrobenzene or 1-bromo-5-nitrobenzene. R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethan-1-ol, or (6) 2-amino 3-methylpropan-1-ol. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium tert-butoxide. This step is followed by reduction with Pd / C in the presence of a suitable palladium catalyst and a hydrogen source, such as hydrogen gas, or reduction in the presence of iron to form compound A-2.

[0181] Step A-1-b: Ring Ar 1 Compound (X 1 is N or -CR 6 and X 2 (wherein is N) Preparation of: [ka] Compound A-3(W 1 is halogen, e.g., fluoro, chloro, bromo) in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, etc., in the presence of a suitable base, 2 Compound A-3 may be reacted with a group-containing agent to form compound A-4. Compound A-3 may be commercially available or synthesized by methods known to those skilled in the art. Examples of compound A-3 include, but are not limited to, 6-fluoropyridin-2-amine, 2-chloro-6-methylpyrimidin-4-amine, or 2-chloro-6-methylpyridin-4-amine. R 2Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethan-1-ol, (6) 2-amino 3-methylpropan-1-ol, or (7) 3,3,3-trifluoropropan-1-ol. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0182] Step A-1-c: Ring Ar 1 Compound (X 1 HA-CR 6 and X 2 is N or -CR 3a Preparation of: [ka] Alternatively, compound A-5 (W 1 is a halogen, e.g., chloro, bromo, or iodo) via metal catalyzed amination in the presence of a suitable base in a suitable organic solvent, such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, DMSO, etc., to afford R 13 R has the formula -NH 2 Compound A-5 may be reacted with an inclusion agent (wherein an appropriate palladium or copper catalyst and base are used) to form compound A-6. Compound A-5 is commercially available or can be synthesized by methods known to those skilled in the art. Examples of compound A-5 include, but are not limited to, 3-bromo-5-methylphenol, 3-bromophenol, 3-bromo-4-methylphenol. R 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, (4) 3,3,3-trifluoropropan-1-ol, (5) 2-aminoethan-1-ol, or (6) 2-amino-3-methylpropan-1-ol.

[0183] Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, cesium carbonate, or sodium tert-butoxide.

[0184] Process A-2: Ar 2 Preparation of compounds: [ka] In step A-2, compound A-7 (W 1 , W 2 , and W 3 is independently a halogen, e.g., fluoro, chloro, bromo, or iodo), in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO, or the like, with R such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride. X A reagent can be reacted to form compound A-8, which is then treated with a protected amine compound, such as a PMB-protected amine compound, in the presence of a base, such as diisopropylethylamine or triethylamine, in a suitable organic solvent to give compound A-9. Compound A-9 is then reacted with a deprotecting agent, such as trifluoroacetic acid, to give compound A-10.

[0185] Step A-3-a: Ring Ar 2 Compound with ring Ar 1 Coupling of compounds and subsequent R 1 to form compound (Ia) or (Ib): [ka] In step A-3, the compound A-10 obtained in step A-2 is reacted with a compound represented by the formula CR 3c (OR) 3 (where R 3cCompound A-11 can be formed by reacting with an orthoformate reagent having R 2 (where R is H or methyl) such as triethyl orthoformate in acetic anhydride to form compound A-11, which can be reacted with compound A-2 in the presence of acetic acid to form compound A-12. The skilled synthetic chemist will readily appreciate that other cyclization agents can be used. 1 by conversion reactions such as metal-catalyzed sulfamidation, sulfination, or sulfonylation in the presence of a reagent such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetan-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoacetate, (8) 2-mercaptopropan-1-ol, (9) 2-mercapto-2-methylpropan-1-ol, (10) 2-aminoethan-1-ol, or (11) cyclopropanethiol; 3 Further manipulation of the formula (Ia) or (Ic) can be used to form compound (Ia) or (Ic). One of ordinary skill in the art will readily appreciate that the coupling reaction as shown in step A-3-a can be carried out under a variety of known conditions.

[0186] Step A-3-b: Ring Ar 2 Compound with ring Ar 1 Compound and then R 1 to form compound (Ic) or (Id): [ka] Alternatively, compound A-10 is treated with formic acid at a high temperature in the range of 100°C to 120°C, and then POCl is added in an organic solvent such as toluene. 3 Compound A-14 can be formed by chlorination with a chlorinating agent such as, where R 3cis H. Compound A-14 can then be treated with compound A-4 to give compound (Ic) or (Id) following a procedure similar to that described above in step A-3-a.

[0187] Scheme B: Preparation of compound (Ie): In another embodiment, Scheme B provides a general preparation of compounds of formula (I) having the formula: [ka] ;this is Embodied herein are compounds of formula (Ie): [ka] .

[0188] Step B-1: Ring Ar 1 Preparation of compounds: Ring Ar of compound (Ie) 1 Compounds of formula (I) can be prepared according to the process described in steps A-1-a through A-1-c of Scheme A above.

[0189] Step B-2: Ring Ar 2 Preparation of compounds: [ka] In step B-2, compound B-1 (W 4 and W 5 wherein each of R is independently halo, e.g., fluoro, chloro, bromo, or iodo, in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, DMSO, or the like, with R such as (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride. XReagents can be reacted to form compound B-2, which is then treated with oxalyl chloride followed by diethylamine to form the diethylamide derivative B-3, which is then treated with nBuLi and DMF to form the aromatic aldehyde derivative. B-4 is then reacted with a cyclizing agent such as hydrazine, followed by POCl 3 Chlorination with gives compound B-5.

[0190] Step B-3: Ring Ar 2 Compound with ring Ar 1 Coupling of compounds and subsequent R 1 Formation of compound (Ie) by introduction of: [ka] In step B-3, compound B-5 can be treated with compound A-4 to give compound (Ie) following procedures and conditions similar to those described above in A-3-a.

[0191] Preparation of synthetic intermediates Ring Ar 1 Preparation of intermediates Intermediate 1: 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline [ka] Step 1: A solution of 1-bromo-3-methyl-5-nitrobenzene (10 g, 46.3 mmol) and 4,4-difluoropiperidine hydrochloride (10.9 g, 69.4 mmol) in toluene (50 mL) was added with sodium tert-butoxide (13.3 g, 139 mmol), Pd 2 (dba) 3 (4.24 g, 4.63 mmol) and Xantphos (2.68 g, 4.63 mmol) were added. The reaction mixture was heated at 100° C. for 1.5 h and allowed to cool to room temperature. The reaction mixture was diluted with water and passed through a bed of CELITE®, washing with EtOAc. The organic extract was washed with brine and sodium 2 SO 4It was dried over ice, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 10% to 20% EtOAc in petroleum ether to give 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine (2.3 g, 9.0 mmol, 19% yield) as a grey solid. 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 7.55(t,J=2.3Hz,1H),7.45(s,1H),7.32(d,J=2.3Hz,1H),3.46(t,J=5.8Hz,4H),2.38(s,3H),2.05(tt,J=14.1,5.8Hz,4H).

[0192] Step 2: To a solution of 4,4-difluoro-1-(3-methyl-5-nitrophenyl)piperidine (2.3 g, 9.0 mmol) in EtOH (23 mL) and water (4.6 mL) was added iron powder (5.01 g, 90 mmol) and ammonium chloride (4.80 g, 90 mmol) at room temperature, followed by heating at 80° C. for 16 h. The reaction mixture was cooled to room temperature, filtered through a CELITE® pad, and washed with MeOH. The filtrate was evaporated to dryness and purified by flash column chromatography eluting with 30%-40% EtOAc in petroleum ether to give 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (1.8 g, 8.0 mmol, 89% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 6.00(d,J=1.7Hz,2H),5.89(q,J=1.4Hz,1H),4.81(s,2H),3.20(d,J=11.5Hz,4H),2.09(s,3H),1.94-2.04(m,4H).m / z(ESI):227.2(M+H) + .

[0193] Intermediate 2: 3-Methyl-5-(3,3,3-trifluoropropoxy)aniline [ka] Step 1: To a solution of 3-methyl-5-nitrophenol (2.0 g, 13.1 mmol) and 3,3,3-trifluoropropan-1-ol (6.0 g, 52.2 mmol) in THF (30 mL) was added PPh 3 (13.70 g, 52.2 mmol) was added followed by diethyl (E)-diazene-1,2-dicarboxylate (8.27 mL, 52.2 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 3 h, it was diluted with water and extracted with EtOAc. The organic extract was washed with brine and diluted with Na 2 SO 4 Drying over 100° C., filtration and concentration in vacuo afforded the crude material as an orange oil. Purification by flash column chromatography eluting with a gradient of 0% to 20% in petroleum ether afforded 1-methyl-3-nitro-5-(3,3,3-trifluoropropoxy)benzene (2.3 g, 8.8 mmol, 67% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 7.63-7.66(m,1H),7.51(t,J=2.4Hz,1H),7.24(dt,J=2.4,0.9Hz,1H),4.29(t,J=5.8Hz,2H),2.79(m,2H),2.37-2.41(s,3H).

