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 also relates to a chemical compound having the formula (I) TIFF2022513971000167.tif39170, 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 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] The present invention provides a novel class of compounds useful for modulating KIF18A protein, alone or in a bound complex with microtubules, to treat KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliopathologies.

[0009] The compounds provided by the present invention have MT-based KIF18A 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 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): [ka] provides any pharma- ceutically acceptable salt thereof, wherein: X 1 is N or CR 6 and X 2 is N or CR 7 and X 3 is N or CR 8 and X 4 is N or CR 9 and X 1 , X 2 , X 3 , and X 4 Of these, 3 or fewer are N, X 2 , X 3 , and X 4When any of is N, L is -(C=O)-NR 3 -OR-NR 3 -(C=O)-, X 2 , X 3 , and X 4 When all of are not N, L is -(C=O)-NR 3 - and R 1 is the group -ZR 12 and In the formula, Z is -C 0-4 alk-, -NR 11 -, -NR 11 SO2-C 0-4 alk-, -SO2NR 11 -C 0-4 alk-, -NR 11 SO2NR 11 -, -NR 11 SO2NR 11 -C(=O)-O-, -C 0-4 alk-S(=O)(=NH)-, C 0-4 alk-NR 11 -S(=O)(=NH), -C 0-4 alk-S-, -C 0-4 alk-S(=O)-, -C 0-4 alk-SO2-, -O-, -P-, -P(=O), -P(=O)2, -(C=O)-, -(C=O)NR 11 - or -NR 11 (C=O) or Group-ZR 12 is -N=S(=O)-(R 12 )2, wherein two R 12 can alternatively combine with the sulfur atom bonded to each of them to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 2 is a halo or a group -YR 13 wherein Y is -C 0-4 alk-, -N(C 0-1 alk)-C 0-4 alk-, -C(=O)NRa R a (C 1-4 alk)-, -OC 0-4 alk-, -S-, -S=O, -S(=O)2-, -SO2N(C 0-1 alk)-C 0-4 alk-, -N(C 0-1 alk)-SO2-C 0-4 alk-, -C 0-4 alk-S(=O)(=NH)-, -(C=O)-, -C 0-4 alk-(C=O)-O-; or Group -YR 13 is -N=S(=O)-(R 13 )2, wherein two R 13 can alternatively combine with the sulfur atom bonded to each of them to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R 3 is H, methyl, or ethyl; R 4 H, halo, C 1-4 alk or C 1-4 Helloalk, R 5 H, halo, C 1-8 alk or C 1-4 Helloalk, R 6 H, halo, CN, -O-C0-6alk-, R 6a or R 6b and R 7 H, halo, C 1-4 alk or C 1-4 Helloalk, R 8 H, halo, C 1-8 alk or C 1-4 Helloalk, R 9 H, halo, C 1-4 alk or C 1-4 Helloalk, R x teeth, [ka] is selected from the group consisting of R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j Each of these is H, halo, and R. 10k , or R 10l or Or, R 10a and R 10b vs. R 10c and R 10d vs. R 10e and R 10f vs. R 10g and R 10h or R 10i and R 10j Each pair of independently, in combination with the carbon atom bonded to each of them, represents R x and forming a saturated or partially saturated 3-, 4-, 5-, 6-membered monocyclic ring that is spiro to the ring, said 3-, 4-, 5-, 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S, and further comprising no 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 11 is H or C 1-8- alk, R 12 H, halo, R 12a , or R 12b and R 13 is R 13a or R 13b and R 6a , R10k , R 12a , and R 13a is independently, in each occurrence, F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2-6 alkNR a R a , -OC 2-6 alkOR a , -SR a , -S(=O)R b , -S(=O)2R b , -S(=O)2NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O)2R b , -N(R a )S(=O)2NR a R a , -NR a C 2-6 alkNR a R a , -NR a C 2-6 alkOR a , -C 1-6 alkNR a R a , -C1-6 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 14 and oxo; R 6b , R 10l , R 12b , and R 13b is independently, at each occurrence, F, Cl, Br, -C(=O)OR a , -OR a , -C 1-2 Helloalk, -OC 1-4 substituted by 0, 1, 2, 3, 4, or 5 groups selected from haloalk, CN, NH2, NH(CH3), or N(CH3)2; 1-6 alk is selected from the group consisting of R 14 are F, Cl, Br, and C 1-6 alk, C 1-4 Haloalk, -OR a , -OC 1-4 Haloalk, CN, -C(=O)R b , -C(=O)OR a , -C(=O)NR a R a , -C(=NR a )NR a R a , -OC(=O)R b , -OC(=O)NR a R a , -OC 2-6 alkNR a Ra , -OC 2-6 alkOR a , -SR a , -S(=O)R b , -S(=O)2R b , -S(=O)2NR a R a , -NR a R a , -N(R a )C(=O)R b , -N(R a )C(=O)OR b , -N(R a )C(=O)NR a R a , -N(R a )C(=NR a )NR a R a , -N(R a )S(=O)2R b , -N(R a )S(=O)2NR a R a , -NR a C 2-6 alkNR a R a , -NR a C 2-6 alkOR a , -C 1-6 alkNR a R a , -C 1-6 alkOR a , -C 1-6 alkN(R a )C(=O)R b , -C 1-6 alkOC(=O)R b , -C 1-6 alkC(=O)NR a R a , -C 1-6 alkC(=O)OR a and oxo; R a is independently, at each occurrence, H or R b and R b independently, in each occurrence, C 1-6 alk, phenyl, or benzyl; C 1-6 Alk is halo, -OH, -OC 1-4 alk, -NH2, -NHC 1-4 alk, -OC(=O)C 1-4 alk, or -N(C 1-4 alk)C 1-4 alkoxy; phenyl or benzyl is substituted by 0, 1, 2, or 3 substituents selected from halo, C 1-4 alk, C 1-3 Haloalk, -OH, -OC 1-4 alk, -NH2, -NHC 1-4 alk, -OC(=O)C 1-4 alk, or -N(C 1-4 alk)C 1-4 alk is substituted by 0, 1, 2, or 3 substituents selected from

[0011] In embodiment 2, the present invention provides a compound according to the invention, wherein L is -NR 3 -(C=O) and X 1 is CR 6 and X 2 is CR 7 and X 3 is N and X 4 is CR 9 and formula (Ia): [ka] The present invention provides a compound having the formula:

[0012] In embodiment 3, the present invention provides a compound according to the present invention, wherein L is -(C=O)-NR 3 - and X 1 is CR 6 and X 2 is CR 7 and X 3 is CR 8 and X 4is N and has formula (Ib): [ka] The present invention provides a compound having the formula:

[0013] In embodiment 4, the present invention provides a compound according to the present invention, wherein L is -(C=O)-NR 3 - and X 1 is CR 6 and X 2 is CR 7 and X 3 is CR 8 and X 4 is CR 9 and formula (Ic): [ka] The present invention provides a compound having the formula:

[0014] In embodiment 5, the present invention provides a compound according to the present invention, wherein L is -(C=O)-NR 3 - and X 1 is N and X 2 is CR 7 and X 3 is CR 8 and X 4 is CR 9 and formula (Id): [ka] The present invention provides a compound having the formula:

[0015] In embodiment 6, the present invention provides a compound according to the present invention, wherein L is -(C=O)-NR 3 - and X 1 is CR 6 and X 2 is N and X 3 is CR 8 and X 4 is N, and has the formula (Ie): [ka] The present invention provides a compound having the formula:

[0016] In embodiment 7, the present invention provides a compound according to the present invention, wherein L is -(C=O)-NR 3 - and X 1 is CR 6 and X 2 is CR 7 and X 3 is CR 8 and X 4 is N, and the formula (If): [ka] The present invention provides a compound having the formula:

[0017] In embodiment 8, the present invention provides a compound according to any of embodiments 1-7, or a pharma- ceutically acceptable salt thereof, wherein R 3 is H or methyl.

[0018] In embodiment 9, the present invention provides a compound according to any of embodiments 1-8, or a pharma- ceutically acceptable salt thereof, wherein R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j Each of these is H, halo, and C. 1-6 alk or C 1-4 Haloalk is R 10a and R 10b Each of the pairs of R x Forms a saturated 3-, 4-, or 5-membered monocyclic ring that is spiro to the ring, said ring containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S.

[0019] In embodiment 10, the present invention provides a compound according to any of embodiments 1-9, or a pharma- ceutically acceptable salt thereof, wherein R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i, and R 10j is H, methyl, or ethyl; 10a and R 10b Each of the pairs of R x It forms a cyclopropyl, cyclobutyl, or cyclopentyl ring which is spiro to the ring.

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

[0021] In embodiment 12, the present invention provides a compound according to any of embodiments 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein Z is absent, -NH-, -NHSO2-, -O-, -SON2NH-, -S(=O)(=NH)-, -CH2-S(=O)(=NH)-, -SO2-, -CH2-SO2, or CH3(CH)-SO2.

[0022] In embodiment 13, the present invention provides a compound according to any of embodiments 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein R 12 is substituted by 0, 1, 2, or 3 groups selected from a) H, (b) F, (c) F, Cl, Br, -CF3, -C(=O)CH3, -OH, -OCH3, -NH2, cyclopropyl, cyclopropylmethanol, or 3-(trifluoromethyl)-3H-diazirinyl; 1-6 alk, or (d) F, Cl, Br, methyl, ethyl, -CF3, -C 1-6 AlkOH, -OH, -OCH3, -NH 2、 or oxo.

[0023] In embodiment 14, the present invention provides a compound according to any of embodiments 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein R 12 is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxazolidinyl, 1,3-dioxolanyl, or pyrrolidinyl.

[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, comprising a group -ZR 12 is -N=S(=O)-(R 12 )2, wherein two R 12 pairs may alternatively combine with the sulfur atom bonded to each of them to form [ka] and 0, 1, or 2 atoms selected from O and S.

[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 12 Z is -NHSO2- or -SO2NH-; R 12 is cyclopropyl, or R 12 is substituted by 0, 1, 2 or 3 OH groups; 1-6 It is alk.

[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 12 Z is -NHSO2-, and R 12 is -CH2-CH2-OH.

[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 2 is the group -YR 13 Y is absent, -NH-, or -NHSO2-; R 13 is a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or an 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, ethyl, CF, CHOH, -OH, -OCH, -NH, -NH(CH), and oxo, or R 13 are F, Cl, Br, -OH, -OC 1-4 substituted by 0, 1, 2, 3, 4, or 5 groups selected from halo, alk, or CN; 1-6 It is alk.

[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 2 is a saturated 5- or 6-membered monocyclic ring, each of said rings containing 1 or 2 N atoms and 0 or 1 O atom, and each of said rings containing F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -OH, -OC 1-4 Haloalk, CN, R 14 and oxo.

[0029] In embodiment 20, the present invention provides a compound according to any of embodiments 1-19, or a pharma- ceutically acceptable salt thereof, wherein R 2 teeth, (a) F, Br; (b) Group -YR 13 wherein Y is absent or SO2; 13is morpholinyl, oxazolidinyl, oxazolyl, pyrrolidinyl, piperidinyl, azetidinyl, dihydropyranyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, [ka] and each said ring is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, methyl, ethyl, -OH, -OCH3, CH2OH, NH2, NH(CH3) or oxo; 13 or (c) Group -YR 13 wherein Y is NH or -SO2NH-; 13 is substituted by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, methyl, CF3, or -OH; 1-6 alk, the group -YR 13 It is.

[0030] In embodiment 21, the present invention provides a compound according to any of embodiments 1 to 20, or a pharma- ceutically acceptable salt thereof, wherein R 2 is the group -YR 13 wherein Y is absent and R 13 is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, tetrahydrofuranyl, [ka] and Each of the above rings is substituted by 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF, -OH, -OCHF, CN, and oxo; 13 or a group -YR 13 wherein Y is NH, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-; R 13 teeth [ka] or R 13 is F, Cl, Br, methyl, CF 3、 C is substituted by 0, 1, 2, 3, 4, or 5 groups selected from -OH, or CN; 1-6 alk, the group -YR 13 It is.

[0031] In embodiment 22, the present invention provides a compound according to any of embodiments 1 to 21, wherein R 2 teeth, [ka] It is.

[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 morpholinyl or piperidinyl substituted by 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2, 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 1, 2 or 3 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 4 is H or halo.

[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 5 is H.

[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 R 6 is H or F.

[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 7 is substituted by 0, 1, 2, or 3 groups selected from: (a) H; (b) F, Cl, Br, -OH, -OCH3, or cyclopropyl; 1-6 alk; or (c) F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -C 1-6 is selected from saturated, partially saturated, or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2, or 3 groups selected from alkOH, -OH, -OCH3, -NH2, 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 R 6 is H.

[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 7 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 8 is H.

[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 9 is H.

[0043] In embodiment 34, the present invention provides a compound selected from the following, or a pharma- ceutically acceptable salt thereof, or any pharma- ceutically acceptable salt thereof:

[0044] [Table 1]

[0045] [Table 2]

[0046] [Table 3]

[0047] In embodiment 35, the present invention provides a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 31, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

[0048] In embodiment 36, the present invention provides a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering a therapeutically effective amount of a compound described in embodiments 1 to 34, or a composition described in embodiment 35, to a patient in need thereof.

[0049] In embodiment 37, the invention provides the method of embodiment 36, wherein the condition is (a) a solid tumor or tumor of hematological origin 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) a tumor of hematological origin or a tumor of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, or ovarian cancer; (c) hematopoietic tumors of the lymphatic system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) cancer selected from the group consisting of melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0050] In subembodiment 37a, the present invention provides the method of embodiment 36, 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.

[0051] In embodiment 38, 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 1-34, or a composition described in embodiment 35, to a subject in need thereof.

[0052] In embodiment 39, 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 1-34, or a composition described in embodiment 35, to a subject in need thereof.

[0053] In embodiment 40, the present invention provides a method for inhibiting KIF18A in a cell, comprising contacting the cell with a compound described in embodiments 1 to 34, or a pharma- ceutically acceptable salt thereof, or a composition described in embodiment 35.

[0054] In embodiment 41, the present invention provides a method of preparing a compound of formula (I) described herein.

[0055] In embodiment 42, the present invention provides intermediate compounds used in the processes for preparing compounds of formula (I) described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0063] 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.

[0064] Unless otherwise stated, the following definitions apply to terms found in the specification and claims.

[0065] "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. The designation COalk refers to a direct bond. 1-6 Examples of alkyl include, but are not limited to, the following: [ka]

[0066] The term "benzo group", alone or in combination, means the divalent radical CH=, one representation of which is -CH=CH-CH=CH-, which when attached adjacent to another ring forms a benzene-like ring, e.g., tetrahydronaphthylene, indole, etc.

[0067] The terms "oxo" and "thioxo" refer to the groups =O (as in carbonyl) and =S (as in thiocarbonyl), respectively.

[0068] "Halo" or "halogen" means a halogen atom selected from F, Cl, Br, and I.

[0069] "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. 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:

[0070] Group N(C α-β alk)C α-βAs 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:

[0071] "Bicyclic ring" means a group characterized by two joined rings. Bicyclic rings 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). Both rings may be aliphatic (e.g., decalin and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Bicyclic rings include (a) spirocyclic compounds, in which the two rings share only one single atom, a spiroatom, which is usually a quaternary carbon. Examples of spirocyclic compounds include: [ka] (b) Fused bicyclic compounds include, but are not limited to, compounds in which two rings share two adjacent atoms. In other words, the rings share one covalent bond, i.e., the bridgehead atoms are directly connected (e.g., α-thujene and decalin). Examples of fused bicyclic compounds include: [ka] and (c) bridged bicyclic compounds in which two rings share three or more atoms and a bridge containing at least one atom separates the two bridgehead atoms. 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:

[0072] 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.

[0073] "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:

[0074] "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).

[0075] "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.

[0076] "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.

[0077] "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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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).

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] "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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] The term "comprising" is meant to be open-ended, including the indicated components, but not excluding other elements.

[0111] The term "Formula I" includes any subformulas.

[0112] 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.

[0113] 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 hematological origin tumors, such as carcinomas, including but not limited to bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer (including squamous cell lung cancer 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, They are useful in the treatment of: 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).

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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 (e.g., Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), and adriamycin, as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates such as busulfan, improsulfan, and piposulfan; benzodopa, carboquone, metholedopa, cyclosulfonates ... aziridines such as cyclopentasiloxane 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, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, 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.

[0125] 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).

[0126] 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).

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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."

[0135] 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).

[0136] 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).

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.;

[0145] 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.

[0146] MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0147] 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.

[0148] 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).

[0149] 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).

[0150] 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).

[0151] 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).

[0152] 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.

[0153] 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.

[0154] experiment Abbreviations: The following abbreviations may be used herein:

[0155] [Table 4]

[0156] [Table 5]

[0157] 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.

[0158] In the synthesis of 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 can be displaced by a nucleophile. Such leaving groups are well known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylates, tosylates), sulfides (e.g., SCH3), N-hydroxysuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions), and the like.

[0159] 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.

[0160] Note that when percent (%) is used with respect to liquids, it is the volume percent relative to the solution. When used with solids, it 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 measured using a high performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6×150 mm, 5 μm, 5-100% CH3CN in H2O with 0.1% TFA, 1.5 mL / min for 15 min; System B: Zorbax SB-C8, 4.6×75 mm, 10-90% CH3CN in H2O with 0.1% formic acid, 1.0 mL / min for 12 min) (Agilent Technologies, Santa Clara, CA). 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).

[0161] 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.

[0162] 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.

[0163] For the sake of clarity in this general synthesis section, compounds of formula (I) may be prepared by the steps of: 1 and ring Ar 2 It can be depicted diagrammatically as containing: [ka] where the group L is a linker as defined in the Summary of the Invention, i.e. -NR 3 -(C=O)- or -(C=O)-NR 3 and the ring Ar 1 is located to the left of the linker, and the ring Ar 2 is located to the right of the linker.

[0164] 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 Coupling to compounds.

[0165] The general schemes set forth below 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 well within the skill and judgment of one of ordinary skill in the art.

[0166] Scheme A In one embodiment, the compound of formula (I) has the formula (Ia): [ka] Examples of compounds of formula (Ia) include, but are not limited to, the following: [ka]

[0167] Step 1a: Ring Ar 1 Preparation of compounds: Ring Ar1 One embodiment of the compound includes compound A-1 having the formula: [ka] In the formula, the group R 4 and R 5 are independently H, which are commercially available or may be prepared by known methods and reagents by one of ordinary skill in the art. 2 is ZR 12 and Z is -C 0-4 alk-, -NR 11 - or -NR 11 SO2-C 0-4 alk- and R 12 Compounds of formula A-1, wherein A is as defined in the Summary of the Invention, can be prepared from the appropriate starting materials: [ka]

[0168] Step 2a: Ring Ar 2 Preparation of compounds: [ka] Each W in the formula 1 Compound A-2, where A is a halogen, e.g., fluoro or chloro, can be converted to the acid chloride (via SOCl2) followed by addition of the alcohol PG in a suitable organic solvent such as acetonitrile, tetrahydrofuran, methylene chloride, etc. 1 Compound A-3 can be formed by reaction with 4,4-dimethyloxazolidin-2-one in a suitable organic solvent such as tetrahydrofuran, DMF, dioxane, etc., in the presence of a base such as tBuOK to form compound A-4, where W 1is as defined for compound A-2. Compound A-4 is then reacted with an R 1 , such as (1) 6-azaspiro[2.5]octane, (2) 4,4-dimethylpiperidine, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane, or (5) 7-azaspiro[3.5]nonane, in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or the like. x Reaction with a reagent to form compound A-5, which can then be reacted with a suitable deprotecting agent, such as Pd / C in the presence of hydrogen gas to form compound A-6.