[0194] Step 2: To a solution of 1-methyl-3-nitro-5-(3,3,3-trifluoropropoxy)benzene (1.3 g, 5.22 mmol) in EtOH (20 mL) and water (2 mL) was added ammonium chloride (1.67 g, 31.3 mmol), iron powder (1.75 g, 31.3 mmol) and HCl (12 N, 2.0 mL, 5.22 mmol). After the reaction mixture was heated at 80° C. for 4 h, it was filtered through a pad of CELITE® and washed with EtOAc. The organic layer was washed with brine and concentrated to 100° C. with 100% NaCl. 2 SO 4 The crude material was purified by flash column chromatography eluting with 5% to 50% EtOAc in petroleum ether to give 3-methyl-5-(3,3,3-trifluoropropoxy)aniline (0.6 g, 2.7 mmol, 52% yield) as a brown oil.1 H NMR (400MHz, DMSO-d 6 ):δppm 6.01(q,J=1.3Hz,1H),5.96(t,J=2.2Hz,1H),5.93(t,J=2.0Hz,1H),4.05(t,J =5.9Hz,2H),2.69(qt,J=11.5,5.9Hz,2H),2.10(s,3H).m / z(ESI):220.1(M+H) + .

[0195] Intermediate 3: 6-(3,3,3-trifluoropropoxy)pyridin-2-amine [ka] A mixture of 6-fluoropyridin-2-amine (1.00 g, 8.92 mmol) and 3,3,3-trifluoropropan-1-ol (2.03 g, 17.84 mmol) in dioxane (15 mL) was treated with NaH (0.86 g, 35.7 mmol) at 0° C. under nitrogen atmosphere and then heated at 90° C. for 2 h. The reaction mixture was quenched with cold water and extracted with EtOAc. The organic extract was washed with brine and diluted with Na 2 SO 4 It was dried over ice, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with 10% to 20% EtOAc in petroleum ether to afford the title compound (1.30 g, 6.31 mmol, 71% yield) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.29(t,J=7.8Hz,1H),6.01(dd,J=7.8,0.7Hz,1H),5.80-5.91(m,3H),4.34( t,J=6.2Hz,2H),2.74(dtd,J=17.7,11.6,6.2Hz,2H).m / z(ESI):207.2(M+H) + .

[0196] Intermediate 4: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine [ka] A mixture of 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) was brought into an autoclave (1 L) and heated at 180° C. for 30 h. The reaction mixture was cooled to room temperature, quenched with water (500 mL) and extracted with EtOAc (2×1000 mL). The organic layer was washed with brine (500 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude material was adsorbed onto a plug of silica gel and purified by column chromatography on silica gel eluting with 50% to 100% EtOAc in hexanes. The product was redissolved in EtOAc (500 mL) and washed with water (2x500 mL). The organic layer was dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The yellow solid was resuspended in hexanes (400 mL) and stirred for 30 min. The slurry was filtered, washed with hexanes (100 mL) and dried under vacuum to give the title compound (58 g, 79% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ ppm 6.33(s,2H),5.63(s,1H),3.80-3.78(dd,J=6.8,4.7Hz,4H),2.06(s,3H),1.95-1.85(tt,J=14.2,5.7Hz,4H).m / z(ESI):229.2(M+H) + .

[0197] Intermediate 5: 2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-amine [ka] A mixture of 2-bromo-6-methylpyridin-4-amine (1.70 g, 9.09 mmol) and 4,4-difluoropiperidine hydrochloride (2.86 g, 18.18 mmol) in NMP (10 mL) was heated at 180° C. for 10 h. The reaction mixture was stirred at 37° C. for 10 h. 2 The mixture was diluted with O and extracted with EtOAc. The organic layer was washed with brine and 2 SO 4 The mixture was dried over ice and concentrated under reduced pressure. SFC [Method: Greensep Silica (250 × 30 mm, 5 μm), 70:30 (liquid CO 2 :20mM NH in MeOH 3 The crude material was purified by )] to afford 2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-amine (1.00 g, 4.40 mmol, 49% yield) as a brown oil. 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 5.85(s,1H),5.79-5.91(m,3H),3.45-3.59(m,4H),2.13(s,3H),1.90-2.01(m,4H).m / z(ESI):228.2(M+H) + .

[0198] Intermediate 6: 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine [ka] Step 1: In an autoclave (3 L) was added 2,6-dichloro-4-methylpyridine (80 g, 490 mmol), 4,4-difluoropiperidine hydrochloride (86 g, 540 mmol), and DIPEA (342 mL, 1980 mmol) in NMP (800 mL). The reaction mixture was heated at 180° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with 10% NaHCO 3 The reaction mixture was basified to pH 9 using aqueous ethyl acetate (1500 mL). The reaction mixture was extracted with EtOAc (2x1500 mL), washed with water (1500 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (60-120 mesh) using 5-10% EtOAc in hexanes to give a 1:3 ratio of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (102 g) as a light brown oil. This mixture (102 g) was purified by column chromatography on silica gel (60-120 mesh) using 5-10% EtOAc in hexanes to give a 1:3 ratio of 2,6-dichloro-4-methylpyridine and 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine as a light brown oil. 3 CN / H 2 Further purification by reverse phase chromatography using O gave 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (70 g, 58% yield) as a light brown liquid. 1 H NMR (400MHz, DMSO-d 6 ):δ 6.76(s,1H),6.57(s,1H),3.66(t,J=5.6Hz,4H),2.22(s,3H),2.03-1.91(m,4H).m / z(ESI):247.1(M+H) + .

[0199] Step 2: To a solution of 2-chloro-6-(4,4-difluoropiperidin-1-yl)-4-methylpyridine (30.0 g, 122 mmol) in 1,4-dioxane (300 mL) was added (4-methoxyphenyl)methanamine (23.8 mL, 182 mmol) and Cs 2 CO 3 (79 g, 240 mmol) was added. The reaction mixture was degassed and purged with nitrogen for 30 min. BINAP (7.57 g, 12.2 mmol) and Pd(OAc) 2 (2.73 g, 12.2 mmol) was added and the reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and filtered through a bed of CELITE®, washing with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was extracted with EtOAc (2×500 mL) and washed with water (500 mL) followed by brine (500 mL). The organic layer was dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using 5-8% EtOAc in hexanes to give 6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (48 g, 76% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d 6 ):δ 7.22(d,J=7.2Hz,2H),6.85(d,J=7.2Hz,2H),6.64(t,J=6.0Hz,1H),5.84(s,1H),5.68(s,1H),4.31(d,J =6.0Hz,2H),3.71(s,3H),3.56(t,J=5.6Hz,4H),2.05(s,3H),1.90-1.80(m,4H).m / z(ESI):348.1(M+H) + .

[0200] Step 3: To a solution of 6-(4,4-difluoropiperidin-1-yl)-N-(4-methoxybenzyl)-4-methylpyridin-2-amine (48.0 g, 138 mmol) in dry DCM (480 mL) was added anisole (30.2 mL, 276 mmol) and TFA (240 mL, 3120 mmol). The reaction mixture was stirred at 55° C. for 4 h and concentrated under reduced pressure. The residue was dissolved in water (200 mL), basified to pH ∼8 with 10% aqueous sodium bicarbonate, and extracted with EtOAc (2×500 mL). The combined organic layers were washed with water (200 mL), followed by brine (200 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel using 25%-35% EtOAc in hexanes to give 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine as a brown oil. This material was purified by elution with 50-60% CH 3 CN / H 2 Purification by reverse phase chromatography using O gave 6-(4,4-difluoropiperidin-1-yl)-4-methylpyridin-2-amine (16.5 g, 72 mmol, 53% yield) as a brown oil. 1 H NMR (400MHz, DMSO-d6 ):δ 5.86(s,1H),5.65(s,1H),5.48(s,2H),3.56(t,J=5.2Hz,4H),2.06(s,3H),1.96-1.87(m,4H).m / z(ESI):228.2(M+H) + .

[0201] Intermediate 7: 3-(4,4-difluoropiperidin-1-yl)-5-methylphenol [ka] 3-Bromo-5-methylphenol (1.00 g, 5.35 mmol), 4,4-difluoropiperidine hydrochloride (1.26 g, 8.02 mmol), K 2 CO 3 A mixture of (1.48 g, 10.69 mmol), copper(I) iodide (0.20 g, 1.07 mmol) and L-proline (0.25 g, 2.14 mmol) in DMSO (10 mL) was heated at 65° C. for 16 h. The reaction mixture was filtered through a bed of CELITE® and washed with EtOAc. The organic layer was washed with brine and diluted with Na 2 SO 4 The crude material was purified by flash column chromatography eluting with 0% to 15% EtOAc in petroleum ether to give 3-(4,4-difluoropiperidin-1-yl)-5-methylphenol (0.20 g, 0.88 mmol, 16% yield) as a brown oil. 1 H NMR (400MHz, DMSO-d 6 ):δppm 9.06(s,1H),6.26(t,J=2.0Hz,1H),6.16(t,J=2.3Hz,1H),5.95-6.11(m,1H ),3.12-3.28(m,4H),2.15(s,3H),1.85-2.09(m,4H).m / z(ESI):228.3(M+H) + .

[0202] Ring Ar 2 Preparation of intermediates Intermediate 8: 2-Amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile [ka] Step 1: A solution of 4-bromo-2,6-difluorobenzonitrile (10 g, 46 mmol) and DIPEA (16 mL, 92 mmol) in DMSO (100 mL) was cooled to 0° C. and then treated with 6-azaspiro[2.5]octane (4.1 g, 36.7 mmol). The reaction mixture was heated at room temperature for 16 h, after which it was diluted with water and extracted with EtOAc. The organic extract was washed with brine and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (CH 3 CN / H 2 Purification by elution with 0.1% TFA in O gave 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (12 g, 39 mmol, 85% yield) as an off-white solid. 1 H NMR (400MHz, chloroform-d): δ ppm 6.93(t,J=1.4Hz,1H),6.88(dd,J=8.1,1.6Hz,1H),3.31-3.40(m,4H),1.59(d,J=1.5Hz,4H),0.40(s,4H).m / z(ESI):309.2(M) + .

[0203] Step 2: To a solution of 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.0 g, 3.2 mmol) and DIPEA (1.13 mL, 6.47 mmol) in NMP (8 mL) was added (2,4-dimethoxyphenyl)methanamine (0.52 g, 3.10 mmol) at room temperature, and the resulting solution was heated at 120° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine and diluted with Na 2 SO 4The mixture was dried over ice, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using 10% to 60% EtOAc in petroleum ether to give 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.05 g, 2.30 mmol, 71% yield) as a white solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.11(d,J=8.4Hz,1H),6.52-6.61(m,2H),6.49(dd,J=8.4,2.4Hz,1H),6.35-6.42(m,2H),4.26(d,J=6.0Hz,2H),3 .85(s,3H),3.74(s,3H),3.10(t,J=5.3Hz,4H),1.47(t,J=5.2Hz,4H),0.33(s,4H).m / z(ESI):456.1 / 458.1(M+H) + .

[0204] Step 3: A solution of 4-bromo-2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.0 g, 2.2 mmol) and anisole (0.60 mL, 5.48 mmol) in TFA (5 mL) was stirred at room temperature for 16 h. The reaction mixture was then diluted with saturated aqueous NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. The organic layer was washed with brine and 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ​​EtOAc in petroleum ether to give 2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.61 g, 1.99 mmol, 91% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 6.87-7.01(s,2H),6.42(s,1H),6.32(d,J=1.8Hz,1H),3.04-3.11(m,4H),1.47(t,J=5.3Hz,4H),0.33(s,4H).m / z(ESI):306.0 / 308.0(M+H)+ .

[0205] Intermediate 9: Ethyl (E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate [ka] A solution of 2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.4 g, 1.3 mmol, intermediate 8) in triethyl orthoformate (5 mL, 30 mmol) was dissolved in AcOEt at room temperature. 2 O (0.1 mL, 1.1 mmol) and then heated at 145° C. for 16 h. The reaction mixture was then concentrated under reduced pressure and ice-cold water was added to give a solid which was filtered to give the title compound (0.4 g, 1.1 mmol, 85% yield) as a brown solid which was carried on directly without further purification. 1 H NMR (400MHz, DMSO-d 6 ):δppm 8.11(s,1H),6.88-7.14(m,2H),4.29(q,J=7.1Hz,2H),3.64-3.83(m,4H),1.49( t,J=5.3Hz,4H),1.33(t,J=7.1Hz,3H),0.35(s,4H).m / z(ESI):362.0 / 364.0(M) + .

[0206] [Table 5]

[0207] Intermediate 10: 2-Amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile. [ka] Step 1: To a solution of 4-bromo-2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (2.1 g, 6.8 mmol) in DMSO (1.6 mL), tetrabutylammonium bromide (2.41 g, 7.47 mmol), 1,10-phenanthroline (0.184 g, 1.019 mmol), palladium(II) acetate (0.076 g, 0.340 mmol), triphenylphosphine (0.267 g, 1.019 mmol), sodium formate (1.02 g, 14.94 mmol), and dipotassium disulfite (3.02 g, 13.58 mmol) were added at room temperature and heated at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, iodomethane (0.64 mL, 10.19 mmol) was added to it and stirred at room temperature for 16 hours. The resulting reaction mixture was filtered through a pad of CELITE® and washed with EtOAc. The organic layer was washed with brine, filtered and concentrated to give the crude material which was purified by flash column chromatography eluting with a gradient of 20% to 25% in petroleum ether to give 2-fluoro-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.68 g, 2.21 mmol, 32% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 7.36-7.46(m,2H),3.37-3.46(m,4H),3.34(s,3H),1.49-1.56(m,4H),0.39(s,4H).m / z(ESI):309.1(M+H) + .

[0208] Step 2: To a mixture of 2-fluoro-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.65 g, 2.11 mmol) and DIPEA (1.11 mL, 6.32 mmol) in NMP (6.5 mL) was added (2,4-dimethoxyphenyl)methanamine (0.38 g, 2.27 mmol) at room temperature and then heated at 125° C. for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, filtered and concentrated to give the crude material, which was purified by flash column chromatography eluting with a gradient of 0% to 20% in petroleum ether to give 2-((2,4-dimethoxybenzyl)amino)-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.68 g, 1.49 mmol, 71% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.14(d,J=8.4Hz,1H),6.85(t,J=6.1Hz,1H),6.69(dd,J=17.5,1.5Hz,2H),6.57(d,J=2.4Hz,1H),6.49(dd,J=8.4,2.4Hz,1H),4.34( d,J=6.0Hz,2H),3.84(s,3H),3.74(s,3H),3.20-3.18(m,4H),2.70(s,3H),1.50(t,J=5.3Hz,4H),0.36(s,4H).m / z(ESI):456.1(M+H) + .

[0209] Step 3: To a solution of 2-((2,4-dimethoxybenzyl)amino)-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.66 g, 1.45 mmol) in TFA (3.3 mL, 42.8 mmol) was added anisole (0.37 mL, 3.62 mmol) at room temperature and stirred for 6 h. The reaction mixture was evaporated to dryness and diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. 2 SO 4The mixture was dried over ice, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using 20% ​​EtOAc in petroleum ether to give 2-amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.41 g, 1.31 mmol, 90% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 6.89(d,J=1.5Hz,1H),6.60(d,J=1.6Hz,1H),6.49(s,2H),3.18(d,J=7.4Hz,7H),1.50(t,J=5.3Hz,4H),0.35(s,4H).m / z(ESI):306.0(M+H) + .

[0210] Intermediate 11: 2-Amino-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile [ka] Step 1: To a solution of 2,6-difluorobenzonitrile (2.0 g, 14.4 mmol) in DMSO (50 mL), DIPEA (5.0 mL, 28.8 mmol) and 6-azaspiro[2.5]octane (1.28 g, 11.50 mmol) were added at 0° C. and then stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted into EtOAc. The organic extract was washed with brine and diluted with Na 2 SO 4 The crude material was purified by flash column chromatography eluting with a gradient of 0% to 5% EtOAc in petroleum ether to give 2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.86 g, 8.08 mmol, 56% yield) as a colorless viscous liquid. 1 H NMR (400MHz, DMSO-d 6 ):δ ppm 7.60(td,J=8.4,7.1Hz,1H),6.91-7.03(m,2H),3.22-3.30(m,4H),1.47-1.54(m,4H),0.36(s,4H).m / z(ESI):231.2(M+H) + .