[0169] Step 3a: Ring Ar 1 Compound ring Ar 2 Coupling to compounds. [ka] Compound A-6 can then be reacted with an activating agent such as an acid chloride (COCl)2 or SOCl2 in a suitable organic solvent such as tetrahydrofuran, methylene chloride, etc. to form an acid chloride derivative, which can then be reacted with compound A-1 to form compound A-7. Alternatively, compound A-6 can be directly coupled with compound A-1 in the presence of T3P or HATU or TATU to provide compound A-7. Compound A-7 can then be treated with a base such as NaOH to provide compound (Ia).

[0170] Scheme B According to Scheme B, in another embodiment of the present invention, compounds of formula (I) disclosed herein having the following structures (Ib) and (Ic): [ka] can be synthesized as follows:

[0171] In another embodiment, a compound of formula (I) having the following formula (Ib) or (Ic), as defined herein: [ka] can be synthesized according to Scheme B. Examples of compounds of formula (Ib) or (Ic) include [ka] These include, but are not limited to:

[0172] Step 1a: Ring Ar 1 Preparation of Compounds: As shown in Scheme A, compound 1, which is commercially available or can be prepared by known methods and reagents by those skilled in the art, has a ring Ar 1 can be used as an example of a compound.

[0173] Step 2b: Ring Ar 2 Preparation of compounds: [ka] In step 2b, compound B-1 (wherein W 3 and W 4 wherein each of is independently a halogen, e.g., fluoro, chloro, bromo, or iodo) can be reacted with a suitable carboxylic acid protecting group (PG1 reagent) such as methyl iodide in the presence of a base such as potassium carbonate to form a methyl ester, or with other suitable protecting groups to form other esters such as benzyl esters in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, and the like, followed by reaction with a suitable protecting group such as R 1 (PG1 reagent) in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, and the like, such as (1) 6-azaspiro[2.5]octane, (2) 4,4-dimethylpiperidine, (3) 3,4,4-trimethylpiperidine, (4) 4-methyl-6-azaspiro[2.5]octane, or (5) 7-azaspiro[3.5]nonane, x React with a reagent to form compound B-2, where W 4is as defined for compound B-1. Examples of compound B-1 include 4,6-dichloronicotinic acid or 4,6-difluoronicotinic acid. Compound B-2 can then be reacted with a deprotecting agent, which can be a base such as lithium hydroxide, and then mixed with an acid such as HCl to form compound B-3, where W 4 is as defined for compound B-2.

[0174] Step 3b: Ring Ar 1 Compound ring Ar 2 Coupling to compounds. [ka] In step 3b, compound B-3 can then be reacted with compound A-1 in the presence of an activating agent such as 1-propanephosphonic anhydride (T3P) or HATU or TATU, and in the presence of DIPEA in a suitable organic solvent such as EtOAc, DMF, methylene chloride, DCE, and the like, to form compound B-4, where W 4 is as defined for compound B-3. Compound B-4 can then be reacted with 4,4-dimethyloxazolidin-2-one in the presence of a catalyst such as Xantphos and Pd2(dba)3 in a suitable organic solvent such as tetrahydrofuran, DMF, dioxane, and the like to form compound B-5, which can be reacted with a base such as sodium hydroxide to form compound (Ib).

[0175] Step 3b-1: Ring Ar 1 Compound ring Ar 2 Coupling to compounds. [ka] Alternatively, in another embodiment, compound B-4 obtained in step 3b above can be further reacted with 2-hydroxyethane-1-sulfonamide in the presence of a metal catalyst such as CuI, a base (such as KPO), and a ligand such as (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine to form a compound of formula (Ic).

[0176] Scheme C In another embodiment, a compound of formula (I) as defined herein has the following formula (Id): [ka] can be synthesized according to Scheme C. Examples of compounds of formula (Id) include, but are not limited to, the following: [ka]

[0177] Step 1c: Ring Ar 1 Preparation of compounds: Ring Ar 1 One embodiment of the compound includes compound C-1 having the formula: [ka] In the formula, the group R 4 and R 5 are independently H and W 5 is halogen, such as fluoro, chloro, bromo, or iodo, preferably fluoro, which are commercially available or can be prepared by known methods and reagents by one of ordinary skill in the art.

[0178] Step 2b: Ring Ar 2 Preparation of compounds: [ka] In step 2b, compound C-2 (wherein W 6 and W 7 is independently a halogen, e.g., fluoro, chloro, bromo, or iodo), in a suitable organic solvent, such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or the like, with R xReaction with a reagent followed by nitro group reduction can form compound C-3, where W 7 is as defined for compound C-2. Examples of compound C-2 include, but are not limited to, 4-bromo-2-fluoro-1-nitrobenzene.

[0179] Step 3b: Ring Ar 1 Compound ring Ar 2 Coupling to compounds. [ka] In step 3b, compound C-3 can then be reacted with compound C-1 in the presence of an activating agent such as T3P or HATU or TATU in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, methylene chloride, and the like, and in the presence of DIPEA to form compound C-4, where W 7 is as defined for compound C-3. Compound C-4 is then reacted with R 2 Reagents such as CuI to form compound C-4, which can then be reacted with 2-hydroxyethane-1-sulfonamide in the presence of a catalyst such as CuI, a ligand such as dimethylglycine, and a base such as potassium phosphate to form a compound of formula (Id). EXAMPLES

[0180] Ring Ar 1 Preparation of intermediates: Intermediate 1: (S)-6-(2-methylmorpholino)pyridin-2-amine. [ka] A microwave vial was charged with 2-amino-6-fluoropyridine (0.20 g, 1.78 mmol), (S)-2-methyl-morpholine (0.50 mL, 4.40 mmol), and water (0.5 mL). The vial was sealed and heated in a microwave at 205 °C for 30 min. The reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and subsequently purified by silica gel chromatography (0% to 40% EtOAc in heptane) to give (S)-6-(2-methylmorpholino)pyridin-2-amine (1, 0.26 g, 1.32 mmol, 74% yield) as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 1.25(d,J=6.26Hz,3H),2.51(dd,J=12.52,10.37Hz,1H),2.87(td,J=12.28,3.42Hz,1H),3.61-3.76(m,2H),3.88-4.08(m,3H),4.20(br s,2H),5.91(d,J=7.63Hz,1H),5.99(d,J=8.22Hz,1H),7.27-7.33(m,1H).m / z(ESI):194.0(m+H) + .

[0181] [Table 6]

[0182] [Table 7]

[0183] Intermediate 31: 6-Amino-N-(tert-butyl)pyridine-2-sulfonamide. [ka] Step 1. To an ice-cold solution of 6-bromopyridine-2-sulfonyl chloride (0.50 g, 1.95 mmol, Suzhou Sibian, PRChina) in DCM (10 mL) was added triethylamine (0.54 mL, 3.90 mmol) followed by tert-butylamine (0.31 mL, 2.92 mmol). The reaction mixture was stirred at RT for 1.5 h and then treated with water (10 mL). It was extracted with dichloromethane (3×15 mL). The combined organic extracts were washed with brine (15 mL) and dried over anhydrous Na2SO4. The solution was filtered and concentrated under reduced pressure to give the crude material as a pale yellow oil. The crude material was purified by silica gel chromatography (17% to 22% ethyl acetate in petroleum ether) to give 6-bromo-N-(tert-butyl)pyridine-2-sulfonamide (31A, 0.35 g, 1.19 mmol, 61% yield) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.98 (dd, J = 7.6, 0.9 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.65 (dd, J = 8.0, 0.9 Hz, 1H), 4.96 (s, 1H), and 1.27 (s, 9H).

[0184] Step 2. In a 500 mL sealed tube, a mixture of 6-bromo-N-(tert-butyl)pyridine-2-sulfonamide (31A, 14.50 g, 49.50 mmol), N1,N2-dimethylethane-1,2-diamine (0.44 g, 4.95 mmol), K2CO3 (1.36 g, 9.89 mmol), copper(I) iodide (0.47 g, 2.473 mmol), aqueous ammonia (100 mL of 21 wt% solution, 970 mmol), and ethylene glycol (100 mL) was stirred at 60 °C for 18 h. The reaction mixture was cooled to RT, diluted with water (150 mL), and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude material as a pale yellow oil. The crude material was purified by silica gel chromatography (5% to 6% methanol in chloroform) to give 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (31, 6.94 g, 30.3 mmol, 61% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.54(ddd,J=8.4,7.2,1.3Hz,1H),7.21(s,1H),7.03(dt,J=7.3,0.9Hz,1H),6.59( dt,J=8.4,1.0Hz,1H),6.33(s,2H),and 1.12(d,J=1.3Hz,9H).m / z(ESI):230.1(M+H) + .

[0185] Intermediate 32: 4-Methyl-6-morpholinopyridin-2-amine. [ka] To a 250 mL pressure tube was added 6-fluoro-4-methylpyridin-2-amine (10.0 g, 79 mmol, Suzhou Sibian chemicals,PR China), morpholine (8.3 g, 95 mmol), and DIPEA (41.5 mL, 238 mmol). The tube was sealed and heated at 150 °C for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 250 mL). The organic layer was washed with brine (200 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (1% to 15% EtOAc in hexanes) to give the title compound as a brown amorphous solid (32, 8.5 g, 44 mmol, 56% yield). 1 H NMR(400MHz,DMSO-d6)δ5.75(s,1H),5.67(s,1H),5.44(s,2H),3.65(t,J=8.4Hz,4H),3.30(t,J=8.4Hz,4H),2.06(s,3H).m / z(ESI):194.2(M+H) + .

[0186] Intermediate 33: (R)-1-(6-amino-4-methylpyridin-2-yl)piperidin-3-ol. This compound was prepared in a manner similar to that described above for intermediate 32. 1 H NMR(400MHz,chloroform-d)δ ppm 1.50-1.70(m,3H),1.81-1.88(m,2H),2.15(s,3H),3.34-3.56(m,3H),3.61-3.67(m,1H),3.87 (dt,J=6.48,3.29Hz,1H),4.04-4.21(m,2H),5.72(s,1H),5.90(s,1H).m / z(ESI):208.0(M+H) + . [ka]

[0187] Intermediate 34: (R)-5-Fluoro-6-(2-methylmorpholino)pyridin-2-amine. [ka] A mixture of 6-bromo-5-fluoropyridin-2-amine (0.90 g, 4.71 mmol), (R)-2-methylmorpholine (0.48 g, 4.71 mmol), potassium acetate (0.92 g, 9.42 mmol), and copper powder (30 mg, 0.471 mmol) in dimethylsulfoxide (8.10 mL) was heated at 110° C. for 16 h. The reaction mixture was cooled to RT, diluted with water (mL), and extracted with EtOAc (2×10 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude material as a yellow solid. The crude material was purified by silica gel chromatography (0% to 10% EtOAc in hexanes) to give (R)-5-fluoro-6-(2-methylmorpholino)pyridin-2-amine (34, 0.510 g, 2.41 mmol, 51% yield) as a yellow oil. m / z (ESI): 212.0 (M+H). + .

[0188] Intermediate 35: 6-(3,6-Dihydro-2H-pyran-4-yl)pyridin-2-amine. [ka] A pressurized vial was charged with 6-bromopyridin-2-amine (0.30 g, 1.73 mmol, Aldrich) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.73 g, 3.47 mmol, Pharma Core), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.12 g, 0.17 mmol, Aldrich), and potassium phosphate (1.10 g, 5.20 mmol). The vial was purged with N2 for 3 min. 1,4-Dioxane (3.0 mL) and water (0.9 mL) were added. The vial was sealed and heated in a 90 °C oil bath for 1 h. The mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (0% to 50% EtOAc in heptane) to give 6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (35, 0.13 g, 0.73 mmol, 42% yield) as a pale yellow solid. 1 H NMR(400MHz,chloroform-d)δ ppm 2.52-2.60(m,2H)3.91(t,J=5.48Hz,2H)4.32-4.43(m,4H)6.39(d,J=8.02Hz,1H)6.66(tt ,J=2.89,1.52Hz,1H)6.71(d,J=7.43Hz,1H)7.41(t,J=7.83Hz,1H).m / z(ESI):177.0(M+H) + .

[0189] Intermediate 36: 1-(6-aminopyridin-2-yl)pyrrolidin-2-one. [ka] A mixture of 2-amino-6-bromopyridine (402 mg, 2.32 mmol), copper(I) iodide (22 mg, 0.116 mmol), cesium carbonate (1514 mg, 4.65 mmol), N,N-dimethylethylenediamine (0.025 mL, 0.232 mmol), and 2-pyrrolidinone (0.265 mL, 3.49 mmol) in 1,4-dioxane (4 mL) was heated in an oil bath at 110 °C for 18 h. The reaction mixture was cooled to RT, filtered through a pad of Celite, and concentrated. The residue was purified by silica gel chromatography (0% to 40% EtOAc in heptane) to give 1-(6-aminopyridin-2-yl)pyrrolidin-2-one (36, 49 mg, 0.28 mmol, 12% yield) as a white solid. m / z(ESI): 178.0(M+H) + .

[0190] Intermediate 37: 1-(6-aminopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one. This compound was prepared in a manner similar to that described above for intermediate 36. m / z (ESI): 206.0 (M+H) + . [ka]

[0191] Intermediate 38: 6-(piperidin-1-ylsulfonyl)pyridin-2-amine. [ka] Step 1. To a solution of 6-bromo-pyridine-2-sulfonyl chloride (519 mg, 2.023 mmol, J&W Pharma Lab, LLC) in DCM (20 mL) was added N,N-diisopropylethylamine (0.70 mL, 4.05 mmol) and piperidine (0.20 mL, 2.02 mmol, Aldrich). The solution was stirred at RT for 15 h and then loaded onto a silica gel column and eluted with 0-50% EtOAc in heptane to give 2-bromo-6-(piperidin-1-ylsulfonyl)pyridine as a white solid (37A, 585 mg, 1.92 mmol, 95% yield). m / z (ESI): 305.0, 307.0 (m+H). + .

[0192] step 2. To a solution of 2-bromo-6-(piperidin-1-ylsulfonyl)pyridine (37A, 580 mg, 1.90 mmol) and 1,4-dioxane (20 mL) was added 4-methoxybenzylamine (0.248 mL, 1.900 mmol, Aldrich) and N,N-diisopropylethylamine (0.36 mL, 2.09 mmol). The solution was heated in a 100 °C oil bath for 4 days. It was cooled to RT and loaded onto a silica gel column (0% to 50% EtOAc in heptane) to give N-(4-methoxybenzyl)-6-(piperidin-1-ylsulfonyl)pyridin-2-amine (486 mg, 1.34 mmol, 70% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.67(t,J=5.9Hz,1H),7.57(dd,J=8.4,7.2Hz,1H),7.22(m,J=8.6Hz,2H),6.94(d,J=7.0Hz,1H),6.85-6.89(m,2H),6.75(d,J= 8.4Hz,1H),4.41(d,J=5.9Hz,2H),3.71(s,3H),2.88-2.96(m,4H),1.35-1.46(m,4H),1.22-1.31(m,2H).m / z(ESI):362.1(m+H) + .

[0193] Step 3: To a RBF charged with N-(4-methoxybenzyl)-6-(piperidin-1-ylsulfonyl)pyridin-2-amine (486 mg, 1.34 mmol) was added TFA (1 mL, 12.98 mmol). The solution was stirred at 80 °C. After 1.5 h, the reaction mixture was cooled to RT and concentrated in vacuo. The mixture was azeotroped once with toluene (20 mL), then dissolved in EtOAc and washed with sat'd NaHCO3. The EtOAc layer was concentrated in vacuo, adsorbed onto a plug of silica gel, and chromatographed on a Redi-Sep® pre-packed silica gel column (Gold, 4 g) eluting with 0-50% EtOAc in heptane to give 6-(piperidin-1-ylsulfonyl)pyridin-2-amine (38, 315 mg, 1.31 mmol, 97% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.57(dd,J=8.2,7.4Hz,1H),6.94(d,J=7.0Hz,1H),6.63(d,J=8.2Hz,1H),6.52(s,2H),3.07-3.15(m,4H),1.47-1.55(m,4H),1.43(br d,J=4.5Hz,2H).m / z(ESI):242.0(m+H) + .

[0194] Intermediate 39: 6-Amino-N-(tert-butyl)-4-methylpyridine-2-sulfonamide. This compound was prepared in a manner similar to that described for 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31). m / z(ESI):244.0(M+H) + . [ka]

[0195] Intermediate 40: 2-amino-6-morpholinoisonicotinonitrile. [ka] 4-Chloro-6-morpholinopyridin-2-amine (0.5 g, 2.34 mmol, Aldrich), zinc dust (0.061 g, 0.936 mmol, Aldrich), racemic 2-(di-t-butylphosphino)-1,1'-binaphthyl (0.187 g, 0.468 mmol, Strem), zinc cyanide (0.330 g, 2.81 mmol, Aldrich), palladium(II) trifluoroacetate (78 mg, 0.234 mmol, Aldrich), and DMF (4.68 mL) were added to a 20 mL vial. The vial was evacuated and backfilled with nitrogen three times with stirring. The mixture was heated at 120 °C for 15 h. The mixture was purified by chromatography on silica gel (40 g, 0-100% EA in heptane) to give 2-amino-6-morpholinoisonicotinonitrile (intermediate 40, 0.24 g, 1.17 mmol, 50% yield). m / z ESI 205.1 (M+H). + .

[0196] Intermediate 73: 4-Cyclopropyl-6-morpholinopyridin-2-amine. [ka] 4-Chloro-6-morpholinopyridin-2-amine (0.52 g, 2.43 mmol), {1,1'-bis(diphenylphosphino)ferrocene}dichloropalladium(II) (0.356 g, 0.487 mmol), cyclopropylboronic acid (0.042 g, 0.489 mmol), and potassium carbonate (0.673 g, 4.87 mmol) were dissolved in 8:1 dioxane-water (4.87 mL) in a 20 mL vial. The solution was degassed with three vacuum / N2 purges, the vial was sealed, and heated at 80 °C for 24 h to achieve approximately 50% conversion. The reaction mixture was purified by chromatography on silica gel (40 g, 0% to 100% EA in heptane) to give 4-cyclopropyl-6-morpholinopyridin-2-amine (0.30 g, 1.36 mmol, 56% yield). m / z ESI 220.1 (M+H). + .