[0211] Step 2: To a solution of 2-fluoro-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.81 g, 7.82 mmol) in NMP (20 mL), DIPEA (4.10 mL, 23.45 mmol) and (2,4-dimethoxyphenyl)methanamine (1.44 g, 8.60 mmol) were added at room temperature and then heated at 145° C. for 30 h. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The organic extract was washed with brine (100 mL) and Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated in vacuo to give the crude material as an orange oil. This material was purified by flash column chromatography eluting with a gradient of 0% to 4% in petroleum ether to give 2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.7 g, 4.5 mmol, 58% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.18(t,J=8.2Hz,1H),7.08(d,J=8.4Hz,1H),6.57(d,J=2.4Hz,1H),6.46(dd,J=8.4,2.4Hz,1H),6.28(d,J=7.9Hz,1H),6.11-6.21(m ,2H),4.27(d,J=6.0Hz,2H),3.83(s,3H),3.73(s,3H),3.03-3.11(m,4H),1.49(t,J=5.3Hz,4H),0.33(s,4H).m / z(ESI):378.2(M+H) + .

[0212] Step 3: To a solution of 2-((2,4-dimethoxybenzyl)amino)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.7 g, 4.50 mmol) in DCM (20 mL) was added TFA (1.74 mL, 22.52 mmol) dropwise at 0° C. and stirred at room temperature for 16 h. The reaction mixture was then evaporated to dryness, diluted with water and washed with saturated NaHCO 3溶 The mixture was neutralized with ethyl acetate and extracted with DCM. The organic layer was separated and 2 SO 4The mixture was dried over ice, filtered and evaporated to give 2-amino-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile as an orange semi-solid which was used in the next step without purification. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.15(t,J=8.1Hz,1H),6.37(dd,J=8.4,0.9Hz,1H),6.22(dd,J=8.0,0.9Hz,1H),5.8 5(s,2H),3.22-3.30(m,4H),1.47-1.54(m,4H),0.36(s,4H).m / z(ESI):228.1(M+H) + .

[0213] Intermediate 12: 7-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine [ka] To a solution of ethyl (E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate (0.2 g, 0.55 mmol, Intermediate 9) in acetic acid (1.9 mL) was added 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (0.125 g, 0.55 mmol, Intermediate 1) at room temperature and then stirred at 125° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine and diluted with Na 2 SO 4 The crude product was purified by flash column chromatography eluting with 20% EtOAc in petroleum ether to give 7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine as a yellow solid (54 mg, 18% yield). 1 H NMR (400MHz, DMSO-d 6):δppm 12.73(s,1H),8.55(s,1H),7.76(d,J=1.9Hz,1H),7.65(d,J=2.0Hz,1H), 7.42(s,1H),7.15(t,J=2.0Hz,1H),6.66(s,1H),3.35-3.43(m,4H),2.98( td,J=11.8,2.5Hz,2H),2.52(s,3H),2.23(d,J=9.5Hz,2H),2.03-2.14(m ,6H),1.93-2.05(m,2H),0.35-0.48(m,4H).m / z(ESI):542.1 / 544.1(M+H) + .

[0214] [Table 6]

[0215] Example 100: N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide [ka] To a solution of 7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.125 g, 0.230 mmol, intermediate 12) and 2-hydroxyethane-1-sulfonamide (0.058 g, 0.461 mmol) in DMF (2 mL) was added potassium phosphate tripotassium (0.147 g, 0.691 mmol), copper(I) iodide (0.088 g, 0.461 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.033 g, 0.230 mmol) at room temperature and heated at 95° C. for 16 h. The reaction mixture was filtered through a CELITE® pad and washed with EtOAc. The combined organic extracts were washed with brine and Na 2 SO 4The crude product was purified by preparative HPLC [Sun fire C-18 (150x19) mm, 5.0 μm, CH 3 0.1% TFA / H in CN 2 0] to give N-(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide 2,2,2-trifluoroacetate (0.03 g, 0.04 mmol, 19% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 13.28(s,1H),10.86(s,1H),8.84(s,1H),7.39-7.47(m,2H),7.25(s,1H),7.11(t,J=2 .1Hz,1H),6.83(s,1H),4.98(s,1H),3.81(t,J=6.1Hz,2H),3.50(t,J=6.1Hz,2H),3.41 (t,J=5.7Hz,4H),3.26(d,J=11.0Hz,2H),2.87(dd,J=12.8,10.2Hz,2H),2.33(s,3H),1 .99-2.22(m,6H),1.10(d,J=13.3Hz,2H),0.42(q,J=3.2Hz,4H).m / z(ESI):587.2(M+H) + .

[0216] [Table 7]

[0217] Example 101: N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine [ka] Step 1: A solution of 2-amino-4-(methylsulfonyl)-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (0.41 g, 1.34 mmol, Intermediate 10) in triethyl orthoformate (2.0 mL, 12 mmol) was added with Ac 2 2H (0.1 mL, 1.06 mmol) was added at room temperature and then heated at 140 °C for 16 h. The reaction mixture was evaporated to dryness and ice-cold water was added. The resulting solid was filtered and dried under suction to give ethyl (E)-N-(2-cyano-5-(methylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate (0.41 g, 1.13 mmol, 84% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 8.21(s,1H),7.28(d,J=1.5Hz,1H),7.22(d,J=1.5Hz,1H),4.33(q,J=7.0Hz,2H),3.29(s,3H),3.28(d d,J=6.4,4.5Hz,4H),1.53(t,J=5.3Hz,4H),1.35(t,J=7.1Hz,3H),0.37(s,4H).m / z(ESI):362.1(M+H) + .

[0218] Step 2: 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (0.121 g, 0.537 mmol, intermediate 1) was added to a solution of ethyl (E)-N-(2-cyano-5-(methylsulfonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate (0.19 g, 0.54 mmol) in AcOH (2 mL) at room temperature and heated at 125° C. for 1 h. Water was then added to the reaction mixture and extracted with EtOAc. The organic layer was concentrated to Na 2 SO 4 The mixture was dried over ice, filtered and evaporated. The crude product was purified by preparative HPLC [X-Select C18 (250x19) mm, 5 μm, CH 3 0.1% TFA / H in CN 20] to give N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-7-(methylsulfonyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine 2,2,2-trifluoroacetate (0.18 g, 0.27 mmol, 51% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 13.44(s,1H),8.88(s,1H),8.03-8.09(m,2H),7.37(s,1H),7.17(t,J=2. 0Hz,1H),6.80(s,1H),3.39-3.43(m,7H),3.25-3.32(m,2H),3.10(dd,J= 12.7,10.1Hz,2H),2.34(s,3H),2.18-2.28(m,2H),2.07(tt,J=14.0,5.6 Hz,4H),1.11(d,J=13.3Hz,2H),0.44-0.42(m,4H).m / z(ESI):542.2(M+H) + .

[0219] [Table 8]

[0220] Examples 102-1 and 102-2: (R)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone (Example 102-1) and (S)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone (Example 102-2) [ka] Step 1: 1,2-Dicyclopropyldisulfane (2.0 g, 13.7 mmol) in Et 2 LiAlH in O (20 mL) solution 4 (Et2 2H2O (4.0 M, 3.42 mL, 13.67 mmol) was added dropwise under nitrogen atmosphere at 0° C. and stirred at 0° C. for 1 h. The reaction mixture was diluted with Et 2 Dilute with saturated NH 4 Quench with aqueous Cl and Et 2 The combined organic extracts were washed with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated in vacuo to give crude cyclopropanethiol (0.44 g, 5.90 mmol) as a colorless liquid, which was used for the next reaction. A solution of 7-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.32 g, 0.59 mmol, Intermediate 12) and DIPEA (0.41 mL, 2.36 mmol) in dioxane (3.2 mL) was added with Xantphos (0.068 g, 0.118 mmol), Pd 2 (dba) 3 (0.054 g, 0.059 mmol) and cyclopropanethiol (0.437 g, 5.90 mmol) were added and the resulting mixture was heated at 90° C. for 16 h. The reaction mixture was diluted with EtOAc and passed through a bed of CELITE®, washing with EtOAc. The organic layer was extracted with Na 2 SO 4 The crude product was purified by flash column chromatography using a gradient of 20% EtOAc in petroleum ether to give 7-(cyclopropylthio)-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.30 g, 0.56 mmol, 95% yield) as a light brown solid. 1 H NMR (400MHz, DMSO-d 6):δppm 12.74(s,1H),8.50(s,1H),7.53(d,J=1.8Hz,1H),7.44(s,1H),7.36(d,J=1.9Hz,1H),7.15 (s,1H),6.63(s,1H),3.39(t,J=5.7Hz,4H),3.30(d,J=10.0Hz,2H),3.17(d,J=11.0Hz,2H) ,2.20-2.33(m,5H),2.07(tt,J=14.0,5.5Hz,4H),1.16-1.29(m,2H),1.06(t,J=11.4Hz,2H ),0.78-0.89(m,1H),0.67(dt,J=6.7,4.4Hz,2H),0.35-0.47(m,4H).m / z(ESI):536.2(M+H) + .

[0221] Step 2: To a solution of 7-(cyclopropylthio)-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.27 g, 0.50 mmol) in MeOH (2.7 mL) was added phenyl-13-iodanediyl diacetate (0.49 g, 1.51 mmol) and ammonium carbonate (0.29 g, 3.02 mmol) at room temperature and stirred for 4 h. The reaction mixture was evaporated, diluted with water and extracted into EtOAc. The combined organic extracts were washed with brine and diluted with Na 2 SO 4 After drying, filtration and concentration, the crude product was obtained as a black viscous oil. This material was purified by flash column chromatography eluting with 60%-70% EtOAc in petroleum ether to give cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone (0.08 g, 0.14 mmol, 28% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6):δppm 12.87(s,1H),8.65(s,1H),7.99(d,J=1.8Hz,1H),7.87(d,J=1.8Hz,1H),7.45(s,1H),7 .18(t,J=2.1Hz,1H),6.68(s,1H),4.61(s,1H),3.41-3.40(s,4H),3.25(d,J=11.0Hz,2H ),3.00(t,J=11.4Hz,2H),2.89(m,1H),2.54(s,3H),2.43-2.48(m,2H),2.08(td,J=13. 9,7.0Hz,4H),0.96-1.13(m,2H),0.91-1.00(m,2H),0.44(s,4H).m / z(ESI):567.3(M+H) + The racemic mixture was subjected to chiral preparative SFC using a Chiralpak AD (250x21mm, 5mm) column in 50% liquid CO 2 and 50% IPA mobile phase to obtain 25 mg of (R)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone (peak 1, Example 102-1), 1 H NMR (400MHz, DMSO-d 6 ):δppm 12.87(s,1H),8.65(s,1H),7.99(d,J=1.8Hz,1H),7.87(d,J=1.8Hz,1H),7.45(s,1H),7 .18(t,J=2.1Hz,1H),6.68(s,1H),4.61(s,1H),3.41-3.40(s,4H),3.25(d,J=11.0Hz,2H ),3.00(t,J=11.4Hz,2H),2.89(m,1H),2.54(s,3H),2.43-2.48(m,2H),2.08(td,J=13. 9,7.0Hz,4H),0.96-1.13(m,2H),0.91-1.00(m,2H),0.44(s,4H).m / z(ESI):567.3(M+H) +and 24 mg of (S)-cyclopropyl(4-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)(imino)-16-sulfanone (Peak 2, Example 102-2), 1 H NMR (400MHz, DMSO-d 6 ):δppm 12.87(s,1H),8.65(s,1H),7.99(d,J=1.8Hz,1H),7.87(d,J=1.8Hz,1H),7.44(s,1H),7 .17(t,J=2.1Hz,1H),6.68(s,1H),4.61(s,1H),3.43-3.40(s,4H),3.26(d,J=11.0Hz,2H ),3.00(t,J=11.4Hz,2H),2.85(m,1H),2.55(s,3H),2.41-2.48(m,2H),2.08(td,J=13. 9,7.0Hz,4H),0.96-1.13(m,2H),0.91-1.00(m,4H),0.44(s,4H).m / z(ESI):567.3(M+H) + . was obtained.

[0222] The stereochemistry of examples 102-1 and 102-2 has been arbitrarily assigned.

[0223] Example 103: 2-Hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide) [ka] Step 1: A solution of ethyl IN-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate (0.35 g, 0.97 mmol, Intermediate 9) and 3-methyl-5-(3,3,3-trifluoropropoxy)aniline (0.21 g, 0.97 mmol, Intermediate 2) in AcOH (2 mL, 35 mmol) was heated at 100° C. for 2 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic layer was washed with water, brine and concentrated with Na2 SO 4 The crude material was purified by flash column chromatography eluting with a gradient of 30% to 35% in petroleum ether to provide 7-bromo-N-(3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (220 mg, 31% yield). m / z (ESI): 535.1 (M) + .

[0224] Step 2: To a solution of 7-bromo-N-(3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.220 g, 0.411 mmol) and 2-hydroxyethane-1-sulfonamide (0.062 g, 0.493 mmol) in DMF (4 mL), potassium phosphate tripotassium (0.174 g, 0.822 mmol) and copper(I) iodide (0.078 g, 0.411 mmol) were added at room temperature, followed by (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.029 g, 0.205 mmol) and the reaction mixture was heated at 100°C for 16 hours. The reaction mixture was passed through a bed of CELITE® and washed with EtOAc. The organic layer was washed with water, brine and Na 2 SO 4 The mixture was dried over ice, filtered and evaporated to dryness. The crude product was purified by reverse phase preparative HPLC (C-18 gold column, CH 3 CN / H 2 3H, gradient 65% to 70%) to give 2-hydroxy-N-(4-((3-methyl-5-(3,3,3-trifluoropropoxy)phenyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)ethane-1-sulfonamide (0.040 g, 0.069 mmol, 17% yield) as an off-white solid. 1 H NMR (400MHz, DMSO-d 6):δppm 10.78(s,1H),8.79(s,1H),7.35-7.45(m,2H),7.31(t,J=2.2Hz,1H),7.2 4(d,J=2.0Hz,1H),6.76(s,1H),5.02(s,1H),4.24(t,J=5.9Hz,2H),3.80 (t,J=6.2Hz,2H),3.21-3.25(m,5H),2.84(m,4H),2.36(s,3H),2.16(t,J =12.0Hz,2H),1.09(d,J=13.3Hz,2H),0.43(m,4H).m / z(ESI):580.2(M+H) + .

[0225] [Table 9]

[0226] Example 104: N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide [ka] Step 1: A solution of ethyl (E)-N-(5-bromo-2-cyano-3-(6-azaspiro[2.5]octan-6-yl)phenyl)formimidate (0.50 g, 1.38 mmol, Intermediate 9) and 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (0.31 g, 1.38 mmol, Intermediate 4) in AcOH (2 mL) was heated at 125° C. for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and concentrated with Na 2 SO 4The crude material was purified by flash column chromatography eluting with 0% to 30% EtOAc in petroleum ether to give 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.15 g, 0.28 mmol, 20% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 13.67(s,1H),8.76(s,1H),7.89-7.88(m,2H),7.76(s,1H),3.95(t,J=5.8Hz,4H),3.19(d,J=11.1Hz,2H),3.05(q, J=12.2,11.3Hz,2H),2.36(s,3H),1.96-2.05(m,4H),1.14-1.26(m,4H),0.38(s,4H).m / z(ESI):544.2 / 546.2(M+H) + .

[0227] Step 2: A mixture of 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.14 g, 0.26 mmol), 2-hydroxyethane-1-sulfonamide (0.048 g, 0.386 mmol), potassium phosphate tripotassium (0.164 g, 0.771 mmol), copper(I) iodide (0.098 g, 0.514 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (0.037 g, 0.257 mmol) in DMF (2 mL) was heated at 90 for 16 h. The reaction mixture was filtered through a pad of CELITE® and washed with EtOAc. The organic layer was washed with brine and concentrated to dryness. 2 SO 4 The mixture was dried over ice, filtered and evaporated to dryness. The crude product was purified by preparative HPLC [Kinetex Evo C-18 (250x30) mm, 5 μm, 0.1% TFA, CH 3 CN / H 20] to give N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide 2,2,2-trifluoroacetate (0.07 g, 0.10 mmol, 39% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 13.86(s,1H),10.74(s,1H),8.90(s,1H),7.86(s,1H),7.46(s,2H),3.95( t,J=5.8Hz,4H),3.80(t,J=6.2Hz,2H),3.48(d,J=12.4Hz,2H),3.22(d,J= 10.8Hz,2H),2.88(t,J=11.5Hz,2H),2.43-2.48(m,2H),2.38(s,3H),2.02 (m,4H),1.03(d,J=12.9Hz,2H),0.40-0.46(m,4H).m / z(ESI):589.2(M+H) + .