[0197] Ring Ar 2Preparation of intermediates: Intermediate 41: 2-(6-Azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid. [ka] Step 1. A mixture of methyl 2,6-dichloronicotinate (5.0 g, 24.3 mmol, Combi-Blocks), N,N-diisopropylethylamine (4.7 mL, 26.7 mmol), and 6-azaspiro[2.5]octane (2.70 g, 24.27 mmol, AstaTech, Inc.) in acetonitrile (50 mL) was stirred at RT for 24 h. The mixture was concentrated and the residue was purified by silica gel chromatography (0% to 30% EtOAc in heptane) to give methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (41A, 4.34 g, 15.46 mmol, 64% yield). m / z (ESI): 281.0 (M+H). + .

[0198] Step 2. A mixture of methyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (41A, 4.10 g, 14.60 mmol), tributyl(1-ethoxyvinyl)tin (5.80 g, 16.06 mmol, Aldrich), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.41 g, 0.58 mmol, Aldrich) in toluene (30 mL) was stirred at 90° C. for 16 h. The reaction mixture was cooled to RT and treated with HCl (4 M in dioxane, 18.25 mL, 73.00 mmol) and stirred for 2 h. Subsequently, the reaction mixture was filtered through a pad of Celite and washed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3, dried, filtered, and concentrated. The residue was purified by ISCO (0% to 30% EtOAc in heptane) to give methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (41B, 2.75 g, 9.54 mmol, 65% yield). 1H NMR(400MHz,DMSO-d6)δ ppm 8.02(d,J=7.8Hz,1H),7.28(d,J=7.6Hz,1H),3.84(s,3H),3.38-3.51(m,4H),2.57(s,3H),1.33-1.53(m,4H),0.35(s,4H).

[0199] Step 3. To a stirred solution of methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (41B, 2.50 g, 8.67 mmol) in tetrahydrofuran (1 mL) was added (trifluoromethyl)trimethylsilane (1.54 mL, 10.40 mmol, Aldrich) at 0° C. After the addition, the mixture was stirred for 2 h. The solid was filtered off and washed with EtOAc. The filtrate was concentrated, adsorbed onto a plug of silica gel, and chromatographed on a Redi-Sep® pre-packed silica gel column (Gold, 12 g) eluting with 0-30% EtOAc in heptane to give methyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinate (41C, 2.87 g, 8.01 mmol, 92% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 8.05(d,J=7.8Hz,1H),6.85(d,J=7.8Hz,1H),6.01(s,1H),3.91(s,3H),3.39-3 .56(m,4H),1.69(s,3H),1.45-1.53(m,4H),0.38(s,4H).m / z(ESI):359.0(m+H) + .

[0200] Step 4. To a stirred solution of methyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinate (41C, 2.87 g, 8.01 mmol) in MeOH (20 mL) at RT was added aqueous NaOH (8.0 mL of a 5 M solution, 40.0 mmol). After the addition, the reaction mixture was stirred for 3 days. The reaction mixture was concentrated, diluted with H2O, and acidified (to pH approx. 4) with 5N aqueous HCl. The precipitated solid was collected, washed with H2O, and dried to give 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid (41, 2.70 g, 98% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 13.23(br s,1H),7.97(d,J=7.8Hz,1H),7.15(d,J=7.8Hz,1H),6.62(s,1H),3.36-3.43 (m,4H),1.65(s,3H),1.33-1.44(m,4H),0.33(s,4H).m / z(ESI):345.0(m+H) + .

[0201] Intermediate 42: 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylic acid. [ka] step 1. To a solution of 3,5-dichloropyrazine-2-carboxylic acid (3.25 g, 16.84 mmol, Frontier Scientific, Inc.) and MeOH (20 mL) was added 10 drops of concentrated sulfuric acid. The reaction was stirred at reflux. After 16 h, LC-MS shows complete conversion. The reaction was cooled to RT and concentrated in vacuo. The material was dissolved in EtOAc (25 mL) and washed with saturated NaHCO3 (20 mL). The aqueous layer was back extracted with EtOAc (2 x 20 mL). The combined EtOAc layers were dried over MgSO4 and concentrated in vacuo to give crude methyl 3,5-dichloropyrazine-2-carboxylate (42A, 3.15 g, 15.22 mmol, 90% yield) as a brown solid. The material was carried forward without further purification. 1H NMR (400 MHz, chloroform-d) δ ppm 8.58 (s, 1H), 4.04 (s, 3H).

[0202] Step 2. To a solution of methyl 3,5-dichloropyrazine-2-carboxylate (42A, 2.02 g, 9.78 mmol) and DSMO (40 mL) was added N,N-diisopropylethylamine (3.41 mL, 19.56 mmol) and 2-amino-2-methyl-1-propanol (0.934 mL, 9.78 mmol, Aldrich). The solution was stirred at RT for 4 days, then treated with water (150 mL) and extracted with EtOAc (5×20 mL). The combined EtOAc layers were concentrated in vacuo, adsorbed onto a plug of silica gel, and chromatographed on a Redi-Sep® pre-packed silica gel column (Gold, 40 g) eluting with 0-75% EtOAc in heptane to give methyl 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylate as an orange solid (42B, 1.463 g, 5.63 mmol, 57.6% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 7.94(s,1H),7.80(s,1H),4.84(t,J=5.9Hz,1H),3.78(s,3H),3.55(d,J=5.9Hz,2H),1.31(s,6H).m / z(ESI):260.0(m+H) + Methyl 5-chloro-3-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylate (42C, 0.563 g, 2.168 mmol, 22.16% yield) was also isolated as an orange solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.42(s,1H),7.88(s,1H),5.09(t,J=5.5Hz,1H),3.84(s,3H),3.49(d,J=5.5Hz,2H),1.36(s,6H).m / z(ESI):260.0(m+H) + .

[0203] Step 3. To a solution of methyl 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylate (42B, 1.46 g, 5.62 mmol) in THF (40 mL) and MeOH (13 mL) was added LiOH (20 mL of 1 M aqueous solution, 20.00 mmol). The resulting dark brown solution was stirred at RT for 16 h and then concentrated under reduced pressure to remove the organic solvent. The aqueous solution was neutralized to about pH 7 with 2N HCl followed by the determination of significant product by LCMS (m / z (ESI): 246.0 (M+H)). + The combined organic layers were concentrated under reduced pressure to give 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylic acid (42, 1.15 g, 4.68 mmol, 83% yield) as a yellow solid. m / z (ESI): 246.1 (M+H). + .

[0204] Intermediate 43: 3-chloro-5-((1-(hydroxymethyl)cyclopropyl)amino)pyrazine-2-carboxylic acid. m / z(ESI): 244.1(M+H) + . This compound was prepared in a manner similar to that described above for intermediate 42. [ka]

[0205] Intermediate 44: 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid. [ka] Step 1. A mixture of 3,5-dichloropyrazine-2-carboxylic acid (17.0 g, 88 mmol) in thionyl chloride (50 mL, 820 mmol) was heated in a 90° C. oil bath for 16 hours. The dark solution was evaporated to dryness under reduced pressure. The crude oil was dissolved in toluene (120 mL) and evaporated to dryness again before placing the crude acid chloride under house vac. Benzyl alcohol (10 ml, 96 mmol) and triethylamine (25 mL, 178 mmol) were dissolved in dry tetrahydrofuran (100 mL) and cooled in an ice bath. The crude acid chloride was added slowly while maintaining an internal temperature of <35° C. Once the addition was complete, the mixture was removed from the cold bath and stirred for an additional 10 minutes. Saturated ammonium chloride (75 mL), water (100 mL), and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic layer was evaporated to dryness under reduced pressure and purified on a silica gel column (10% to 40% ethyl acetate in heptane) to give benzyl 3,5-dichloropyrazine-2-carboxylate (44A, 22.4 g, 79 mmol, 90% yield). m / z (ESI): 304.8 (M+Na). + .

[0206] Step 2. 4,4-Dimethyloxazolidin-2-one (4.1 g, 35.6 mmol) was dissolved in dimethylformamide (80 mL) in a jacketed reactor. The temperature was set to 15° C. A solution of potassium tert-butoxide (1.0 M in THF, 35.5 mL, 35.5 mmol) was added, causing the mixture to become a thick gel. A solution of benzyl 3,5-dichloropyrazine-2-carboxylate (44A, 10.0 g, 35.3 mmol) in dimethylformamide (50 mL) was added in one portion. The reaction mixture turned red-brown. The stirring speed was increased to 400 rpm to aid in homogenization of the mixture. The gel was slowly incorporated into the reaction. Water (100 mL), saturated ammonium chloride (50 mL), and ethyl acetate (100 mL) were added and the mixture was stirred for 5 minutes. The aqueous solution was allowed to settle and then drained. The organics were washed with water (100 mL), dried over Na2SO4, and evaporated to dryness under reduced pressure. Purification on a silica gel column (0% to 100% ethyl acetate in heptane) gave benzyl 3-chloro-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)pyrazine-2-carboxylate (44B, 10.7 g, 29.6 mmol, 84% yield) as an off-white solid. m / z (ESI): 362.3 (M+H). + .

[0207] Step 3. Benzyl 3-chloro-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)pyrazine-2-carboxylate (10.7 g, 29.6 mmol), 6-azaspiro[2.5]octane (44B, 3.5 g, 31.5 mmol) and cesium carbonate (12 g, 36.8 mmol) were combined in DMF (75 mL) under nitrogen. The mixture was stirred at RT for 16 h. Water (200 mL) and ethyl acetate (200 mL) were added and the phases were mixed and separated. The organics were washed with water (200 mL) and subsequently evaporated to dryness under reduced pressure. The crude material was suspended in methyl tert-butyl ether (50 mL) and stirred for 10 min. Heptane (50 mL) was slowly added and the mixture was stirred for another 10 min. This was filtered through a sintered glass frit and the solid was washed with 2:1 heptane:methyl tert-butyl ether (10 mL). The solid was dried under house vacuum to give benzyl 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (44C, 12.2 g, 27.9 mmol, 95% yield) as a pale yellow solid. The filtrate was evaporated to dryness under reduced pressure to give a yellow oil (0.7 g). Purification using an ISCO (heptane to ethyl acetate gradient) afforded an additional 0.5 g of intermediate 44C. m / z (ESI): 437.2 (M+H). + .

[0208] Step 4. Benzyl 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (44C, 12.2 g, 27.9 mmol) was dissolved in a 1:1 mixture of dichloromethane:ethanol (120 mL). Palladium on carbon (50 wt% water, 5 wt% Pd (anhydrous basis)) (0.350 g, 0.082 mmol) was added and the suspension was hydrogenated under 40 psi. After 1 h, hydrogen uptake appeared to cease and LC / MS showed that the starting material had been consumed. The suspension was filtered through a pad of Celite and the solid was washed with dichloromethane (10 mL). The filtrate was evaporated to dryness under reduced pressure to give 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (44, 9.17 g, 26.5 mmol, 95% yield) as a pale yellow solid. 1 H NMR(400MHz,chloroform-d)δ ppm 10.1(br.,1H)8.60-8.78(m,1H)4.06-4.26(m,2H)3.49-3.63(m,4H)1.65 -1.81(m,6H)1.49-1.61(m,4H)0.34-0.50(m,4H).m / z(ESI):347.1(m+H) + .

[0209] Intermediate 45: 5-(5-oxo-6-oxa-4-azaspiro[2.4]heptan-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid. m / z(ESI): 345.2(M+H) + . This compound was prepared in a manner similar to that described above for intermediate 44. [ka]

[0210] Intermediate 46: 3-(6-Azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid. [ka] Step 1. A mixture of benzyl 3,5-dichloropyrazine-2-carboxylate (44A, 3.03 g, 10.70 mmol), tributyl(1-ethoxyvinyl)tin (4.25 g, 11.77 mmol, Aldrich), and bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ii) (0.30 g, 0.42 mmol) in toluene (1 mL) was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, treated with 15 mL of 1 M KF solution, and stirred for 30 min. The mixture was diluted with t-butyl methyl ether, and the precipitated solid was filtered off and washed with heptane. The filtrate was separated. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified on a silica gel column (10% EtOAc / heptane) to give 46A (3.03 g) containing a mixture of benzyl 3-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylate and benzyl 5-chloro-3-(1-ethoxyvinyl)pyrazine-2-carboxylate. m / z (ESI): 319.5 (M+H). + .

[0211] Step 2. A mixture of 46A (2.81 g, 8.82 mmol), DIPEA (4.62 mL, 26.4 mmol), and 6-azaspiro[2.5]octane (1.176 g, 10.58 mmol, Wuxi) in DMSO (10 mL) was heated at 70 °C for 3 h. The reaction mixture was cooled to RT, diluted with water (10 mL), and extracted with EtOAc (3 x 20 mL). The organic extract was concentrated and the residue was purified by ISCO column (0%-20% EtOAc / heptane) to give two compounds (m / z (ESI): 394.1 (M+H) + The first elution was benzyl 3-(1-ethoxyvinyl)-5-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (46B, 1.428 g, 3.63 mmol, 41% yield): 1H NMR (chloroform-d) δ: 8.06 (s, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.29-7.39 (m, 3H), 5.36 (s, 2H), 4.81 (d, J = 2.3 Hz, 1H), 4.35 (d, J = 2.2 Hz, 1H), 3.72-3.82 (m, 6H), 1.46 (dd, J = 6.5, 4.7 Hz, 4H), 1.21 (t, J = 7.0 Hz, 3H), 0.40 (s, 4H). The second elution was benzyl 5-(1-ethoxyvinyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (46C, 1.33 g, 3.40 mmol, 38% yield): 1 H NMR(chloroform-d)δ:8.30(s,1H),7.45-7.51(m,2H),7.31-7.40(m,3H),5.42(s,2H),5.40(d,J=1.8Hz,1H),4.41(d,J=2 .0Hz,1H),3.96(q,J=7.0Hz,2H),3.41-3.47(m,4H),1.43(t,J=6.9Hz,3H),1.38(dd,J=6.5,4.7Hz,4H),0.33(s,4H).

[0212] Step 3. To a stirred solution of benzyl 5-(1-ethoxyvinyl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (46C, 1.33 g, 3.38 mmol) in THF (15 mL) was added 5N HCl (3.38 mL, 16.90 mmol). After the addition, the mixture was stirred at RT for 3 h. The mixture was diluted with EtOAc and slowly neutralized with saturated aqueous NaHCO3. The organic layer was separated, dried over MgSO4, and concentrated to give 46D. 1 H NMR(chloroform-d)δ:8.51(s,1H),7.46-7.50(m,2H),7.31-7.41(m,3H),5.44(s,2H),3. 42-3.52(m,4H),2.62(s,3H),1.33-1.41(m,4H),0.36(s,4H).m / z(ESI):366.1(m+H) + .

[0213] Step 4. To a stirred mixture of benzyl 5-acetyl-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (46D, 1.21 g, 3.31 mmol) and cesium fluoride (2.01 g, 13.23 mmol) in THF (2 mL) was added trimethyl(trifluoromethyl)silane (0.59 mL, 3.97 mmol, Aldrich). After addition, the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on a silica gel column (0% to 30% EtOAc / heptane) to give benzyl 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxylate (46E, 1.21 g, 2.78 mmol, 84% yield). 1 H NMR (chloroform-d) δ:8.10(s,1H),7.49(dd,J=7.8,1.4Hz,2H),7.37(dd,J=7.5,1.9Hz,3H),5.44(s,2H),5.2 1(s,1H),3.40-3.47(m,4H),1.74(s,3H),1.39(dd,J=6.5,4.7Hz,4H),0.36(s,4H).m / z(ESI):436.3(m+H) + .

[0214] Step 5. A solution of benzyl 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxylate (46E, 1.2 g, 2.76 mmol) in ethanol (15 mL) was hydrogenated in the presence of Pd / C (0.293 g of 10 wt%, 0.276 mmol) at 50 PSI for 2 h. The catalyst was filtered off through a pad of Celite and the solid was rinsed with EtOH. The filtrate was concentrated to give 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid (46, 904 mg, 95% yield) as a yellow solid. m / z (ESI): 346.3 (M+H). + .

[0215] Intermediate 47. 5-(N-(methylsulfonyl)methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid. [ka] Step 1. A 20 mL scintillation vial was charged with benzyl 3,5-dichloropyrazine-2-carboxylate (44A, 0.209 g, 0.738 mmol), 1,1-dimethylethyl carbamate (0.107 g, 0.917 mmol), Xantphos (0.044 g, 0.077 mmol), Pd2(dba)3 (0.035 g, 0.038 mmol), cesium carbonate (0.482 g, 1.479 mmol), and 1,4-dioxane (2 mL). The mixture was degassed by bubbling argon through the reaction mixture for 5 min. The vial was capped and the mixture was stirred at 80° C. for 1 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with water (20 mL) and then concentrated. The brown residue was loaded onto a silica gel column and subsequently eluted with EtOAc in heptane (5%-50%) to give 47A (0.138 g, 51% yield) as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 9.26(1H,s),7.50(2H,m),7.37(4H,m),5.45(2H,s),1.55(9H,s).m / z(ESI):364.1(m+H) + .

[0216] Step 2. To a solution of benzyl 5-((tert-butoxycarbonyl)amino)-3-chloropyrazine-2-carboxylate (47A, 0.138 g, 0.379 mmol) and DMSO (1 mL) was added 6-azaspiro[2.5]octane (0.060 mL, 0.455 mmol) and N,N-diisopropylethylamine (0.165 mL, 0.948 mmol). The solution was stirred at 60° C. for 4 h, then cooled to RT and partitioned between water (8 mL) and EtOAc (8 mL). The aqueous phase was extracted with EtOAc (8 mL). The combined organic phase was washed with water (2×8 mL) and concentrated. The crude product was purified by Biotage (SNAP25, Ultra, eluent: EtOAc in heptane 5% to 60%) to give benzyl 5-((tert-butoxycarbonyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (47B, 0.153 g) as a white foam. 1 H NMR(400MHz,chloroform-d)δ ppm 8.59(1H,s),7.47(2H,d,J=6.8Hz),7.29-7.39(3H,m),6.97(1H,s),5.41 (2H,s),3.33-3.43(4H,m),1.54(9H,s),1.32-1.40(4H,m),0.32(4H,s).

[0217] Step 3. A 20 mL scintillation vial was charged with benzyl 5-((tert-butoxycarbonyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (47B, 0.153 g, 0.349 mmol) and DCM (2 mL). TFA (1 mL, 12.98 mmol) was added and the mixture was stirred at RT for 45 min. The mixture was concentrated under reduced pressure and the resulting yellow paste was dissolved in 50 mL of DCM and washed with 3 mL of 1N NaOH. The organic solution was concentrated to give benzyl 5-amino-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate as a viscous yellow oil (m / z (ESI): 339.1 (M+H)). +) was obtained and used crude. The viscous yellow oil was dissolved in DCM (2 mL). Methanesulfonyl chloride (0.030 mL, 0.384 mmol) was added followed by DIPEA (0.305 mL, 1.745 mmol). The mixture was stirred at RT for 30 min and then treated with methanesulfonyl chloride (0.030 mL, 0.384 mmol) and DIPEA (0.305 mL, 1.745 mmol). After 18 h, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (5% to 70% EtOAc in heptane) to give benzyl 5-(N-(methylsulfonyl)methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (47C, 0.112 g) as an orange solid. 1 H NMR(400MHz,chloroform-d)δ ppm 7.89(1H,s),7.48(2H,dd,J=7.8,1.3Hz),7.34-7.41(3H,m),5.43(2H,s),3.56( 6H,s),3.39-3.44(4H,m),1.35-1.40(4H,m),0.35(4H,s).m / z(ESI):495.3(m+H) + .

[0218] Step 4. A mixture of benzyl 5-(N-(methylsulfonyl)methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (47C, 0.112 g, 0.226 mmol) and P / C (10 wt%, 10 mg) in 3:1 EtOAc / EtOH (4.5 mL) was hydrogenated under 30 psi of H2 for 1 h. The mixture was filtered through a pad of Celite and the solid was rinsed with 2 x 5 mL of EtOAc. The filtrate was concentrated to give 5-(N-(methylsulfonyl)methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (47, 0.088 g) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.17(1H,s),3.68(6H,s),3.48-3.54(5H,m),1.39-1.46(4H,m),0.36(4H,s).m / z(ESI):405.1(m+H) + .

[0219] Intermediate 48: 6-Fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] A 250 mL round bottom flask was charged with 2,6-difluoronicotinic acid (5.0 g, 31.5 mmol), 6-azaspiro[2.5]octane (3.8 g, 34.6 mmol), and 1,4-dioxane (60 mL). Hunig's base (6.6 mL, 37.9 mmol) was added and the light brown solution was stirred at RT for 18 h. The mixture was concentrated and the residue was diluted with EtOAc (80 mL) and subsequently washed with water (2×10 mL) and then brine (10 mL). The organic phase was reduced to about 50 mL and some solid began to appear. The suspension was allowed to stand for 18 h. The solid was collected to give the title compound as a yellow solid (2.35 g). The mother liquor was concentrated and a minimal amount of EtOAc was added to dissolve all the residue. The volume was reduced to approximately 20 mL and the second crop was collected to give the title compound as a yellow solid (2.23 g). This procedure was repeated until a third crop of the title compound (1.10 g) was obtained. All three batches were combined to give 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (48, 5.68 g, 72% yield). 1 H NMR(400MHz,chloroform-d)δ 10.50(s,1H),8.68(t,J=8.2Hz,1H),7.00(dd,J=3.1,8.4Hz,1H),3.19(t,J=5.6Hz,4H),1.69(br.s.,4H),0.47(s,4H).m / z(ESI):251.0(m+H) + .

[0220] Intermediate 49: 6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1. Oxalyl chloride (2M solution in DCM, 13.0 mL, 26.0 mmol) and one drop of DMF were added to a mixture of 2,6-dichloropyridine-3-carboxylic acid (4.0 g, 20.8 mmol, Aldrich) in DCM (50 mL). The mixture was stirred for 2 h, followed by removal of the solvent under reduced pressure to give the acid chloride as a yellow oil. The oil was dissolved in THF (50 mL) and benzyl alcohol (2.2 mL, 20.8 mmol, Combi-Blocks, Inc.) and triethylamine (11.7 mL, 83.0 mmol) were added. The mixture was stirred for 1 h, followed by addition of EtOAc and water. The resulting biphasic mixture was separated and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give benzyl 2,6-dichloronicotinate (49A, 6.01 g, 21.3 mmol, 102% yield) as a brown oil. m / z(ESI):282.0(M+H) + .

[0221] Step 2. A mixture of benzyl 2,6-dichloronicotinate (49A, 1.0 g, 3.54 mmol), 6-azaspiro[2.5]octane (0.43 g, 3.90 mmol, Wuxi AppTech), and DIPEA (0.74 mL, 4.25 mmol) in THF (10 mL) was stirred at RT for 16 h, followed by addition of EtOAc and HO. The resulting biphasic mixture was separated and the organic layer was dried over anhydrous MgSO, filtered, and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography eluting with a 0-20% EtOAc / heptane gradient to give benzyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (49B, 0.63 g, 1.76 mmol, 49.6% yield) as a colorless oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.89(d,J=7.82Hz,1H)7.32-7.44(m,5H)6.62(d,J=7.82Hz,1H)5.31(s,2 H)3.40-3.46(m,4H)1.25-1.44(m,4H)0.33(s,4H).m / z(ESI):357.0(m+H) + .

[0222] Step 3. A mixture of benzyl 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (49B, 0.55 g, 1.54 mmol), sodium carbonate (2N aqueous, 2.31 mL, 4.62 mmol), tetrakistriphenylphosphinepalladium(0) (89 mg, 0.077 mmol), and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (684 mg, 3.08 mmol, Frontier Scientific) was dissolved in dioxane (6 mL) in a microwave tube and the solvent was sparged with argon for 5 minutes, followed by sealing the tube. The mixture was heated in a microwave at 110° C. for 90 minutes, followed by cooling to RT. EtOAc and H2O were added and the resulting biphasic mixture was separated. The organic material was fused to silica gel and the material was purified by silica gel chromatography eluting with a 0-100% EtOAc / heptane gradient to give benzyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate (49C, 0.47 g, 1.13 mmol, 73.2% yield) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.98(d,J=7.82Hz,1H)7.31-7.45(m,5H)6.87(d,J=7.43Hz,1H)6.57(s,1H) )6.10(s,1H)5.33(s,2H)3.42-3.48(m,4H)1.38-1.45(m,4H)0.32(s,4H). 19 F NMR (376 MHz, chloroform-d) δ ppm-63.77 (s, 3F). m / z (ESI): 417.2 (m+H) + .

[0223] Step 4. A mixture of benzyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(3,3,3-trifluoroprop-1-en-2-yl)nicotinate (49C, 0.47 g, 1.13 mmol), 4-methylmorpholine-N-oxide (50 wt% in water, 0.46 mL, 1.98 mmol) and osmium tetroxide solution (0.059 mL, 1.129 mmol) in acetone (5 mL) and water (2 mL) was stirred at RT for 3 days. EtOAc and H2O were added and the resulting biphasic mixture was separated. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography (0% to 100% EtOAc / heptane gradient) to give benzyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)nicotinate (49D, 0.43 g, 0.96 mmol, 85% yield) as an oil. 1 H NMR(400MHz,chloroform-d)δ ppm 8.08(d,J=7.82Hz,1H)7.33-7.45(m,5H)6.89(d,J=7.82Hz,1H)6.15(s,1H)5.34(s,2H)4.11(br d,J=4.69Hz,1H)3.93-4.06(m,1H)3.41-3.47(m,4H)1.96-2.08(m,1H)1.39-1.47(m,4H)0.34(s,4H). 19 F NMR (376 MHz, chloroform-d) δ ppm-77.34 (s, 3F). m / z (ESI): 451.1 (m+H) + .

[0224] Step 5. A mixture of benzyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)nicotinate (49D, 0.43 g, 0.96 mmol), 2,2-dimethoxypropane (0.35 mL, 2.88 mmol, Aldrich) and p-toluenesulfonic acid monohydrate (18 mg, 0.096 mmol) in THF (5 mL) was heated to 60° C. for 4 h and then cooled to RT. EtOAc and saturated aqueous NaHCO3 were added, the resulting biphasic mixture was separated, and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give benzyl 6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.47 g, 0.96 mmol, 99% yield) as an oil. 1 H NMR(400MHz,chloroform-d)δ ppm 7.98(d,J=7.83Hz,1H)7.32-7.46(m,5H)7.06(d,J=7.83Hz,1H)5.33(s,2H)4.56 (s,2H)3.41(dd,J=6.55,3.62Hz,4H)1.55(s,6H)1.35-1.41(m,4H)0.32(s,4H). 19 F NMR (376 MHz, chloroform-d) δ ppm-77.35 (s, 3F). m / z (ESI): 491.1 (m+H) +A mixture of benzyl 6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (0.47 g, 0.96 mmol), palladium (10 wt% on activated carbon, 477 mg, 3.76 mmol), and ammonium formate (0.60 g, 9.6 mmol) in EtOH (5 mL) was heated to 60° C. for 20 min and then cooled to RT. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting solid was partitioned between EtOAc and water, the resulting biphasic mixture was separated, and the organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (49, 0.36 g, 0.90 mmol, 94% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 8.57-8.69 (m, 1H) 7.75-7.89 (m, 1H) 4.57-4.70 (m, 2H) 3.19 (br s, 4H) 1.32-1.38 (m, 4H) 0.45 (br s, 4H) 0.00 (s, 6H). 19 F NMR (376 MHz, chloroform-d) δ ppm-77.25 (s, 3F). m / z (ESI): 401.1 (m+H) + .

[0225] Intermediate 50: 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1. 2,6-Difluoronicotinic acid (10.6 g, 66.6 mmol) and thionyl chloride (35 mL, 480 mmol) were combined under nitrogen and heated to gentle reflux for 2 h. The solution was concentrated to dryness under reduced pressure. Toluene (100 mL) was added to the crude and it was evaporated to dryness once more. The crude acid chloride was dissolved in DCM (50 mL) under nitrogen and cooled in an ice bath. A mixture of triethylamine (25 mL, 180 mmol) and benzyl alcohol (7.25 ml, 70.1 mmol) in DCM (50 mL) was added dropwise over 10 min. 0.1 N HCl (100 mL) was added, the phases mixed and separated. The organics were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give benzyl 2,6-difluoronicotinate (50A), which was used without purification. m / z (ESI): 250.0 (M+H) + .

[0226] Step 2. 4,4-Dimethyloxazolidin-2-one (0.80 g, 6.95 mmol) was dissolved in THF (15 mL) under nitrogen. Potassium t-butoxide (0.750 g, 6.68 mmol) was added and the suspension was stirred at RT for 5 min. The mixture became a thick gel. A solution of benzyl 2,6-difluoronicotinate (50A, 1.60 g, 6.42 mmol) in N,N-dimethylacetamide (40 mL) was added and the mixture was stirred at RT for 10 min, at which point LC / MS showed that the starting material was essentially consumed and the desired mass (m / z (ESI): 345.0 (M+H) was obtained. + ). Water (75 mL), ethyl acetate (150 mL), and saturated ammonium chloride (25 mL) were added, the phases mixed and separated. The organics were washed with brine (50 mL) and evaporated to dryness under reduced pressure. Purification using an ISCO (gradient from heptane to ethyl acetate) gave benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-fluoronicotinate as a white solid (50B, 1.82 g, 5.29 mmol, 82% yield). This material was approximately 92% pure, the remainder was benzyl 2-(4,4-dimethyl-2-oxooxazolidin-3-yl)-6-fluoronicotinate.

[0227] Step 3. Benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-fluoronicotinate (50B, 1.81 g, 5.23 mmol) was dissolved in NMP (20 mL). Cesium carbonate (2.00 g, 6.14 mmol) and 6-azaspiro[2.5]octane (0.60 g, 5.40 mmol) were added and the mixture was stirred at RT for 18 h. Water (100 mL) and ethyl acetate (150 mL) were added and the phases were mixed and separated. The organics were washed with brine and evaporated to dryness under reduced pressure. Purification by ISCO (0% to 40% ethyl acetate in heptane) afforded benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (50C, 1.77 g, 4.06 mmol, 78% yield) as a milky oil. m / z (ESI): 436.1 (M+H). + .

[0228] Step 4. Benzyl 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (50C, 1.77 g, 4.06 mmol) was dissolved in ethyl acetate (30 mL) and transferred to a pressure vessel. Ethanol (60 mL) was added, followed by 5% palladium on carbon (dry weight, 50% water, 0.250 g, 0.117 mmol). The suspension was stirred under 40 psi of hydrogen for 15 minutes. The mixture was filtered through a pad of Celite and the solids were washed with ethyl acetate (50 mL). The combined filtrate was evaporated to dryness under reduced pressure to give 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid as a white solid (Intermediate 50, 1.15 g, 3.33 mmol, 82% yield). m / z (ESI): 346.0 (M+H). + .

[0229] Intermediate 51: 2-(6-Azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinic acid. [ka] Steps 1-3. Methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (Intermediate 51C) was prepared in a three-step procedure similar to that described for benzyl 5-acetyl-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylate (Intermediate 46D). 1 H NMR (400MHz, chloroform-d): δ 8.04(d,J =7.8Hz,1H),7.39(d,J =7.8Hz,1H),3.93(s,3H),3.54(t,J =5.2Hz,4H),2.66(s,3H),1.51(t,J =5.2Hz,4H),0.40(s,4H).m / z(ESI):289.0(m+H) + .

[0230] Step 4. To a solution of trimethylsulfoxonium iodide (4.62 g, 20.98 mmol) in DMSO (55.0 mL) was added potassium tert-butoxide (2.14 g, 19.07 mmol) and stirred at RT for 15 min. A solution of methyl 6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (51C, 5.5 g, 19.07 mmol) in DMSO (55.0 mL) was added dropwise at RT and the reaction mixture was stirred for 3 h. The reaction was quenched with cold water (50 mL) and extracted with ethyl acetate (2×75 mL). The organic layer was washed with water (50 mL) followed by brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography through Isolera-One (SNAP 100 g) using 6% ethyl acetate in hexane to give methyl 6-(2-methyloxiran-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (51D, 4.6 g, 15.2 mmol, 80% yield) as a yellow oil. 1H NMR(400MHz,chloroform-d)δ 7.94(d,J =7.9Hz,1H),6.72(d,J =7.9Hz,1H),3.89(s,3H),3.49(t,J =5.4Hz,4H),3.00(d,J =5.6Hz,1H),2.93(d,J =5.6Hz,1H),1.76(s,3H),1.50(t,J =5.4Hz,4H),0.37(s,4H).m / z(ESI):303.0(m+H) + .

[0231] Step 5. To a solution of methyl 6-(2-methyloxiran-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (51D, 4.60 g, 15.21 mmol) in 1,4-dioxane (30 mL) and water (30 mL) was added concentrated HCl (3.0 mL) at RT and stirred for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (4×100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude residue which was purified by flash chromatography through Isolera-One (SNAP 100 g) using a gradient of 25-30% ethyl acetate in hexanes to give methyl 6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (51E, 3.1 g, 9.68 mmol, 64% yield) as a yellow oil. m / z (ESI): 321.0 (M+H). + .

[0232] Step 6. To a solution of methyl 6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (51E, 3.1 g, 9.68 mmol) in acetone (62.0 mL), 2,2-dimethoxypropane (3.02 g, 29.0 mmol) and p-toluenesulfonic acid monohydrate (0.184 g, 0.968 mmol) were added and stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with 5% aqueous NaHCO3 and extracted with ethyl acetate (2 x 75 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give methyl 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinate as a yellow oil (3.0 g, 8.33 mmol, 86% yield). m / z (ESI): 361.2 (M+H). + .. The yellow oil was dissolved in methanol (30.0 mL) and subsequently treated with sodium hydroxide (2.5 M aqueous solution) (16.65 mL, 41.6 mmol) followed by stirring at RT for 24 h. The reaction mixture was concentrated to half its volume and subsequently acidified with 10% citric acid solution to pH approx. 5-6. The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with water (40 mL) followed by brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinic acid as a pale yellow gum (intermediate 51, 2.6 g, 7.5 mmol, 90% yield), which solidified on standing to form a pale yellow solid. The crude material was used without further purification. 1H NMR(400MHz,chloroform-d)δ 10.5(br.,1H),8.58(dd,J =8.0,0.9Hz,1H),7.76(dd,J=8.0,0.9Hz,1H),4.48-4.40(m,1H),4.12(dd,J=8.6,0.9Hz,1H),3.22(t,J=5 .7Hz,4H),1.63(s,3H),1.56(s,3H),1.42(s,3H),1.40-1.20(bs,4H),0.50(s,4H).m / z(ESI):347.0(m+H) + .

[0233] Intermediate 52: 6-(2-Fluoro-1,3-dimethoxy-1,3-dioxopropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1. To a 50 mL round bottom flask was added benzyl 2,6-difluoronicotinate (50A, 1.00 g, 4.01 mmol), 6-azaspiro[2.5]octane (0.47 g, 4.21 mmol), and DIPEA (1.40 mL, 8.03 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at RT for 16 h. The crude material was absorbed onto a plug of silica gel and purified by chromatography eluting with 5%-10% EtOAc in hexanes to give benzyl 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (52A, 900 mg, 2.64 mmol, 66% yield) as a colorless gummy liquid. m / z (ESI): 341.0 (M+H) + .

[0234] Step 2. A mixture of benzyl 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (52A, 8.6 g, 25.3 mmol), dimethyl malonate (28.9 mL, 253 mmol), and cesium carbonate (20.58 g, 63.2 mmol) in NMP (50 mL) was stirred at 60 °C for 24 h. The reaction mixture was cooled to RT. Water and EtOAc were added. The layers were separated and the organic layer was concentrated. The residue was purified by ISCO (0% to 20% EtOAc / heptane) to give dimethyl 2-(5-((benzyloxy)carbonyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)malonate (52B, 8.23 ​​g, 18.19 mmol, 72% yield). 1 H NMR (chloroform-d) δ:7.97(d,J=7.8Hz,1H),7.41-7.46(m,2H),7.31-7.40(m,3H),6.74(d,J=7.8Hz,1H),5.32( s,2H),4.81(s,1H),3.78(s,6H),3.40-3.44(m,4H),1.35-1.43(m,4H),0.31(s,4H).m / z(ESI):453.0(m+H) + .

[0235] Step 3. To a solution of dimethyl 2-(5-((benzyloxy)carbonyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)malonate (52B, 3.0 g, 6.63 mmol) in THF (15 mL) was added sodium hydride (0.318 g of 60 wt%, 7.96 mmol). After stirring at RT for 20 min, selectfluor fluorination reagent (3.05 g, 8.62 mmol, Aldrich) was added and the mixture was stirred at RT for 16 h. The reaction mixture was cooled in an ice bath, treated with 5% H2SO4 (30 mL) and extracted with EtOAc (3x). The extract was dried over MgSO4 and concentrated to give dimethyl 2-(5-((benzyloxy)carbonyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-2-fluoromalonate (52C, 3.5 g, 7.44 mmol, 112% yield), which was used crude in the next step. m / z (ESI): 471.0 (M+H). +.