[0228] Example 105: N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide: [ka] Step 1: A mixture of formic acid (5 mL) and sulfuric acid (0.2 mL, 3.75 mmol) was heated at 100° C. for 5 min. A solution of 2-amino-4-bromo-6-(6-azaspiro[2.5]octan-6-yl)benzonitrile (1.6 g, 5.2 mmol, intermediate 8) in formic acid (5 mL) was added dropwise to the above mixture at the same temperature for 5 min and heating was continued for 16 h. The reaction mixture was treated with ice and saturated NaHCO 3 The mixture was neutralized with aqueous solution of 1,000 ml of ethyl acetate and extracted with EtOAc (2x). The combined organic extracts were washed with brine and 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure. The residue was extracted with Et 2Trituration with O gave 7-bromo-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4(3H)-one (1.6 g, 4.8 mmol, 92% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 11.96(s,1H),7.99(s,1H),7.27(d,J=1.9Hz,1H),7.02(d,J=2.0Hz,1H),3.04(s,4H),1.53(s,4H),0.32(s,4H).m / z(ESI):334.1 / 336.1(M+H) + .

[0229] Step 2: A solution of 7-bromo-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4(3H)-one (0.35 g, 1.05 mmol) in toluene (7 mL) was treated with phosphorus oxychloride (0.195 mL, 2.094 mmol) and N,N-diethylaniline (0.313 g, 2.094 mmol) at room temperature and heated at 120° C. for 2 h. It was cooled to room temperature and the volatiles were evaporated under reduced pressure to give a crude residue which was co-distilled with toluene to give 7-bromo-4-chloro-5-(6-azaspiro[2.5]octan-6-yl)quinazoline as a brown solid (0.43 g), which was used directly for the next step without further purification. m / z (ESI): 352.1 / 354.1 (M+H). + .

[0230] Step 3: A glass microwave vial was successively charged with 7-bromo-4-chloro-5-(6-azaspiro[2.5]octan-6-yl)quinazoline (0.21 g, 0.57 mmol), 2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-amine (0.16 g, 0.68 mmol, intermediate 5) and DIPEA (0.099 mL, 0.567 mmol) in NMP (6 mL) and subjected to microwave irradiation at 150° C. for 4 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic extracts were washed with brine and diluted with Na 2 SO 4The crude material was absorbed onto a plug of silica gel and purified by flash column chromatography eluting with a gradient of 0% to 30% in petroleum ether to give 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.045 g, 0.083 mmol, 15% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 12.92(s,1H),8.68(s,1H),7.83(d,J=2.0Hz,1H),7.71(d,J=1.9Hz,1H),7.27(d,J=7.6Hz,1H),7.18(s,1H),3.70(s,4H),2.99(t,J=12.0Hz,2 H),2.56(q,J=1.9Hz,2H),2.43-2.48(m,2H),2.27(s,3H),2.02-2.04(s ,4H),0.85(s,2H),0.42(d,J=8.9Hz,4H).m / z(ESI):543.1 / 545.1(M+H) + .

[0231] Step 4: A solution of 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-4-amine (0.04 g, 0.07 mmol), 2-hydroxyethane-1-sulfonamide (0.014 g, 0.110 mmol), potassium phosphate tripotassium (0.047 g, 0.221 mmol), copper(I) iodide (0.028 g, 0.147 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (10 mg, 0.074 mmol) in DMF (2 mL) was heated at 95°C for 16 h. The reaction mixture was filtered through a pad of CELITE® and washed with EtOAc. The combined organic extracts were washed with brine and diluted with Na 2 SO 4 The mixture was dried over ice, filtered and evaporated in vacuum. The crude product was purified by preparative HPLC [Kinetex EVO C18 (250x21.2) mm, 5 μm, 0.1% TFA CH 3CN / H 2 0] to afford N-(4-((2-(4,4-difluoropiperidin-1-yl)-6-methylpyridin-4-yl)amino)-5-(6-azaspiro[2.5]octan-6-yl)quinazolin-7-yl)-2-hydroxyethane-1-sulfonamide 2,2,2-trifluoroacetate (0.014 g, 0.020 mmol, 27% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ):δppm 13.23(s,1H),10.70(s,1H),8.83(s,1H),7.45(q,J=2.1Hz,3H),7.27(s,1H) ),3.69-3.84(m,6H),3.47(t,J=6.2Hz,2H),3.23(d,J=10.9Hz,2H),2.86(t, J=11.5Hz,2H),2.46(dq,J=3.7,2.1Hz,2H),2.23(t,J=11.9Hz,2H),2.12-2. 18(m,6H),1.09(d,J=13.3Hz,2H),0.39-0.48(m,4H).m / z(ESI):588.3(M+H) + .

[0232] [Table 10]

[0233] Example 106: N-(1-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide. [ka] Step 1: To a solution of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (4 g, 12.9 mmol) in DCM (100 mL) was added oxalyl chloride (2.26 mL, 25.8 mmol) followed by DMF (0.20 mL, 2.58 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and co-distilled with toluene to give crude 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (4.2 g, 12.8 mmol, 99% yield) as a yellow solid, which was carried on to the next step without further purification.

[0234] Step 2: A solution of diethylamine (1.87 g, 25.6 mmol) in dioxane (100 mL) was added with Et 3 N (7.13 mL, 51.1 mmol) was added followed by 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (4.2 g, 12.8 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 16 h, it was quenched with cold water and extracted with EtOAc. The organic layer was washed with water, brine and Na 2 SO 4 It was dried over ice, filtered, and concentrated under reduced pressure to give 4-bromo-N,N-diethyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.5 g, 12.3 mmol, 96% yield) as a light brown syrup, which was carried onto the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 ):δppm 7.21(d,J=7.7Hz,2H),7.03-7.08(m,1H),3.55(s,3H),3.07-3.22(m,3H),2.82(ddd,J=11.0,7.0, 3.6Hz,2H),1.32-1.48(m,4H),1.17(t,J=7.1Hz,3H),0.94(t,J=7.1Hz,3H),0.31(d,J=1.9Hz,4H).

[0235] Step 3: A solution of 2,2,6,6-tetramethylpiperidine (0.97 g, 6.84 mmol) in THF (20 mL) was cooled to -78 °C and treated with n-BuLi (2.5 M solution in hexane, 2.74 mL, 6.84 mmol). The reaction mixture was stirred at the same temperature for 30 min, and then a solution of 4-bromo-N,N-diethyl-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.0 g, 2.7 mmol) in THF (10 mL) was added dropwise to it. The resulting brown solution was stirred at the same temperature for 45 min, and then DMF (1.06 mL, 13.69 mmol) was added dropwise to it at the same temperature. The reaction mixture was stirred for 1 h and then diluted with saturated NH 4 The aqueous layer was extracted with EtOAc, washed with brine, and 2 SO 4 After drying over 50° C. and concentration under reduced pressure, 4-bromo-N,N-diethyl-2-formyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (1.1 g crude) was obtained as a light brown gum. The crude product was carried onto the next step without further purification. m / z (ESI): 393.1 / 395.1 (M+H). + .

[0236] Step 4: To a solution of 4-bromo-N,N-diethyl-2-formyl-6-(6-azaspiro[2.5]octan-6-yl)benzamide (3.4 g, 8.6 mmol) in AcOH (12 mL), hydrazine hydrate (0.86 g, 17.29 mmol) was added at room temperature and heated to 110° C. for 24 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with 10% NaHCO 3 Solution, washed with brine, Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ​​EtOAc in petroleum ether to give 6-bromo-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1(2H)-one (0.5 g, 1.5 mmol, 17% yield) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d 6):δ ppm 12.29(s,1H),8.11(s,1H),7.32(d,J=1.9Hz,2H),3.10-3.20(m,4H),1.55(br s,4H),0.34(s,4H).m / z(ESI):334.1 / 336.1(M) + .

[0237] Step 5: To a solution of 6-bromo-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1(2H)-one (0.4 g, 1.2 mmol) in toluene (8 mL), phosphorus oxychloride (0.223 mL, 2.394 mmol) and N,N-diethylaniline (0.357 g, 2.394 mmol) were added at room temperature. After heating the resulting mixture at 120° C. for 2 h, it was evaporated under reduced pressure and the residue was co-distilled with toluene to give 6-bromo-1-chloro-8-(6-azaspiro[2.5]octan-6-yl)phthalazine as a brown solid (0.6 g). The crude material was carried to the next step without further purification.