[0236] Step 4. A mixture of dimethyl 2-(5-((benzyloxy)carbonyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-2-fluoromalonate (52C, 3.5 g, 7.44 mmol) and Pd / C (1.6 g of 10 wt%, 1.48 mmol) in ethanol (40 mL) was hydrogenated under 50 psi of hydrogen for 2 h. The catalyst was filtered off through a pad of Celite, rinsed with EtOAc, and the filtrate was concentrated to give 6-(2-fluoro-1,3-dimethoxy-1,3-dioxopropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (intermediate 52, 2.63 g, 93% yield). The crude material was used without further purification. 1 H NMR (DMSO-d6) δ: 7.74 (d, J = 7.7 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 3.59 (s, 6H), 3.12-3.15 (m, 4H), 1.11-1.17 (m, 4H), 0.09 (s, 4H). No CO2H peak was observed. m / z (ESI): 381.0 (M+H) + .

[0237] Intermediate 53: 6-((1-methoxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] Step 1. A mixture of benzyl 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (52A, 1.20 g, 3.53 mmol), 1-methoxy-2-methylpropan-2-amine (0.54 g, 5.29 mmol) and DIPEA (1.84 mL, 10.58 mmol) in DMSO (5 mL) was stirred at 100° C. for 36 h. It was cooled to RT and partitioned between water (10 mL) and EtOAc (50 mL). The layers were separated and the organic layer was dried over MgSO4 and concentrated. The residue was purified by ISCO (0% to 30% EtOAc in heptane) to give benzyl 6-((1-methoxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (53A, 0.42 g, 1.00 mmol, 28% yield). 1 H NMR (chloroform-d) δ:7.85(d,J=8.5Hz,1H),7.40-7.45(m,2H),7.29-7.38(m,3H),5.76(d,J=8 .7Hz,1H),5.26(s,2H),4.79(s,1H),3.46(s,2H),3.39-3.43(m,4H),3.37(s,3H),1.46(br d,J=5.4Hz,4H),1.44(s,6H),0.32(s,4H).m / z(ESI):424.1(m+H) + .

[0238] Step 2. Benzyl 6-((1-methoxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (53A, 0.42 g, 1.00 mmol) was hydrogenated using the procedure described for Intermediate 52 to give 6-((1-methoxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 53, 298 mg, 0.89 mmol, 89% yield). m / z (ESI): 334.0 (M+H). + .

[0239] Intermediate 54: 6-Chloro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] A mixture of 2,6-dichloronicotinic acid (4.2 g, 21.9 mmol), 6-azaspiro[2.5]octane (2.4 g, 21.9 mmol), and 1,4-dioxane (40 mL). Hunig's base (7.7 mL, 44.1 mmol) was added and the brown solution was stirred at 60 °C for 18 h. The mixture was diluted with EtOAc (80 mL) and washed with water (2 x 10 mL) followed by brine (5 mL). The organic phase was concentrated and the residue was purified on a silica gel column (50% to 100% EtOAc / hexanes mediated by 0.25% AcOH) to give the title compound as a tan solid (54, 2.60 g, 44% yield). 1 H NMR (400 MHz, chloroform-d) δ = 8.52 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 3.21 (t, J = 5.4 Hz, 4H), 1.69 (br.s., 4H), 0.47 (s, 4H). -CO2H was not observed. m / z (ESI): 267.0 (m+H). + .

[0240] Intermediate 55: 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid. [ka] A mixture of methyl 2-chloro-6-methylnicotinate (5.0 g, 26.9 mmol), AIBN (4.4 g, 26.9 mmol), and 1-bromopyrrolidine-2,5-dione (4.78 g, 26.9 mmol) in carbon tetrachloride (50 mL) was heated at 70° C. for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The organic extracts were concentrated under reduced pressure. The resulting yellow oil [m / z (ESI): 264.0 / 266.0 (M+H) +[55A, 4.0 g] was dissolved in 50 mL of DMF and treated with sodium methanesulfinate (2.73 g, 26.8 mmol). The reaction mixture was stirred at RT for 1 h, then diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The organic extract was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g) eluting with a gradient of 1–50% EtOAc in hexanes to give methyl 2-chloro-6-((methylsulfonyl)methyl)nicotinate (55A, 4.0 g) as an off-white solid. m / z (ESI): 264.0 (M+H) + .

[0241] A mixture of methyl 2-chloro-6-((methylsulfonyl)methyl)nicotinate (55A, 2.0 g, 7.58 mmol) and 6-azaspiro[2.5]octane (1.012 g, 9.10 mmol) in dimethylsulfoxide (10 mL) was heated in a microwave at 140 °C for 60 min. The reaction mixture was loaded onto a silica gel column (120 g) eluted with a gradient of 1-20% EtOAc in hexanes to give methyl 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (1.4 g, 4.14 mmol, 55% yield) as an off-white solid. m / z (ESI): 339.0 (M+H) +Methyl 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (55A, 1.4 g, 4.14 mmol) in ethanol (10 mL) and water (10 mL) was treated with sodium hydroxide (0.49 g, 12.41 mmol). After 3 h, the mixture was concentrated under reduced pressure to remove the ethanol. The aqueous solution was neutralized to pH 7 using 1.5 N HCl, followed by extraction with ethyl acetate (3×100 mL). The organic extract was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude material as a pale yellow solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g) eluting with a gradient of 1-6% MeOH in DCM to give 6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (intermediate 55, 680 mg, 2.10 mmol, 51% yield) as an off-white solid. 325.0 (M+H) + .

[0242] Preparation of Examples 100 to 248 Example 100: 5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(piperidin-1-ylsulfonyl)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka] Step 1. To a solution of 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)pyrazine-2-carboxylic acid (Intermediate 42, 118 mg, 0.48 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.976 mmol) and 6-(piperidin-1-ylsulfonyl)pyridin-2-amine (Intermediate 38, 120 mg, 0.50 mmol). The solution was stirred at RT for 3 min and then treated with HATU (183 mg, 0.48 mmol, Aldrich). The reaction was heated to 50° C. for 4 days. Additional Intermediate 42 (50 mg) and HATU (100 mg) were added and the mixture was heated for an additional 2 days. The mixture was diluted with water (50 mL) and stirred for 30 min. The solid was filtered, washed with water (2×10 mL), loaded onto a silica gel column, and eluted with 10% to 100% EtOAc in heptane to give 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(piperidin-1-ylsulfonyl)pyridin-2-yl)pyrazine-2-carboxamide (100A, 55 mg, 0.11 mmol, 24% yield) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.42(s,1H),8.42(d,J=8.4Hz,1H),8.13(t,J=7.9Hz,1H),8.01(s,1H),7.90(s,1H),7.63(d,J=7.6 Hz,1H),4.88(t,J=5.9Hz,1H),3.58(d,J=5.7Hz,2H),3.10-3.19(m,4H),1.47-1.56(m,4H),1.43(br d,J=6.8Hz,2H),1.34(s,6H).m / z(ESI):469.1(m+H) + .

[0243] Step 2. To a solution of 3-chloro-5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(piperidin-1-ylsulfonyl)pyridin-2-yl)pyrazine-2-carboxamide (Intermediate 100A, 53 mg, 0.113 mmol) and 6-azaspiro[2.5]octane (19 mg, 0.170 mmol, AstaTech, Inc.) in DMSO (2 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.230 mmol). The solution was stirred at RT for 16 h, then diluted with water (20 mL) and stirred for 20 min. The precipitated solid was filtered and washed with water (2×5 mL). The solid was purified by silica gel chromatography (0% to 80% EtOAc in heptane) to give a mixture of starting material and product. The starting chloride eluted at the top of the desired fractions, leaving only 4 mg of the desired product (m / z (ESI): 544.2 (M+H) + ) was obtained pure. The remaining combined fractions were concentrated under reduced pressure, dissolved in DMSO (1 mL) and treated with 6-azaspiro[2.5]octane (20 mg). After stirring at RT for 3 days, the reaction was diluted with water, stirred for 1 h and then filtered. The solid was dissolved in EtOAc (15 mL), washed with brine (2×40 mL) and then concentrated under reduced pressure to give 5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(piperidin-1-ylsulfonyl)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a pale yellow solid (Example 100, 40 mg, 0.074 mmol, 65% yield). 1H NMR (400MHz, chloroform-d) δ ppm 10.30 (s, 1H), 8.59 (d, J = 8.4Hz, 1H), 7.86 (t, J = 8.0Hz, 1H), 7.59 (d, J = 7.4Hz, 1H), 7.32 (s, 1H), 4.93 (s, 1H), 3.77 (d, J = 5.7Hz, 2H), 3.60-3.67 (m, 1H), 3.49-3.58 (m, 4H ),3.23-3.31(m,4H),1.65(quin,J=5.6Hz,4H),1.57-1.59(m,2H,unclear due to water peak),1.4 8-1.53(m,2H),1.46(s,6H),0.79-0.88(m,2H),0.38(s,4H).m / z(ESI):544.2(m+H) + .

[0244] Example 101: 5-((1-(hydroxymethyl)cyclopropyl)amino)-N-(6-(piperidin-1-ylsulfonyl)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. m / z(ESI): 542.2(M+H) + . This compound was prepared in a manner similar to that described above for Example 100. [ka]

[0245] Examples 102 and 119. [ka] Step 1. To a solution of 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (44, 17.0 g, 49.1 mmol) in DMF (100 mL) was added 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (31, 13.5 g, 58.9 mmol), HATU (28.0 g, 73.6 mmol), and DIPEA (16.14 mL, 98.2 mmol). The reaction mixture was heated at 70° C. for 16 h. The reaction mixture was cooled to RT and quenched with water (200 mL). The precipitated solid was filtered, washed with water (200 mL), followed by methanol (50 mL) and dried under vacuum to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a white solid (Example 119, 13.5 g, 50% yield). 1 H NMR (400MHz, chloroform-d): δ 10.36(s,1H),8.68(s,1H),8.56(d,J =8.3Hz,1H),7.90(d,J =8.3,8.0Hz,1H),7.74(d,J=8.0Hz,1H),5.03(s,1H),4.18(s,2H),3.65-3.57(m, 4H),1.75(s,6H),1.56(bs,4H),1.26(s,9H),0.41(s,4H).m / z(ESI):558.2(m+H) + .

[0246] Step 2. To a solution of N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (Example 119, 13.5 g, 24.17 mmol) in ethanol (250 mL), NaOH (24.17 mL of a 2N solution, 48.3 mmol) was added and the resulting mixture was stirred at RT for 4 h. The reaction mixture was acidified with 1.5 N aqueous HCl to pH 6. The reaction mixture was extracted with ethyl acetate (3×1000 mL) and washed with water (1000 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0% to 40% ethyl acetate in hexanes) followed by recrystallization in acetonitrile (50 mL) and methanol (50 mL) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a white solid (Example 102, 8.4 g, 84% yield). 1 H NMR(400MHz,DMSO-d6):δ 10.22(s,1H),8.39(d,J =8.4Hz,1H),8.02(dd,J =8.0,7.5Hz,1H),7.67(s,1H),7.60(d,J =7.5Hz,1H),7.47(s,1H),7.27(s,1H),4.81(t,J =5.7Hz,1H),3.58(d,J =5.7Hz,2H),3.44(td,J =6.7,3.8Hz,4H),1.46(t,J =6.7,3.9Hz,4H),1.34(s,6H),1.11(s,9H),0.34(s,4H).m / z(ESI):532.3(m+H) + .

[0247] [Table 8]

[0248] [Table 9]

[0249] [Table 10]

[0250] Examples 103 and 104. [ka] Step 1. To a solution of 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (Intermediate 44, 0.100 g, 0.289 mmol) in DCM (3.0 mL) was added oxalyl chloride solution (2.0 M in DCM, 0.217 mL, 0.433 mmol) followed by 2 drops of DMF. The reaction was stirred at RT for 20 min and then concentrated. The residue was dissolved in DCM (3.0 mL), cooled to 0° C., and treated with (R)-6-(2-methylmorpholino)pyridin-2-amine (56 mg, 0.289 mmol) followed by Hunig's base (0.151 mL, 0.866 mmol). The mixture was stirred at RT for 3 h, then concentrated and purified by silica gel chromatography (0-35% EtOAc / heptane) to give (R)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a yellow solid (Example 103, 0.106 g, 0.203 mmol, 70% yield). 1H NMR(400MHz,chloroform-d)δ ppm 0.38(s,4H)1.27(d,J=6.26Hz,3H)1.50-1.54(m,4H)1.71(s,6H)2.57(dd,J=12.52,10.37Hz,1 H)2.93(td,J=12.37,3.62Hz,1H)3.53-3.60(m,4H)3.63-3.77(m,2H)3.95-4.03(m,2H)4.09(br d,J=12.13Hz,1H)4.14(s,2H)6.37(d,J=8.22Hz,1H)7.53(t,J=8.02Hz,1H)7.68(d,J=7.82Hz,1H)8.67(s,1H)9.87(s,1H).m / z(ESI):522.2(m+H) + .

[0251] Step 2. To a suspension of (R)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (Example 103, 0.097 g, 0.186 mmol) in methanol (5.0 mL) was added sodium hydroxide (5.0 N solution, 0.5 mL, 2.5 mmol). The mixture was heated at 70° C. for 2 h until the conversion was complete. The mixture was neutralized with 2N HCl and then concentrated to dryness. The residue was diluted with EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel chromatography (0% to 40% EtOAc:EtOH (3:1) / heptane) to give (R)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-methylmorpholino)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a pale yellow solid (Example 104, 0.070 g, 0.141 mmol, 76% yield). 1H NMR(400MHz,クロロホルム-d)δ ppm 0.37(s,4H)1.27(d,J=6.26Hz,3H)1.44(s,6H)1.57-1.62(m,4H)2.57(dd,J=12.52,10.37Hz,1H)2.92(td,J=12.32 ,3.52Hz,1H)3.45-3.52(m,4H)3.62-3.73(m,2H)3.76(d,J=5.28Hz,2H)3.84-3.92(m,1H)3.96-4.04(m,2H)4.08(br d,J=12.72Hz,1H)4.84(s,1H)6.35(d,J=8.22Hz,1H)7.36(s,1H)7.53(t, J=8.02Hz,1H)7.72(d,J=8.02Hz,1H)10.01(s,1H).m / z(ESI):496.3(m+H) + .

[0252]

Table 11

[0253]

Table 12

[0254]

Table 13

[0255]

Table 14

[0256]

Table 15

[0257]

Table 16

[0258] Example 108: N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka] Step 1. To a 250 mL round bottom flask was added 2-amino-2-methyl-1,3-propanediol (1.00 g, 9.56 mmol) and DMF (30 mL), tert-butyldimethylsilane chloride (7.11 mL, 38.2 mmol), followed by imidazole (3.52 mL, 57.4 mmol). The mixture was stirred at RT for 21 h, then diluted with saturated NaHCO3 and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with water (150 mL), dried over Na2SO4, and concentrated to give 5.24 g of a clear oil. The crude product was purified by Biotage (sNAP50, Ultra, eluent: EtOAc in heptane 10% to 90%) to give 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine (108A, 2.86 g, 90% yield). 1 H NMR (400 MHz, chloroform-d) δ 3.35-3.45 (m, 4H), 0.99 (s, 3H), 0.90 (s, 18H), 0.05 (s, 12H).

[0259] Step 2. To a solution of 3,5-dichloropyrazine-2-carboxylic acid (1.01 g, 5.23 mmol) and toluene (10 mL) was added thionyl chloride (0.57 mL, 7.81 mmol). The solution was stirred at reflux for 1.5 h, the reaction was allowed to cool to RT, concentrated under reduced pressure, and then azeotroped with toluene (3×10 mL). The residue was dissolved in DCM (10 mL) and treated with 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (31, 1.08 g, 4.71 mmol) and N,N-diisopropylethylamine (1.82 mL, 10.47 mmol). After 4 h the reaction was diluted with DCM (20 mL) and washed with water (30 mL). The aqueous layer was back extracted with DCM (20 mL). The combined DCM layers were concentrated to ½ volume and the solid was filtered and rinsed with additional DCM to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-3,5-dichloropyrazine-2-carboxamide (108B, 1.61 g, 3.99 mmol, 76% yield) as a white solid.

[0260] Step 3. To a solution of 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine (108A, 1.00 g, 3.00 mmol) in DMSO (8 mL) was added N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-3,5-dichloropyrazine-2-carboxamide (108B, 1.01 g, 2.49 mmol) and N,N-diisopropylethylamine (1.30 mL, 7.49 mmol). The solution was stirred at 60° C. for 23 h, then cooled to RT, diluted with water (60 mL) and stirred for 5 min. The mixture was extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with water (2×50 mL) and concentrated. The crude product was purified by Biotage (SNAP50, Ultra, eluent: EtOAc in heptane 0% to 30%), m / z (ESI): 702.0 (M+H). + The first eluate was 108C (0.457 g of a pale yellow solid): 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.98 (s, 1H), 8.28 (d, J = 8.41 Hz, 1H), 8.15 (t, J = 8.12 Hz, 1H), 8.00 (s, 1H), 7.70-7.81 (m, 2H), 3.85 (d, J = 9.59 Hz, 2H), 3.74 (d, J = 9.59 Hz, 2H), 1.39 (s, 3H), 1.11 (s, 9H), 0.86-0.89 (m, 18H), 0.04 (d, J = 8.22 Hz, 12H). The second elution was 108D (0.5451 g yellow solid): 1 H NMR(400MHz,DMSO-d6)δ 10.27(s,1H),8.37(d,J=8.22Hz,1H),8.11(d,J=8.02Hz,1H),8.03(s,1H),7.80(s,1H),7.64-7.73(m,2H),3.8 8(d,J=9.59Hz,2H),3.77(d,J=9.59Hz,2H),1.32(s,3H),1.12(s,9H),0.84(s,18H),-0.02(d,J=3.52Hz,12H).

[0261] Step 4. To a solution of 6-azaspiro[2.5]octane (91 mg, 0.82 mmol) in DMSO (4 mL) was added N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-3-chloro-5-((2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)amino)pyrazine-2-carboxamide (108D, 540 mg, 0.77 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.92 mmol). The solution was stirred at 60° C. for 4 h. The reaction was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were concentrated under reduced pressure to give crude N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-((2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a dark yellow oil (0.61 g). Assuming 100% conversion, this material was used in the next reaction without further purification.

[0262] Step 5. A 250 mL round bottom flask was charged with N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-((2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (0.60 g, 0.77 mmol) and THF (10 mL). Tetrabutylammonium fluoride (2.31 mL of 1 M in THF, 2.31 mmol) was added and the mixture was stirred at RT for 30 min. The reaction mixture was partitioned between water (30 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and the organics were dried and concentrated. The crude product was purified by silica gel chromatography (30% to 100% EtOAc in heptane) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-5-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a pale yellow solid (Example 108, 0.19 g). 1 H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.39(d,J=8.41Hz,1H),8.02(t,J=8.02Hz,1H),7.66(s,1H),7.60(d,J=7.43Hz,1H) ,7.51(s,1H),7.06(s,1H),4.68(t,J=5.67Hz,2H),3.59-3.71(m,4H),3.39-3.48(m,4H),1.47(br d,J=4.50Hz,4H),1.30(s,3H),1.11(s,9H),0.35(s,4H).m / z(ESI):548.5(m+H) + .

[0263] Example 110: N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxamide. [ka] To a stirred mixture of 3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxylic acid (Intermediate 46, 200 mg, 0.58 mmol), 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 159 mg, 0.69 mmol), and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was added HATU (286 mg, 0.75 mmol). The reaction mixture was heated to 65° C. for 6 h. It was cooled to RT and treated with water (3 mL). The solid was filtered and purified on a silica gel column (0% to 30% EtOAc / EtOH (3 / 1) in heptane) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyrazine-2-carboxamide (Example 110, 123 mg, 0.22 mmol, 38% yield).

[0264] 1 H NMR(DMSO-d6)δ:10.89(s,1H),8.33(br d,J=8.0Hz,1H),8.27(s,1H),8.11(t,J=8.0Hz,1H),7.72(d,J=7.4Hz,1H),7.60(s,1H),6.96(s,1H) ,3.50-3.59(m,4H),1.69(s,3H),1.36-1.44(m,4H),1.14(s,9H),0.33(s,4H).m / z(ESI):557.2(m+H) + .

[0265] Example 113: N-(4-chloro-6-morpholinopyridin-2-yl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka] Step 1. To a solution of 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (Intermediate 44, 0.10 g, 0.29 mmol) in DMF (3 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TATU, 0.12 g, 0.38 mmol, FSSI), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt, 0.05 g, 0.38 mmol, Chempep), 4-chloro-6-morpholinopyridin-2-amine (0.07 g, 0.34 mmol, Aurum), and diisopropylethylamine (0.23 mL, 1.33 mmol) were added. The mixture was stirred at RT for 45 min and then at 80 °C for 2.5 h. The reaction was quenched with methanol and the crude mixture was purified by chromatography on silica gel (24 g) eluting with 0% to 80% EA in heptane to give N-(4-chloro-6-morpholinopyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (113A, 0.166 g, impure). m / z ESI 542.2 (M+H). + .

[0266] Step 2. N-(4-chloro-6-morpholinopyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (113A, 0.040 g, 0.074 mmol) was treated with 2 mL of methanol / NaOH solution (5 mL of methanol, 33 μL of 1N NaOH) at 70 °C for 2.5 h. DMSO (0.5 mL) was added and heating was continued for 2 h. The mixture was filtered into an Agilent autosampler vial and purified by preparative HPLC (5-95% ACN in water (0.1% TFA)) for 14 min at 40 mL / min (X-Bridge C18 10 μm 18 × 100 mm). Pure fractions were combined and lyophilized to give N-(4-chloro-6-morpholinopyridin-2-yl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a yellow powder (Example 113, 0.0226 g, 0.044 mmol, 59% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.34(s,4H)1.34(s,6H)1.42-1.51(m,5H)3.36-3.40(m,4H)3.43-3.49(m,4H)3.58(s,2H)3.64-3.70(m,4H)6.60(s,1H)7.22(br s,1H)7.45-7.48(m,1H)7.57(s,1H)10.05-10.09(m,1H).m / z(ESI):516.2(m+H) + .

[0267] Example 116: 5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(4-methoxy-6-morpholinopyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka] Step 1. To a solution of 5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (Intermediate 44, 0.10 g, 0.29 mmol) in DMF (3 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TAT U, 0.124 g, 0.384 mmol, FSSI), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt, 0.052 g, 0.384 mmol, Chempep), 2-amino-6-chloro-4-methoxypyridine (0.055 mL, 0.346 mmol, Oxchem), and diisopropylethylamine (0.231 mL, 1.33 mmol) were added. The mixture was stirred for 15 min and then heated to 80° C. for 3 h. The mixture was purified by chromatography on silica gel (40 g, 0% to 100% EA in heptane) to give N-(6-chloro-4-methoxypyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a yellow oil (116A, 0.068 g). m / z ESI 487.1 (M+H). + .

[0268] Step 2. N-(6-chloro-4-methoxypyridin-2-yl)-5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (116A, 0.034 g, 0.070 mmol) was dissolved in morpholine (1.08 mL, 12.2 mmol) in a sealed tube and heated in a microwave at 160° C. for 1 h, followed by 180° C. for 1 h, followed by 200° C. for 1 h. The mixture was evaporated and the residue was treated with 5 mL of methanol and 0.13 mL of 1N NaOH and heated at 70° C. for 1 h. The pH was neutralized with 0.13 mL of 1N HCl and the mixture was evaporated. The crude material was purified by HPLC (Kinetex EVO100 C18 150×21.1 mm×5 μm, 30 mL / min, 5-95% ACN in water (and 0.1% TFA) over 13 min). Pure fractions were combined and lyophilized to give 5-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(4-methoxy-6-morpholinopyridin-2-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (Example 116, 0.003 g, 5.86 μmol, 9% yield). 1 H NMR (400 MHz, methanol-d4) δ ppm 0.24 (s, 4H) 1.22-1.30 (m, 6H) 1.32-1.40 (m, 4H) 3.34-3.44 (m, 8H) 3.63 (s, 2H) 3.66-3.74 (m, 4H) 3.80 (s, 3H) 6.08 (d, J=1.76 Hz, 1H) 6.54 (br s, 1H) 7.26-7.40 (m, 1H), two protons hidden and one proton exchanged. m / z ESI 512.1 (m+H) + .

[0269] Example 117: N-(4-cyano-6-morpholinopyridin-2-yl)-5-((1-hydroxy-2-methylpropan-2-yl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. This compound was prepared using the procedure described for Example 113.

[0270] 1H NMR (400 MHz, methanol-d4) δ ppm 0.52 (s, 4H) 1.47 (s, 6H) 1.67-1.86 (m, 4H) 3.50-3.63 (m, 8H) 3.73-3.88 (m, 6H) 6.89 (s, 1H) 7.81 (s, 2H). Two protons hidden and one proton exchanged. m / z ESI 507.2 (m+H) + . [ka]

[0271] Example 118: 3-(6-azaspiro[2.5]octan-6-yl)-N-(4-cyclopropyl-6-(4-morpholinyl)-2-pyridinyl)-5-((1-hydroxy-2-methyl-2-propanyl)amino)-2-pyrazinecarboxamide. 1 H NMR (400MHz, methanol-d4) δ ppm 0.39(s,4H)0.89-0.97(m,2H)1.14-1.20(m,2H)1.41(s,6H)1.43-1.52(m,1H)1.55(br s,4H)1.94-2.01(m,1H)3.46(s,1H)3.53(t,J=4.99Hz,8H)3.74-3.87(m,4H)6.50(s,1H)6.71(br s,1H)7.50(s,1H).m / z ESI 522.3(m+H) + . This compound was prepared using the procedure described for Example 113. [ka]

[0272] Example 121: (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-5-(methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka] A 20 mL scintillation vial was charged with 5-(N-(methylsulfonyl)methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxylic acid (47, 85 mg, 0.21 mmol), (R)-6-(2-methylmorpholino)pyridin-2-amine (12, 44 mg, 0.228 mmol), and DMF (1 mL). DIPEA (0.073 mL, 0.420 mmol) was added, followed by TATU (81 mg, 0.252 mmol). The brown mixture was stirred at RT for 4 h. Sodium carbonate (23 mL, 0.218 mmol) was added and the mixture was stirred at RT for 4 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (3 x 5 mL). The aqueous phase was saturated with NaCl and further extracted with EtOAc (2 x 20 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Biotage (SNAP25, Ultra, eluent: 20% to 100% EtOAc in heptane) to give the title compound as a pale yellow solid (Example 121, 10 mg, 10% yield). 1 H NMR (400MHz, chloroform-d) δ ppm 9.67(1H,s), 7.74(1H,s), 7.67(1H,d,J=7.9Hz), 7.55(1H,t,J=8.0Hz), 6.39(1H,d,J=8.3Hz), 4.08(1H,br d,J=12.2Hz),3.95-4.05(2H,m),3.65-3.78(2H,m),3.58-3.65(5H,m),3.33(3H,s),2.94(1H,td,J=12.3 ,3.5Hz),2.54-2.66(1H,m),1.51-1.54(4H,m),1.28(3H,d,J=6.2Hz),0.39(4H,s).m / z(ESI):502.3(m+H) + .

[0273] Example 122: (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-5-(methylsulfonamido)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide. [ka]

[0274] N-(6-bromopyridin-2-yl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (122A) was prepared in a manner similar to that described for Example 103. m / z (ESI): 500 / 502 (M+H). + .

[0275] A mixture of N-(6-bromopyridin-2-yl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (122A, 0.085 g, 0.170 mmol), Pd(PPh3)4 (0.020 g, 0.017 mmol), and 2-(tri-n-butylstannyl)oxazole (0.053 mL, 0.255 mmol) in 1,4-dioxane (2.0 mL) was heated in an oil bath at 120° C. for 24 h. The mixture was filtered through a pad of Celite and the solid was rinsed with 2×5 mL of EtOAc. The filtrate was concentrated and subsequently purified by Shimadzu HPLC to give 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(oxazol-2-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as an off-white solid (0.043 g, 0.088 mmol, 52% yield). m / z (ESI): 489.2 (M+H). +The purity was about 83%. To a solution of 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(oxazol-2-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.043 g, 0.073 mmol) in methanol (2.0 mL) was added sodium hydroxide (0.073 mL of a 5N solution, 0.365 mmol). The mixture was heated at 70 °C for 2.5 h. The reaction mixture was concentrated and subsequently purified by silica gel chromatography (0% to 50% EtOAc:EtOH (3:1) / heptane) to give 6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(oxazol-2-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid (Example 122, 0.021 g, 0.045 mmol, 62% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 0.41(s,4H)1.45(s,6H)1.82(br.s.,4H)3.24(t,J=5.38Hz,4H)3.76(d,J=5.48Hz,2H)4.74(s,1H)5.27(t,J=5.77Hz,1H)6.26(d,J=8.61H) z,1H)7.31(s,1H)7.79(s,1H)7.81-7.90(m,2H)8.21(d,J=8.61Hz,1H)8.42(dd,J=7.83,1.37Hz,1H)12.53(s,1H).m / z(ESI):463.3(m+H) + .

[0276] Example 134: 6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] 6-Fluoro-N-(6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (134A) was prepared in a manner similar to that described for Example 103. m / z (ESI): 438.1 (M+H) + .

[0277] To a 15 mL reaction vial was added N-(6-(4,4-dimethyl-2-oxopyrrolidin-1-yl)pyridin-2-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (134A, 49 mg, 0.11 mmol), DIPEA (0.06 mL, 0.33 mmol), 2-amino-2-methyl-1-propanol (20 mg, 0.22 mmol), and DMSO (2 mL). The vial was closed and the reaction mixture was stirred at 120° C. for 12 h. The reaction mixture was cooled to RT, then diluted with water (4 mL) and extracted with EtOAc (5 mL). The organic extract was washed with water (3 mL), dried over Na2SO, filtered, and concentrated under reduced pressure to give the crude material as a white solid. The white solid was stirred in 2 mL of heptane, filtered, and dried to give N-(6-(4,4-dimethyl-2-oxopyrrolidin-1-yl)pyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 134, 51 mg, 0.101 mmol, 90% yield). 1 H NMR(400MHz,DMSO-d6)δ 12.80(s,1H),7.96-8.02(m,3H),7.80(t,J=8.02Hz,1H),6.85(s,1H),6.47(d,J= 8.80Hz,1H),4.82(t,J=5.67Hz,1H),3.81(s,2H),3.62(d,J=5.67Hz,2H),3.08(br t,J =5.28Hz,4H),2.49(s,2H),1.76(br s,4H),1.38(s,6H),1.20(m,2H),0.40(s,4H).m / z(ESI):479.2(m+H) + .

[0278] Example 135: N-(6-(4,4-dimethyl-2-oxopyrrolidin-1-yl)pyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. m / z(ESI):507.0(M+H) + . This compound was prepared according to the method described above for Example 134. [ka]

[0279] Examples 140, 141, and 142. These compounds were prepared in a manner similar to that described below for Examples 143, 153, and 154. m / z (ESI): 506.1 (M+H) + . [ka]

[0280] Examples 143, 153, and 154. [ka] To a stirred mixture of 2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinic acid (Intermediate 41, 350 mg, 1.01 mmol), 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 256 mg, 1.11 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.23 mL, 1.32 mmol) in N,N-dimethylformamide (5 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (464 mg, 1.22 mmol). The mixture was stirred at RT for 2 h and then at 60° C. for 24 h. The reaction mixture was cooled to RT and then partitioned between water (5 mL) and EtOAc (50 mL). The organic layer was concentrated and the residue was purified on an ISCO (0% to 40% EtOAc / EtOH in heptane (3 / 1)) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide (Example 143, 402 mg, 0.723 mmol, 71% yield) as a yellow solid. 1 H NMR(DMSO-d6)δ:11.36(s,1H),8.37(d,J=8.4Hz,1H),8.00-8.18(m,2H),7.71(d,J=7.4Hz,1H),7.48(s,1H),7.39(d,J= 7.8Hz,1H),6.72(s,1H),3.30(m,4H),1.70(s,3H),1.42-1.49(m,4H),1.18(s,9H),0.29(s,4H).m / z(ESI):556.2(m+H) + The racemic sample was subjected to chiral SFC to obtain the pure enantiomers. Peak 1 was arbitrarily assigned as (R)-N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide as a yellow solid (Example 153, 42 mg, >99% ee). m / z (ESI): 556.2 (m+H).+ Peak 2 was arbitrarily assigned as (S)-N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)nicotinamide as a yellow solid (Example 154, 42 mg, >99% ee). m / z (ESI): 556.2 (m+H). + .

[0281] Example 146: 6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)-N-(6-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)nicotinamide. [ka] A mixture of N-(6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 138, 0.023 g, 0.048 mmol) and palladium (23 mg, 10 wt% on activated carbon, 0.022 mmol) in EtOAc (4 mL) and EtOH (2 mL) was hydrogenated at 50 psi for 4 h. The filtrate was concentrated and dried to give the title compound as a pale yellow solid (Example 146, 22 mg, 95% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 0.39(s,4H)1.44(s,6H)1.72-2.07(m,8H)2.86(tt,J=11.52,3.84Hz,1H)3.21(br t,J=4.79Hz,4H)3.55(td,J=11.79,2.05Hz,2H)3.74(br s,2H)4.05-4.14(m,2H)4.70(br s,1H)5.43(br s,1H)6.25(d,J=8.41Hz,1H)6.87(d,J=7.43Hz,1H)7.63(t,J=7.82Hz,1H)8.18(d,J=8.22Hz,1H)8.23(d,J=8.61Hz,1H)12.42(br s,1H).m / z(ESI):480.3(m+H)+ .

[0282] Example 147: (R)-6-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1. To a solution of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 48, 26.0 g, 104.1 mmol) in DCM (650 mL) was added oxalyl chloride (13.64 mL, 156.2 mmol) followed by DMF (2 drops). The reaction mixture was stirred at RT for 30 min and then concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and treated with (R)-6-(2-methylmorpholino)pyridin-2-amine (Intermediate 12, 20.08 g, 104 mmol) followed by DIPEA (54.40 mL, 312 mmol). The reaction mixture was stirred at RT for 16 h, followed by concentration under reduced pressure and the residue was purified by column chromatography on silica gel (60-120 mesh) using 0%-15% ethyl acetate in hexane as eluent to give (R)-6-fluoro-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (147A, 26 g, 59% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 11.22(s,1H),8.38-8.10(m,1H),7.60(t,J=8.0Hz,1H),7.50(d,J =7.7Hz,1H),6.89-6.79(m,1H),6.60(d,J =8.2Hz,1H),4.19(d,J=12.7Hz,1H),4.01(d,J=12.7Hz,1H)3.91(d,J=11.2Hz,1H),3.55(t,J=11.3Hz,3H),3 .22(bs,4H),2.82(t,J=11.9Hz,1H),1.58(bs,4H),1.16(d,J=6.2Hz,3H),0.34(s,4H).m / z(ESI):426.2(m+H) + .

[0283] Step 2. A mixture of 147A (20.0 g, 47.0 mmol), 2-amino-2-methylpropane-1,3-diol (9.88 g, 94 mmol), and potassium phosphate (19.95 g, 94 mmol) in DMSO (400 mL) was heated at 135° C. for 15 h. The reaction mixture was cooled to RT, quenched by pouring into water (1500 mL), and extracted with ethyl acetate (1500 mL). The organic layer was washed with water (1000 mL), followed by brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (60-120 mesh) using ethyl acetate in hexanes (40%-65%) as eluent to give (R)-6-((1,3-dihydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as an off-white solid (Example 147, 15 g, 63% yield). 1 H NMR (400 MHz, chloroform-d) δ 12.05 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 7.72 (d, J =7.8Hz,1H),7.55(t,J=8.0Hz,1H),6.39(d,J=8.2Hz,1H),6.33(d,J=8.6 Hz,1H),5.24(s,1H),3.42-3.87(m,5H),3.84-3.63(m,6H),3.18(t,J=5.3 Hz,4H),2.95(td,J=12.2,3.6Hz,1H),2.69-2.54(m,1H),1.90-1.63(m,4H ),1.38(s,3H),1.28(d,J=6.2Hz,3H),0.39(s,4H).m / z(ESI):511.3(m+H) + .

[0284] [Table 17]

[0285] Example 156: N-(4-cyano-6-morpholinopyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A mixture of N-(4-chloro-6-morpholinopyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 152, 18.6 mg, 0.036 mmol), zinc dust (1.1 mg, 0.014 mmol, Aldrich), racemic 2-(di-t-butylphosphino)-1,1′-binaphthyl (2.9 mg, 0.007 mmol, Strem), zinc cyanide (5.1 mg, 0.043 mmol, Aldrich), and palladium(II) trifluoroacetate (2.2 mg, 0.004 mmol, Aldrich) in DMF (1.0 mL) was heated at 120° C. for 15 h. The reaction mixture was loaded directly onto a 12 g RediSep gold column and eluted with 0% to 50% (3:1 EtOAc:EtOH) in heptane, m / z (ESI): 506.3 (M+H). + The material was dissolved in 1 mL of DMSO and purified by reverse phase HPLC to give N-(4-cyano-6-morpholinopyridin-2-yl)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 156, 4.8 mg, 9.49 μmol, 26% yield) as a white solid. 1H NMR(400MHz, methanol-d4)δ ppm 0.37-0.52(m,4H)0.91(br d,J=6.06Hz,1H)1.14-1.40(m,2H)1.44(s,6H)1.50-1.55(m,1H)1.57-1.83(m,4H)1.94(s,1H)2.03(s,1H)3.48(br dd,J=6.26,4.70Hz,1H)3.54-3.64(m,4H)3.74-3.83(m,6H)6.54(br d,J=8.22Hz,1H)6.85(s,1H)7.75(s,1H)8.08(d,J=8.80Hz,1H).m / z(ESI):506.3(m+H) + .