[0238] Step 6: A mixture of 6-bromo-1-chloro-8-(6-azaspiro[2.5]octan-6-yl)phthalazine (0.30 g, 0.85 mmol) and 3-(4,4-difluoropiperidin-1-yl)-5-methylaniline (0.385 g, 1.701 mmol) in tert-butanol (2.5 mL) was heated at 90° C. for 16 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC [Kinetex EVO C-18 (250×21.2) mm, 5 μm, CH 3 0.1% TFA / H in CN 2 0] to give 6-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1-amine (0.06 g, 0.11 mmol, 13% yield) as a light brown solid. 1 H NMR (400MHz, DMSO-d 6):δppm 13.34(s,1H),8.99(s,1H),8.34(q,J=1.9Hz,2H),7.05(s,1H),6.93(s,1H),6.89(s,1H),3.43(t,J=5.7Hz,4H),3.27(d,J=11.4 Hz,2H),3.10(t,J=11.4Hz,2H),2.34(s,3H),2.08-2.15(m,6H),1.07(d,J=13.5Hz,2H),0.40(s,4H).m / z(ESI):542.1 / 544.1(M) + .

[0239] Step 7: A mixture of 6-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-1-amine (0.06 g, 0.111 mmol), 2-hydroxyethane-1-sulfonamide (0.021 g, 0.166 mmol), potassium phosphate tripotassium (0.047 g, 0.221 mmol), copper(I) iodide (0.021 g, 0.111 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (8 mg, 0.055 mmol) in DMF (2 mL) was heated at 95°C for 16 h. The reaction mixture was filtered through a bed of CELITE® and washed with EtOAc. The organic layer was washed with brine and concentrated to dryness. 2 SO 4 The mixture was dried over 1000 ml, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Kinetex EVO C-18 (250x21.2) mm, 5 μm, CH 3 0.1% TFA / H in CN 2 0] to give N-(1-((3-(4,4-difluoropiperidin-1-yl)-5-methylphenyl)amino)-8-(6-azaspiro[2.5]octan-6-yl)phthalazin-6-yl)-2-hydroxyethane-1-sulfonamide as a white solid. 1 H NMR (400MHz, DMSO-d 6): δ ppm 12.97(s,1H),10.93(s,1H),9.05(s,1H),7.72-7.78(m,2H),7.03(t,J=2.1Hz, 1H),6.89(d,J=14.3Hz,2H),3.82(t,J=6.1Hz,3H),3.55(t,J=6.1Hz,2H),3.43( d,J=11.5Hz,4H),3.31(d,J=11.1Hz,2H),2.84-2.95(m,2H),2.34(s,3H),1.99 -2.12(m,6H),1.09(d,J=13.2Hz,2H),0.36-0.46(m,4H).m / z(ESI):587.2(M+H) + .

[0240] Further examples. The following Examples 107 to 140 can be prepared by procedures similar to those of the above examples using commercially available starting materials, or by procedures well known to those skilled in the art.

[0241] [Table 11]

[0242] [Table 12]

[0243] [Table 13]

[0244] [Table 14]

[0245] [Table 15]

[0246] [Table 16]

[0247] Biological Examples The following assays were used to test exemplary compounds of the invention. The data for these examples, which were tested according to the procedures set forth below, are presented in Table A below.

[0248] KIF18A enzyme assay: Microtubule-stimulated ATPase activity assay is used to measure KIF18A enzyme activity after compound treatment. Compounds are serially diluted 2-fold in DMSO (Sigma Inc) over a 22-point concentration range. Recombinant human KIF18A (1-467His tagged) protein is expressed using the baculovirus system and purified by affinity chromatography by Amgen Inc. The concentrations of KIF18A protein, microtubules (MTs) and ATP in the reaction are optimized in a standardized homogeneous enzyme assay using the ADP-Glo™ Kinase / ATPase Assay Kit (Promega Inc). The assay measures the ADP formed from the ATPase reaction. Reaction buffer is prepared [(15 mM Tris, pH 7.5 (Teknova Inc), 10 mM MgCl2 (JT Baker Inc), 0.01% Pluronic F-68 (Life Technologies Inc), 1 μM Taxol (Cytoskeleton Inc), and 30 μg / mL porcine microtubules (Cytoskeleton Inc)]. Compounds and KIF18A protein (30 nM) are added to the prepared reaction buffer and incubated at room temperature for 15 min, followed by addition of ATP (K mAdd 5 μl of ADP-Glo™ Reagent and 2.5 μl of the reaction mixture and incubate at room temperature for an additional 15 min. Add 10 μl of ADP-Glo™ Detection Reagent and incubate at room temperature for 40 min. Read luminescence using an EnVision microplate reader (Perkin Elmer Inc) equipped with an ultra-luminescence module. Fit concentration-response curves and IC2000 were determined using Genedata Screener Software (Standard 15.0.1, Genedata Inc) with a 4-parameter logistic regression fitting model. 50 A judgment was made as to the following.

[0249] Table A provides the compounds exemplified in this application as representative compounds of the present invention and their priority document data as follows: chemical names (named either by ACD software or ChemDraw (Professional 15.0)) and biological data (IC 50 (Unit: μM). Ex.# indicates the example number.

[0250] [Table 17]

[0251] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. Those skilled in the art will understand that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the above description is intended to be illustrative, and not limiting. The scope of the invention should, therefore, be determined not with reference to the above description, but with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0252] All patents, patent applications, and publications cited in this specification are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application, or publication was so indicated.

Claims

1. Formula I: 【Chemistry 1】 or any pharma- ceutically acceptable salt thereof, X １ is N or CR ６ and X ２ is N or CR ３ａ and X ３ is N or CR ３ｂ and X ４ is N or CR ３ｃ and X ５ is N or CR ３ｄ and X ６ is N or CR ３ｅ and X ７ is N or CR ３ｆ and Here, X ３ , X ４ , X ５ and X ６ 3 or less of the R １ is —CN or a group -Z—R ８ where Z is -C ０－４ alk-, -NR ７ --, --NR ７ SO ２ -, -SO ２ N.R. ７ -, -N=S(=O)-(R ７ ) ２ (Here, alternatively, two R ７ can combine with the sulfur atom to which each is 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), -NR ７ -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, C ０－４ alk-O-, -(C=O)-, -(C=O)NR ７ -, -C=N(OH)-, or -NR ７ (C=O), R ２ is a halo or a group -Y-R ９ where Y is -C ０－４ alk-, -NR ａ -, -N(C １－４ alk)-, -NH-(CH ２ ) ０－４ -, -C(=O)NR ａ R ａ (C １－４ alk), -O-(CH ２ ) ０－４ , C ０－４ alk-S-, C ０－４ alk-S=O,C ０－４ alk-S(=O) ２ , -SO ２ N.R. ａ -C ０－４ alk-, -C ０－４ alk-S(=O)(=NH)-, -OC ０－４ alk-, -C ０－４ alk-(C=O)-, -C ０－４ alk-(C═O)—O—, or —N═S(═O)<; L is -NR ３ or -O-, R ３ is H, C １－４ alk or C １－４ Helloalk, R ３ａ H, halo, C １－８ alk or C １－４ Helloalk, R ３ｂ H, halo, C １－８ alk or C １－４ Helloalk, R ３ｃ H, halo, C １－８ alk or C １－４ Helloalk, R ３ｄ H, halo, C １－８ alk or C １－４ Helloalk, R ３ｅ H, halo, C １－８ alk or C １－４ Helloalk, R ３ｆ H, halo, C １－８ alk or C １－４ Helloalk, R ４ H, halo, R ４ａ , or R ４ｂ and R ５ H, halo, C １－８ alk or C １－４ Helloalk, R ６ H, halo, C １－８ alk, C １－４ Haloalk, -O-C １－８ alk, 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 Ｘ teeth, 【Chemistry 2】 is selected from R ７ H, R ７ａ , or R ７ｂ and R ８ H, R ８ａ , or R ８ｂ and R ９ is R ９ａ Or R ９ｂ and R ４ａ , R ７ａ , R ８ａ , and R ９ａ independently, at each occurrence, contains 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; F, Cl, Br, C １－６ alk, C １－４ Haloalk, -OR ａ , -OC １－４ Haloalk, CN, -C(=O)R ｂ , -C(=O)OR ａ , -C(=O)NR ａ R ａ , -C(=NR ａ ) N.R. ａ R ａ , -OC(=O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２－６ alkNR ａ R ａ , -OC ２－６ alkOR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ N.R. 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 ) N.R. ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ , -N(R ａ ) S(=O) ２ N.R. ａ R ａ , -NR ａ C ２－６ alkNR ａ R ａ , -NR ａ C ２－６ alkOR ａ , -C １－６ alkNR ａ R ａ , -C １－６ alkOR ａ , -C １－６ alkN(R ａ ) C(=O)R ｂ , -C １－６ alkOC(=O)R ｂ , -C １－６ alkC(=O)NR ａ R ａ , -C １－６ alkC(=O)OR ａ , R １０ and oxo; R ４ｂ , R ８ｂ , R ８ｂ , and R ９ｂ is independently, at each occurrence, F, Cl, Br, -OR ａ , -OC １－４ C substituted with 0, 1, 2, 3, 4, or 5 groups selected from haloalk, or CN １－６ alk is selected from the group consisting of R １０ independently, at each occurrence, contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S; １－６ alk, C １－４ Haloalk, -OR ａ , -OC １－４ Haloalk, CN, -C(=O)R ｂ , -C(=O)OR ａ , -C(=O)NR ａ R ａ , -C(=NR ａ ) N.R. ａ R ａ , -OC(=O)R ｂ , -OC(=O)NR ａ R ａ , -OC ２－６ alkNR ａ R ａ , -OC ２－６ alkOR ａ , -SR ａ , -S(=O)R ｂ , -S(=O) ２ R ｂ , -S(=O) ２ N.R. 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 ) N.R. ａ R ａ , -N(R ａ ) S(=O) ２ R ｂ , -N(R ａ ) S(=O) ２ N.R. ａ R ａ , -NR ａ C ２－６ alkNR ａ R ａ , -NR ａ C ２－６ alkOR ａ , -C １－６ alkNR ａ R ａ , -C １－６ alkOR ａ , -C １－６ alkN(R ａ ) C(=O)R ｂ , -C １－６ alkOC(=O)R ｂ , -C １－６ alkC(=O)NR ａ R ａ , -C １－６ alkC(=O)OR ａ and oxo; R ａ is independently, at each occurrence, H or R ｂ and R ｂ is independently, in each occurrence, C １－６ alk, phenyl, or benzyl; １－６ alk is halo, -OH, -OC １－４ alk, -NH ２ , -NHC １－４ alk, -OC(=O)C １－４ alk, or -N(C １－４ alk) C １－４ alk, wherein the phenyl or benzyl is substituted with 0, 1, 2 or 3 substituents selected from halo, C １－４ alk, C １－３ Haloalk, -OH, -OC １－４ alk, -NH ２ , -NHC １－４ alk, -OC(=O)C １－４ alk, or -N(C １－４ alk) C １－４ alk is substituted with 0, 1, 2 or 3 substituents selected from

2. R ３ The compound of claim 1 , wherein is H or methyl.

3. R X is 【Chemistry 3】 2. The compound of claim 1 ,

4. R １ is a group -Z-R ８ where Z is -SO ２ , -NHSO ２ -, -SO ２ NH- or -S(=O)(=NH)-, R ８ is H, oxetanyl, cyclopropyl, or R ８ is substituted with 0, 1, 2 or 3 OH groups; １－６ 2. The compound of claim 1, wherein:

5. R １ is a group -Z-R ８ where Z is -NHSO ２ - and R ８ But -CH ２ -CH ２ The compound of claim 1, wherein the radical is -OH.

6. R １ is a group -Z-R ８ where Z is -SO ２ and R ８ The compound of claim 1 , wherein is methyl.

7. R １ is a group -Z-R ８ where Z is -S(=O)(=NH)-, and R ８ The compound of claim 1 , wherein is cyclopropyl.

8. R １ The compound of claim 1 , wherein

9. R ２ is halo or a group -Y-R ９ where Y is absent, -NH-, -NH-(CH ２ ) ０－４ -, or -O-(CH ２ ) ０－４ and R ９ contains 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, and F, Cl, Br, C １－６ alk, C １－４ Haloalk, -OH, -OC １－４ Haroalk, C.N., R. １０ and oxo; or R ９ F, Cl, Br, -OH, -OC １－４ C substituted with 0, 1, 2, 3, 4, or 5 groups selected from haloalk, or CN １－６ 2. The compound of claim 1, wherein:

10. R ２ is a saturated 5- or 6-membered monocyclic ring, wherein each of said rings contains 0, 1, or 2 N atoms and 0 or 1 O atom, and each of said rings is selected from the group consisting of F, Cl, Br, C １－６ alk, C １－４ Haloalk, -OH, -OC １－４ Haroalk, C.N., R. １０ 13. The compound of claim 1 , substituted with 0, 1, 2 or 3 groups selected from:

11. R ２ is F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ 5. The compound of claim 1, which is morpholinyl or piperidinyl substituted with 0, 1, 2, or 3 groups selected from , CN, or oxo.

12. R ２ The compound of claim 1 , wherein is morpholinyl substituted with one, two, or three methyl groups.

13. R ２ The compound of claim 1 , wherein is piperidinyl substituted with 1, 2, or 3 fluoro groups.

14. R ２ but, 【Chemistry 4】 2. The compound of claim 1 ,

15. R ２ is methyl or -O-(CH ２ )-(CH ２ )-CF ３ 2. The compound of claim 1,

16. Z is absent, -NH-, -NHSO ２ -, -SO ２ NH-, -N=S(=O)<(R ａ ) ２ (Here, each R ７ is independently selected from the group consisting of H, methyl, or isopropyl), -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ The compound according to claim 1, which is -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-.

17. R ８ (a) H, (b) F, Cl, Br, -OH, -OCH ３ or cyclopropyl; １－６ alk, or (c) containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, and containing F, Cl, Br, C １－６ alk, C １－４ Haloalk, -C １－６ alkOH, -OH, -OCH ３ , -NH ２ 13. The compound of claim 1, wherein the ring is selected from a saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring substituted with 0, 1, 2, or 3 groups selected from aryl, aryloxy ...

18. R ８ The compound of claim 1, wherein is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiazinanyl.

19. R ３ The compound of claim 1 , wherein

20. R ４ (a) H; (b) C substituted with 0, 1, 2 or 3 OH groups; １－６ 2. The compound of claim 1, wherein the aryl group is selected from (a) aryl, (b) aryl, (c) aryl, (d) aryl, (e) aryl, (f) aryl, (g) aryl, (h) aryl, (i) aryl, (j ...

21. R ４ The compound of claim 1 , wherein is methyl.

22. R ５ The compound of claim 1 , wherein

23. R ６ The compound of claim 1 , wherein is H or F.

24. R ３ａ The compound of claim 1 , wherein is H or F.

25. R ３ｂ The compound of claim 1 , wherein

26. R ３ｃ The compound of claim 1 , wherein

27. R ３ｄ The compound of claim 1 , wherein

28. R ３ｅ The compound of claim 1 , wherein

29. R ３ｆ The compound of claim 1 , wherein

30. below: 【Table 1】 【Table 2】 【Table 3】 2. The compound of claim 1 selected from the group consisting of:

31. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

32. 31. A pharmaceutical composition for use in a method for treating a condition treatable with a KIF18A inhibitor, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 30 or a pharma- ceutical acceptable salt thereof, said method comprising administering said pharmaceutical composition to a patient in need thereof, said condition being selected from (a) solid or blood-borne tumors selected from bladder cancer, endometrial cancer, lung squamous cell carcinoma, 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) leukemia, acute lymphocytic leukemia, acute lymphoblastic ... (c) hematopoietic tumors of the lymphatic system selected from blastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkitt's lymphoma; (d) hematopoietic tumors of the myeloid lineage selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (e) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (f) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (g) cancer selected from the group consisting of melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, or Kaposi's sarcoma.

33. 31. A pharmaceutical composition for use in a method of reducing the size of a solid tumor in a subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 30 or a pharma- ceutical acceptable salt thereof, said method comprising administering said pharmaceutical composition to said subject in need thereof.

34. 31. A pharmaceutical composition for use in a method of treating a cell proliferation disorder in a subject, comprising a therapeutically effective amount of a compound of any one of claims 1 to 30 or a pharma- ceutical acceptable salt thereof, said method comprising administering said pharmaceutical composition to said subject in need thereof.

35. 31. A pharmaceutical composition for use in a method of inhibiting KIF18A in a cell, comprising a compound according to any one of claims 1 to 30, or a pharma- ceutical acceptable salt thereof, said method comprising contacting said cell with said pharmaceutical composition.

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