[0286] Example 158: 2-(6-Azaspiro[2.5]octan-6-yl)-6-((1-hydroxy-2-methyl-2-propanyl)amino)-N-(4-methoxy-6-(4-morpholinyl)-2-pyridinyl)-3-pyridinecarboxamide. 1 H NMR (400MHz, methanol-d4) δ ppm 0.33(s,4H)1.34(s,6H)1.56-1.80(m,4H)3.16(br s,4H)3.43-3.47(m,4H)3.66-3.77(m,6H)3.82(s,3H)6.09(s,1H)6.34(br.d ,J=9.00Hz,1H)6.70(br.s,1H)7.90(d,J=8.80Hz,1H).m / z(ESI):511.3(m+H) + . This compound was prepared in a manner similar to that described for Example 116. [ka]

[0287] Example 159: N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A mixture of N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 173, 0.040 g, 0.087 mmol), 3-methylazetidin-3-ol (0.017 g, 0.200 mmol), and DIPEA (0.061 mL, 0.347 mmol) in DMSO (0.8 mL). The mixture was stirred at 90° C. for 24 h. The mixture was cooled to RT and treated with water (3 mL). The solid was collected and purified on a silica gel column (30% to 100% EtOAc in heptane) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as an off-white solid (Example 159, 43 mg, 93% yield). 1 H NMR(400MHz,chloroform-d)δ 12.63(s,1H),8.55(d,J=8.41Hz,1H),8.24(d,J=8.61Hz,1H),7.86(t,J=8.02Hz,1H),7.70(d,J=7. 43Hz,1H),6.11(d,J=8.61Hz,1H),4.79(s,1H),4.00-4.08(m,4H),3.20(t,J=5.38Hz,4H),2.33(br s,1H),1.71(br s,4H),1.63(s,3H),1.27(s,9H),0.40(s,4H).m / z(ESI):529.2(m+H) + .

[0288] Example 160: 2-(6-azaspiro[2.5]octan-6-yl)-N-(4-cyclopropyl-6-(4-morpholinyl)-2-pyridinyl)-6-((1-hydroxy-2-methyl-2-propanyl)amino)-3-pyridinecarboxamide. 1H NMR(400MHz, methanol-d4)δ ppm 0.43(s,4H)0.84-0.95(m,2H)1.08-1.20(m,2H)1.42(s,6H)1.69(s,4H)1.94-2.0 5(m,1H)3.27(m,4H)3.50-3.54(m,4H)3.75-3.85(m,6H)6.38-6.54(m,2H)6.73(br s,1H)7.99(d,J=9.00Hz,1H).m / z(ESI):521.3(m+H) + . This compound was prepared in a manner similar to that described for Example 113. [ka]

[0289] Examples 161 and 162. [ka] Step 1. To a solution of 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (50, 1.92 g, 5.56 mmol) in DCM (50 mL) was added oxalyl chloride solution (2.0 M in DCM, 4.17 mL, 8.34 mmol) followed by 3 drops of DMF. The mixture was stirred at RT for 2 h and then concentrated. The resulting yellow solid was dissolved in DCM (50 mL) and treated with 6-bromopyridin-2-amine (0.96 g, 5.56 mmol) followed by Hunig's base (2.91 mL, 16.68 mmol). The mixture was stirred at RT for 15 h, then concentrated and the residue was purified by silica gel chromatography (0% to 35% EtOAc / heptane) to give N-(6-bromopyridin-2-yl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (161A, 2.75 g, 5.50 mmol, 99% yield) as a yellow solid. m / z (ESI): 500 / 502 (M+H). + .

[0290] Step 2. A pressurized vial was charged with N-(6-bromopyridin-2-yl)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (161A, 0.184 g, 0.368 mmol), 4,4-dimethyloxazolidin-2-one (0.085 g, 0.735 mmol), copper(I) iodide (0.035 g, 0.184 mmol), potassium carbonate (0.102 g, 0.735 mmol), and (1r,2r)-(-)-n,n''-dimethylcyclohexane-1,2-diamine (0.052 g, 0.368 mmol). The vial was purged with N2 for 5 minutes and dioxane (1.5 mL) was added. The vial was sealed and heated at 120° C. for 2 h. The mixture was concentrated and the residue was partitioned between DCM and saturated NH4Cl. The separated organic layer was washed with saturated NH4Cl followed by brine and concentrated. Purification by silica gel chromatography (0% to 45% EtOAc / heptane) gave 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(4,4-dimethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 161, 0.098 g, 0.183 mmol, 50% yield) as a white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 0.38(s,4H)1.64-1.72(m,4H)1.75(s,6H)1.77(s,6H)3.23(t,J=5.48Hz,4H)4.12(d,J=6.46Hz,4H)7.57(d,J=8.22Hz,1H)7. 76(t,J=8.12Hz,1H)7.82(d,J=8.61Hz,1H)8.25(d,J=7.82Hz,1H)8.46(d,J=8.61Hz,1H)11.26(s,1H).m / z(ESI):535.2(m+H) + .

[0291] Step 3. To a solution of 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(4,4-dimethyl-2-oxooxazolidin-3-yl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 161, 0.090 g, 0.168 mmol) in MeOH (5 mL) was added sodium hydroxide (0.7 mL of a 5N solution, 3.50 mmol). The mixture was heated at 70° C. for 6 h. The mixture was cooled to RT and neutralized with 2N HCl. The resulting mixture was concentrated to remove MeOH. The aqueous residue was extracted with DCM. The organic extract was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and purified by silica gel chromatography (0% to 50% EtOAc:EtOH (3:1) / heptane) to give 6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid (Example 162, 0.073 g, 0.151 mmol, 90% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 0.34(s,4H)1.41(s,6H)1.43(s,6H)1.65-1.76(m,4H)3.23(t,J=5.38Hz,4H)3.73(br d,J=2.93Hz,4H)4.31(br s,1H)4.71(s,1H)4.99-5.06(m,1H)5.20(br t,J=4.89Hz,1H)6.14(d,J=8.02Hz,1H)6.17(d,J=8.41Hz,1H)7.40(t,J=8.02Hz,1H )7.69(d,J=7.83Hz,1H)8.09(d,J=8.61Hz,1H)10.86(s,1H).m / z(ESI):483.2(m+H) + .

[0292] Examples 166, 167, and 168 were prepared in a manner similar to that described for Examples 169, 177, and 178. m / z (ESI): 482.2 (M+H) + . [ka]

[0293] Example 170: 2-(6-azaspiro[2.5]octan-6-yl)-6-((1-hydroxy-2-methyl-2-propanyl)amino)-N-(6-((1-hydroxy-2-methyl-2-propanyl)amino)-4-methyl-2-pyridinyl)-3-pyridinecarboxamide. m / z(ESI): 497.3(M+H) + . This compound was prepared in a manner similar to that described for Example 162. [ka]

[0294] Examples 171, 172, 175, and 176. [ka] Step 1. Oxalyl chloride (2.0 M solution in DCM, 0.62 mL, 1.24 mmol) and 1 drop of DMF were added to a solution of 6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 49, 0.33 g, 0.82 mmol) in DCM (4 mL). The mixture was stirred for 2 h, followed by removal of volatiles under reduced pressure to give a yellow solid. 6-Amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 0.18 g, 0.79 mmol) and DIPEA (0.14 mL, 0.80 mmol), and THF (3 mL) were added to the solid prepared above, and the mixture was stirred at RT for 1 h, at which point another portion of DIPEA (0.10 mL) was added. The mixture was stirred for 1 h, another portion of Intermediate 31 (0.18 g) was added, and the mixture was stirred at RT overnight. EtOAc and H2O were added, the resulting biphasic mixture was separated, and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil. This oil was purified by silica gel chromatography eluting with a 0% to 60% EtOAc / heptane gradient to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid (Example 171, 0.49 g, 0.33 mmol, 41% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 12.03(s,1H)8.55(d,J=8.08Hz,1H)8.48(d,J=8.02Hz,1H)7.92(t,J=7.92Hz,1H)7.77(d,J =7.33Hz,1H)7.60(d,J=7.82Hz,1H)4.72(s,1H)4.66(s,2H)3.29(t,J=5.48Hz,4H)1.70(br d,J=5.09Hz,4H)1.56(s,3H)1.33-1.40(m,3H)1.27(s,9H)0.41(s,4H).m / z(ESI):612.2(m+H) + .

[0295] Step 2. A mixture of N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(2,2-dimethyl-4-(trifluoromethyl)-1,3-dioxolan-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 171, 195 mg, 0.32 mmol) and hydrochloric acid (1N aqueous solution, 2.5 mL, 2.5 mmol) in dioxane (5 mL) was heated at 80° C. for 3 h and then cooled to RT. EtOAc and saturated NaHCO3 were added, the resulting biphasic mixture was separated, and the organic extract was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography eluting with a 0% to 100% EtOAc / heptane gradient to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)nicotinamide as a white solid (Example 172, 114 mg). m / z (ESI): 572.3 (M+H). + .

[0296] Step 3. The enantiomers were separated from each other by preparative SFC using a Whelk-01 (SS) column (250×21 mm, 5 μm) with a mobile phase consisting of 80% liquid CO2 and 20% MeOH and ammonia using a flow rate of 80 mL / min. Peak 1 was arbitrarily assigned as (R)-N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)nicotinamide (Example 175, 40 mg, >99% ee). 1H NMR(400MHz,chloroform-d)δ ppm 11.59(s,1H)8.53(dd,J=8.02,4.50Hz,2H)7.93(t,J=7.92Hz,1H)7.79(d,J=7.43Hz,1H)7.43(d,J=7.82Hz,1H)5.96(s,1H) )4.79(s,1H)4.09-4.23(m,2H)3.32-3.39(m,4H)2.18(dd,J=9.19,4.89Hz,1H)1.66-1.77(m,4H)1.27(s,9H)0.42(s,4H). 19 F NMR (376 MHz, chloroform-d) δ ppm-77.39 (s, 3F). m / z (ESI): 572.3 (m+H) + Peak 2 was arbitrarily assigned as (S)-N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2,3-dihydroxypropan-2-yl)nicotinamide (Example 176, 41 mg, >99% ee). 1 H NMR(400MHz,chloroform-d)δ ppm 11.56(s,1H)8.52(t,J=7.19Hz,2H)7.93(t,J=7.92Hz,1H)7.78(d,J=7.43Hz,1H)7.43(d,J=8.02Hz,1H)5.96(br s,1H)4.83(s,1H)4.16-4.23(m,1H)4.14(br s,1H)3.32-3.39(m,4H)2.13-2.30(m,1H)1.66-1.75(m,4H)1.27(s,9H)0.42(s,4H). 19 F NMR (376MHz, chloroform-d) δ ppm-77.38 (s, 3F). m / z (ESI): 572.3 (m+H) + .

[0297] [Table 18] [Table 19]

[0298] Example 173: N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] To a stirred mixture of 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 1.28 g, 5.59 mmol), 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 48, 1.40 g, 5.59 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.29 mL, 7.27 mmol) in DMF (15 mL) was added 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (2.16 g, 6.71 mmol, Aldrich). The reaction mixture was stirred at 60° C. for 16 h, then cooled to RT and treated with 20 mL of water. The mixture was extracted with 3×25 mL of EtOAc. The combined EtOAc solution was concentrated. The residue was purified by ISCO (0% to 50% EtOAc in heptane) to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a yellow solid (Example 173, 0.54 g, 1.17 mmol, 21% yield): m / z (ESI): 462.2 (M+H). + 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinate (173A, 0.89 g, 2.41 mmol, 43% yield) was also isolated as a yellow solid. m / z (ESI): 369.1 (M+H). + .

[0299] Examples 169, 177, and 178. [ka] Step 1. To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-6-(2,2,4-trimethyl-1,3-dioxolan-4-yl)nicotinic acid (Intermediate 51, 1.95 g, 5.63 mmol) in DMF (27.0 mL) was added diisopropylethylamine (2.95 mL, 16.89 mmol), HATU (3.21 g, 8.44 mmol) and 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 1.42 g, 6.19 mmol). The reaction mixture was heated at 70° C. for 24 h. It was cooled to RT, quenched with water (10 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Isolera-One (SNAP 25 g) using a gradient of 10% to 15% ethyl acetate in petroleum ether to give intermediate 169A as a clear gum (0.7 g, 22% yield). 1 H NMR(400MHz,chloroform-d)δ 12.35(s,1H),8.58(dd,J=8.4,0.8Hz,1H),8.49(d,J=8.0Hz,1H),7.94(dd,J=8.4,7.5Hz,1H),7 .79(dd,J=7.5,0.8Hz,1H),7.60(d,J=8.0Hz,1H),4.85(s,1H),4.48(d,J=8.6Hz,1H),4.11(d,J =8.6Hz,1H),3.34(t,J=5.5Hz,4H),1.77(br.s,4H),1.64(s,3H),1.56(s,3H),1.43(s,3H),1.29(s,9H),0.45(s,4H).m / z(ESI):558.2(m+H) + .

[0300] Step 2. To a solution of intermediate 169A (1.3 g, 2.331 mmol) in 1,4-dioxane (10.0 mL) was added 1.5 N aqueous HCl (15.54 mL, 23.31 mmol). The reaction mixture was stirred at RT for 3 h, then basified with 10% aqueous NaHCO3 and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a colorless gum (Example 169, 1.20 g, 2.32 mmol, 99% yield). 1 H NMR(400MHz,DMSO-d6)δ 11.55(s,1H),8.41(d,J =8.3Hz,1H),8.17-8.03(m,2H),7.72(dd,J =7.6,1.4Hz,1H),7.60-7.47(m,1H),7.39(dd,J=7.9,1.6Hz,1H),5.14(d,J=1.5Hz,1H),4.62(td,J=6.1,1.6Hz,1H),3.58(qd,J=6.4,5.9, 4.4Hz,2H),3.24(s,4H),1.52(t,J=5.3Hz,4H),1.39(d,J=1.6Hz,3H),1.19(d,J=1.5Hz,9H),0.31(d,J=1.5Hz,4H).m / z(ESI):518.2(m+H) + .

[0301] Step 3. The enantiomers were separated from each other by preparative SFC using a Chiralpak IC (250×30 mm, 5 μm) column with a mobile phase consisting of 65% liquid CO2 and 35% EtOH using a flow rate of 100 mL / min. Peak 1 was arbitrarily assigned as (S)—N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 177, 460 mg, >99% ee). m / z (ESI): 518.2 (M+H). +.. Peak 2 was arbitrarily assigned as (R)-N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(1,2-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 178, 450 mg, >99% ee). m / z(ESI): 518.2 (M+H) + .

[0302] Examples 193, 194, and 195. [ka] Step 1. A mixture of 6-(2-fluoro-1,3-dimethoxy-1,3-dioxopropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 52, 513 mg, 1.35 mmol), 6-amino-N-(tert-butyl)pyridine-2-sulfonamide (Intermediate 31, 371 mg, 1.62 mmol), DIPEA (0.35 mL, 2.02 mmol), and HATU (667 mg, 1.753 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h. The reaction mixture was cooled to RT and partitioned between water (10 mL) and EtOAc (75 mL). The layers were separated and the organic solution was concentrated. The residue was purified by ISCO (40% EtOAc / heptane) to give dimethyl 2-(5-((6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-2-fluoromalonate (Example 193, 183 mg, 0.31 mmol, 23% yield). 1 H NMR(DMSO-d6)δ:11.05(s,1H),8.09(d,J=8.3Hz,1H),7.85(t,J=8.0Hz,1H),7.72(d,J=7. 9Hz,1H),7.48(d,J=7.7Hz,1H),7.23(s,1H),6.82(d,J=7.9Hz,1H),3.61(s,6H),3.10(br s,4H),1.11-1.16(m,4H),0.93(s,9H),0.04(s,4H).m / z(ESI):592.3(m+H) + .

[0303] Step 2. To a stirred solution of dimethyl 2-(5-((6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)pyridin-2-yl)-2-fluoromalonate (Example 193, 175 mg, 0.30 mmol) in THF (5 mL) and methanol (0.12 mL, 2.96 mmol) at 0° C. was added lithium borohydride (1.48 mL 2M in THF, 2.96 mmol) dropwise. The reaction mixture was stirred for 2 h (LC-MS showed two products: m / z (ESI): 536.0 (M+H) + and m / z (ESI): 506.0 (M + H) + It was subsequently quenched with saturated NH4Cl and extracted with DCM (3x). The combined organic extracts were dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC (10-90% 0.1% TFA in MeCN in 0.1% TFA in water). Pure fractions were neutralized with saturated NaHCO3 and extracted with EtOAc. Two compounds were obtained. The first eluted was N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(2-fluoro-1,3-dihydroxypropan-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 194, 8.5 mg, 0.016 mmol, 5% yield). 1 H NMR(DMSO-d6)δ:11.39(s,1H),8.40(br d,J=8.3Hz,1H),8.04-8.17(m,2H),7.72(d,J=7.3Hz,1H),7.51(s,1H),7.20(br d,J=6.6Hz,1H),4.87-4.97(m,2H),3.81-3.96(m,4H),3.42-3.53(m,4H),1.49(br s,4H),1.19(s,9H),0.31(s,4H).m / z(ESI):536.0(m+H) +The second eluent was N-(6-(N-(tert-butyl)sulfamoyl)pyridin-2-yl)-6-(1-fluoro-2-hydroxyethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 195, 33 mg, 0.065 mmol, 22% yield). 1 H NMR(DMSO-d6,400MHz)δ 11.41(br.s,1H),8.39(d,1H,J=7.0Hz),8.0-8.2(m,2H),7.72(d,1H,J=7.0Hz),7.51(br.s,1H),7.14(d,1H,J=6.6 Hz),5.40-5.53(m,1H),3.8-4.1(m,4H),3.24(m,3H),1.47(s,4H),1.18(s,9H),0.30(s,4H).m / z(ESI):506.0(m+H) + .

[0304] Examples 196 and 197 These compounds were synthesized in a manner similar to that described above for Examples 194 and 195.

[0305] (R)-6-(2-fluoro-1,3-dihydroxypropan-2-yl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (196): m / z (ESI): 500.0 (M+H) + .

[0306] 6-(1-fluoro-2-hydroxyethyl)-N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (197): m / z (ESI): 470.0 (M+H) + . [ka]

[0307] Example 198: dimethyl (6-(6-azaspiro[2.5]octan-6-yl)-5-((6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)carbamoyl)-2-pyridinyl)(fluoro)propanedioate. This compound was synthesized in a similar manner as described for Example 193. m / z (ESI): 556.2 (M+H) + . [ka]

[0308] Example 208: 6-(2-amino-3,3,3-trifluoro-2-(hydroxymethyl)propoxy)-N-(4-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A mixture of 6-fluoro-N-(4-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (208A, 0.030 g, 0.071 mmol) (prepared in a similar manner as described for Intermediate 147A), 2-amino-2-(trifluoromethyl)propane-1,3-diol hydrochloride (0.028 g, 0.141 mmol, FCH Group), and potassium phosphate (0.045 g, 0.212 mmol) in DMSO (1 mL) was heated at 135° C. for 18 h. The mixture was cooled to RT and subsequently filtered. The solid was rinsed with 2×1 mL of MeOH. The filtrate was concentrated and purified by reverse phase HPLC to give: 6-(2-amino-3,3,3-trifluoro-2-(hydroxymethyl)propoxy)-N-(4-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (208, 17.6 mg, 0.031 mmol, 44% yield) as a tan solid. 1H NMR(400MHz,chloroform-d)δ ppm 0.37(s,4H)1.76(br s,4H)2.32(s,3H)3.21(t,J=5.39Hz,4H)3.47-3.56(m,4H)3.73-3.81(m,2H)3.81-3.87(m,4H)4.48-4.72(m, 2H)6.24(s,1H)6.63(d,J=8.50Hz,1H)7.61(s,1H)8.42(d,J=8.50Hz,1H)11.88(s,1H).m / z(ESI):565.2(m+H) + .

[0309] Example 209: 6-(2-amino-3,3,3-trifluoro-2-(hydroxymethyl)propoxy)-N-(4-methyl-6-morpholinopyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A mixture of (R)-6-chloro-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (209A, 0.100 g, 0.226 mmol), 3-amino-3-methyl-butan-1-ol (0.047 g, 0.453 mmol) (prepared in a similar manner as described for Intermediate 147A), potassium phosphate (0.144 g, 0.679 mmol) and DMSO (1 mL) was heated at 135° C. for 18 hours.

[0310] The mixture was cooled to RT and then filtered. The solid was rinsed with 2×1 mL of MeOH. The filtrate was concentrated and purified by reverse phase HPLC to give (R)-6-(3-amino-3-methylbutoxy)-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a tan solid (Example 209, 9 mg, 7% yield). 1H NMR(400MHz,chloroform-d)δ ppm 0.37(s,4H)1.27(d,J=6.22Hz,3H)1.45(s,6H)1.73(br s,4H)2.13(br t,J=6.32Hz,2H)2.60(dd,J=12.54,10.26Hz,1H)2.90-3.00(m,1H)3.21(t,J=5.39Hz,4H)3.63-3.77(m,2H)4.01(dd,J=11.20,2.28Hz,2H)4.11(br d,J=12.02Hz,1H)4.54(t,J=6.32Hz,2H)6.38(d,J=8.09Hz,1H)6.65(d,J=8.50Hz,1H)7.54(t,J =8.09Hz,1H)7.71(d,J=7.88Hz,1H)8.37(d,J=8.50Hz,1H)11.90(s,1H).m / z(ESI):509.3(m+H) + .

[0311] Example 210: (S)-6-((4-hydroxy-2-methylbutan-2-yl)amino)-N-(6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A solution of (S)-6-fluoro-N-(6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (210A, 100 mg) (prepared in a similar manner as described for Example 173), 3-amino-3-methylbutan-1-ol (40 mg, Tyger Scientific), and Hunig's base (0.100 mL, 0.571 mmol) in DMSO (1 mL) was heated at 145° C. for 6 h. The mixture was cooled to RT and subsequently purified by reverse phase HPLC to give (S)-6-((4-hydroxy-2-methylbutan-2-yl)amino)-N-(6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as an off-white solid (Example 210, 0.037 g, 0.071 mmol, 37% yield). 1 H NMR(400MHz,chloroform-d)δ ppm 0.38(s,4H)1.51(s,6H)1.67-1.81(m,4H)2.10(t,J=6.22Hz,2H)2.77(br dd,J=12.34,10.06Hz,1H)2.98(td,J=12.23,3.32Hz,1H)3.17(br t,J=4.98Hz,4H)3.66-3.80(m,4H)3.84(t,J=6.22Hz,2H)4.01-4.14(m,3H)6.18(d,J=8.50Hz,1H)6 .37(d,J=8.29Hz,1H)7.53(t,J=8.09Hz,1H)7.75(d,J=7.88Hz,1H)8.16(d,J=8.71Hz,1H)12.15(br s,1H).m / z(ESI):525.2(m+H) + .

[0312] [Table 20]

[0313] Example 218: (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1. A mixture of (R)-2,6-dibromo-N-(6-(2-methylmorpholino)pyridin-2-yl)nicotinamide (218A, 0.300 g, 0.658 mmol) (prepared in a similar manner as described for Example 173), 6-azaspiro[2.5]octane (0.090 mL, 0.688 mmol), DIPEA (0.138 mL, 0.789 mmol), and DMSO (2 mL) was heated at 60° C. for 18 h. The reaction mixture was partitioned between water (10 mL) and EtOAc (50 mL). The organic phase was concentrated and the crude product was purified by Biotage (SNAP25, Ultra, eluent: EtOAc in heptane 10% to 60%) to give (R)-6-bromo-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (218B, 0.123 g, 39% yield) as a white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 0.39(s,4H)1.28(d,J=6.22Hz,3H)1.74(br s,4H)2.62(dd,J=12.44,10.57Hz,1H)2.97(td,J=12.28,3.63Hz,1H)3.28(t,J=5.39Hz,4H)3.65-3.78(m,2H)3.97-4.06(m,2H)4.13(br d,J=12.44Hz,1H)6.43(d,J=8.09Hz,1H)7.34(d,J=8.09Hz,1H)7.53-7.61(m,1H)7 .69(d,J=7.88Hz,1H)8.29(d,J=8.09Hz,1H)11.58(s,1H).m / z(ESI):486 / 488(m+H) + .

[0314] Step 2. A mixture of (R)-6-bromo-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (218B, 0.120 g, 0.247 mmol), methanesulfonamide (0.029 g, 0.306 mmol), copper(I) iodide (0.016 g, 0.086 mmol), and potassium phosphate (0.141 g, 0.667 mmol) in a glass vial was purged with argon for 3 minutes. DMF (1 mL) was added, followed by (1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.027 mL, 0.173 mmol). The vial was capped and the mixture was stirred at 100 °C for 3 hours. The mixture was diluted with EtOAc (4 mL) and filtered through a pad of Celite, rinsing with 10 mL of EtOAc. The filtrate was washed with water (2×5 mL) and concentrated. The crude product was purified by Biotage (SNAP25, Ultra, eluent: 10% to 80% EtOAc in heptane) to give (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-6-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 218, 59 mg, 96% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ=11.66(br s,1H),10.96(br s,1H),8.21(d,J=8.3Hz,1H),7.63-7.49(m,2H),6.70(d,J=8.3Hz,1H),6.58(d,J=8.1Hz,1H),4.18(br d,J=12.2Hz,1H),4.03(br d,J=12.6Hz,1H),3.91(br dd,J=2.2,11.5Hz,1H),3.63-3.52(m,2H),3.42(s,3H),3.16(br t,J=5.1Hz,4H),2.83(dt,J=2.9,12.1Hz,1H),2.54-2.51(m,1H),1.67(br d,J=2.7Hz,4H),1.17(d,J=6.2Hz,3H),0.35(s,4H).m / z(ESI):501.1(m+H) + .

[0315] Examples 223 to 225. [ka] To a solution of (R)-6-bromo-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (218B, 0.245 g, 0.503 mmol) in THF (1 mL) was added n-Buli (2.5 M in hexanes, 0.423 mL, 1.057 mmol) dropwise over 5 min at -78 °C and the mixture was stirred for 15 min. Zinc chloride (1.9 M in 2-methyltetrahydrofuran, 0.265 mL, 0.503 mmol) was added over 5 min. The cold bath was removed and the mixture was stirred at RT for 1 h, followed by cooling in an ice bath. 2,4,6-trichlorophenyl sulfochloridate (0.149 g, 0.503 mmol) was added over 5 min. The mixture was stirred at 0° C. for 30 min, followed by stirring at RT for 1.5 h. It was diluted with EtOAc (50 mL) and washed with water (5 mL) followed by brine (5 mL). The organic layer was concentrated and the residue was purified on a silica gel column (25-75% EtOAc in heptane) to give intermediate 223A as a brown solid (76 mg, 22% yield). m / z (ESI): 667.1 (M+H). + .

[0316] A solution of 223A (70 mg, 0.11 mmol) and DIPEA (0.10 mL, 0.12 mmol) in 3 mL of THF was divided into three equal portions and added to three glass vials. Each vial was treated with 0.1 mL of either MeNH2 or NH4OH or tBuNH2, sealed, and heated at 60 °C for 18 h. The vials were cooled to RT and the contents were purified by silica gel chromatography to give Examples 223 (2 mg), 224 (2 mg), and 225 (3 mg).

[0317] 2-(6-azaspiro[2.5]octan-6-yl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)-6-(methylsulfamoyl)-3-pyridinecarboxamide (223): 1H NMR (400 MHz, chloroform-d) δ ppm 11.16 (1H, s), 8.59 (1H, d, J = 7.9 Hz), 7.78 (1H, d, J = 7.9 Hz), 7.66-7.71 (1H, m), 7.55-7.62 (1H, m), 6.45 (1H, d, J = 8.1 Hz), 4.70 (1H, q, J = 5.4 Hz), 4.12 (1H, br d,J=12.4Hz),3.97-4.07(2H,m),3.65-3.77(2H,m),3.34(4H,t,J=5.5Hz),2.98(1H, td,J=12.3,3.5Hz),2.86(3H,d,J=5.4Hz),2.62(1H,dd,J=12.5,10.5Hz),1.74(4H,br d,J=2.1Hz),1.28(3H,d,J=6.2Hz),0.40(4H,s).m / z(ESI):501.1(m+H) + .

[0318] 2-(6-Azaspiro[2.5]octan-6-yl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)-6-sulfamoyl-3-pyridinecarboxamide (224): m / z (ESI): 1 H NMR(400MHz,chloroform-d)δ ppm 11.11(1H,s),8.59(1H,d,J=7.9Hz),7.79(1H,d,J=7.9Hz),7.65-7.70(1H,m),7.55-7.62(1H,m),6.45(1H,d,J=8.1Hz),4.98(2H,br s),4.12(1H,br d,J=12.9Hz),3.96-4.06(2H,m),3.66-3.78(2H,m),3.35(4H,t,J=5.5Hz) ,2.98(1H,td,J=12.3,3.6Hz),2.62(1H,dd,J=12.6,10.6Hz),1.74(4H,br d,J=2.3Hz),1.29(3H,d,J=6.2Hz),0.40(4H,s).487.1(m+H) + .

[0319] 2-(6-azaspiro[2.5]octan-6-yl)-N-(6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)-6-((2-methyl-2-propanyl)sulfamoyl)-3-pyridinecarboxamide (225): 1 H NMR(400MHz,chloroform-d)δ ppm 11.35(1H,s),8.60(1H,d,J=7.9Hz),7.82(1H,d,J=7.9Hz),7.69(1H,d,J= 7.9Hz),7.55-7.62(1H,m),6.45(1H,d,J=8.3Hz),4.82(1H,s),4.13(1H,br d,J=12.4Hz),3.97-4.06(2H,m),3.65-3.78(2H,m),3.33(4H,t,J=5.4Hz) ,2.98(1H,td,J=12.3,3.7Hz),2.63(1H,dd,J=12.5,10.5Hz),1.75(4H,br d,J=1.9Hz),1.29(3H,s),1.27(9H,s),0.41(4H,s).m / z(ESI):543.1(m+H) + .

[0320] Examples 232 and 233. [ka] Step 1. To a solution of 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (Intermediate 50, 1.00 g, 2.90 mmol) in DCM (10 mL) at 0° C. was added oxalyl chloride solution (2.17 mL of 2M in DCM, 4.34 mmol) followed by 2 drops of DMF. The mixture was stirred at RT for 1 h and then concentrated. The residue was dissolved in DCM (10 mL), cooled to 0° C., then treated with 6-fluoro-pyridin-2-ylamine (0.422 g, 3.76 mmol) followed by diisopropylethylamine (1.52 mL, 8.69 mmol). The mixture was stirred at RT for 3.75 h and then quenched with methanol and evaporated. The residue was dissolved in ethyl acetate (40 mL), washed with brine (10 mL), dried over sodium sulfate, and evaporated onto silica gel. The residue was purified by chromatography on silica gel (40 g, 0% to 70% ethyl acetate in heptane) to give 6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-fluoropyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (232A, 0.753 g, 1.71 mmol, 59% yield). m / z ESI 440.1.

[0321] Step 2. 6-(4,4-Dimethyl-2-oxooxazolidin-3-yl)-N-(6-fluoropyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (232A, 0.100 g, 0.228 mmol) was dissolved in DMSO (1 mL) and diisopropylethylamine (0.200 ml, 1.14 mmol) and tert-butyl N-(3-piperidinyl)carbamate (0.092 g, 0.456 mmol) were added. The mixture was heated in a microwave at 200° C. for 60 min. The mixture was cooled, diluted with ethyl acetate (40 mL), washed with brine (2×40 mL), dried over sodium sulfate, and evaporated to give 232B, which was carried forward without purification. m / z ESI 634.2 (M+H) + .

[0322] Step 3. tert-Butyl (1-(6-(6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamido)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (232B) was dissolved in methanol (0.6 mL). 2 mL of 5N NaOH was added and the mixture was evaporated under a stream of nitrogen. The residue was dissolved in methanol (4 mL) and the mixture was heated at 70° C. for 8 hours. The mixture was cooled and purified by HPLC (0.1% NHOH in HO (A) and ACN (B) as mobile phase, XBridge column (19 × 100 mm, 10 μm)) to give tert-butyl (1-(6-(6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (Example 232, 17 mg, 0.027 mmol, 25%). 1 H NMR(500MHz,DMSO-d6)δ ppm 0.30-0.37(m,4H)1.33-1.41(m,16H)1.59-1.79(m,5H)2.69-2.79(m,4H)2.89-3. 09(m,5H)3.16(d,J=5.32Hz,1H)3.59(d,J=5.71Hz,3H)4.09-4.20(m,2H)4.31(br m / z ESI 608.2(m+H) + .

[0323] Step 4. tert-Butyl (1-(6-(6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (Example 232, 10.5 mg, 0.017 mmol) was dissolved in 1 mL of DCM, 0.1 mL of TFA was added and the mixture was stirred for 30 min. The mixture was evaporated and purified by silica gel chromatography (1% to 5% 2M NH in MeOH in DCM) to give tert-butyl (1-(6-(6-((1-hydroxy-2-methylpropan-2-yl)amino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (Example 233, 8.4 mg, 16.5 mmol, 96%). 1 H NMR(400MHz,chloroform-d)δ ppm 0.38(s,4H)1.37-1.49(m,8H)1.52-1.71(m,3H)1.71-1.88(m,4H)1.90-2.10(m,1H)2.51(s,3H) )2.58-2.67(m,1H)2.95(dd,J=12.65,8.71Hz,1H)3.07(ddd,J=13.06,10.06,3.21Hz,1H)3.20( t,J=5.39Hz,4H)3.73(s,2H)4.00-4.12(m,2H)4.68(s,1H)6.23(m,J=8.71Hz,1H)6.42(d,J=8. 29Hz,1H)7.49(t,J=7.98Hz,1H)7.65(d,J=7.88Hz,1H)8.22(m,J=8.71Hz,1H)11.94(s,1H).m / z ESI 508.1(m+H) + .

[0324] [Table 21]

[0325] Example 237: (R)-6-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1. To a solution of 4,6-dichloronicotinic acid (10.0 g, 52.1 mmol) in DMF (100 mL) was added potassium carbonate (14.4 g, 104 mmol) and iodomethane (7.4 g, 52.1 mmol) at 0° C. The reaction mixture was stirred at RT for 16 h before being quenched with water. The resulting solid was filtered and dried to give methyl 4,6-dichloronicotinate (237A, 7.0 g, 34.0 mmol, 65% yield) as a white solid. m / z (ESI): 206.1 (M+H). + .

[0326] Step 2. To a solution of methyl 4,6-dichloronicotinate (237A, 7.0 g, 34.0 mmol) in DMF (70 mL), K2CO3 (4.7 g, 34.0 mmol) and 6-azaspiro[2.5]octane (3.8 g, 34.0 mmol) were added and the reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using a gradient of 1% to 35% EtOAc in petroleum ether to give methyl 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinate as a white solid (237B, 6.1 g, 21.7 mmol, 64% yield). 1 H NMR(300MHz,DMSO-d6):δ ppm 8.29(d,J=1.4Hz,1H),7.02(d,J=1.4Hz,1H),3.82(d,J=1.3Hz,3H),3.18- 3.28(m,4H),1.37-1.47(m,4H),0.32- 0.38(m,4H).m / z(ESI):281.1(m+H) + .

[0327] Step 3. To a solution of methyl 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinate (237B, 5.0 g, 17.8 mmol) in water (35 mL) and tetrahydrofuran (15 mL), LiOH (1.3 g, 53.4 mmol) was added and the reaction mixture was stirred for 5 h at 70° C. Subsequently, the reaction mixture was quenched with 3N HCl at 0° C. and the solid thus obtained was filtered and dried to give 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (237C, 5.0 g, 105%) as a white solid, which was used as such in the next step. 1 H NMR(400MHz,DMSO-d6):δ ppm 13.19(s,1H),8.29(s,1H),6.99(s,1H),3.23-3.30(m,4H),1.40-1.47(m,4H),0.35(s,4H).m / z(ESI):267.1(m+H) + .

[0328] Step 4. To a solution of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (237C, 1.5 g, 5.6 mmol) in dichloromethane (15 mL), DIPEA (4.9 mL, 28.1 mmol), (R)-6-(2-methylmorpholino)pyridin-2-amine (12, 1.3 g, 6.7 mmol), T3P (14.31 g 50 wt% in ethyl acetate, 22.5 mmol) were added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then diluted with water (30 mL) and extracted with DCM (3×25 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography using a gradient of 1% to 30% EtOAc in petroleum ether to give (R)-6-chloro-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (237D, 0.65 g, 1.47 mmol, 26% yield) as a pale yellow solid. 442.1 (M+H) + .

[0329] Step 5. A mixture of (R)-6-chloro-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (237D, 650 mg, 1.47 mmol), 2-hydroxyethane-1-sulfonamide (221 mg, 1.76 mmol), KPO (905 mg, 4.27 mmol), (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (105 mg, 0.73 mmol), and copper(I) iodide (280 mg, 1.47 mmol) in DMF (8 mL) was heated at 105° C. for 16 h. The reaction mixture was then filtered through a plug of Celite and the filter cake was rinsed with 2×50 mL of EtOAc. The filtrate was washed with water, then with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by reverse-phase preparative HPLC to give (R)-6-((2-hydroxyethyl)sulfonamido)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 237, 20 mg, 0.38 mmol, 26% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.90(s,1H),8.37(s,1H),7.59(t,J=8.0Hz,1H),7.49(d,J=8.1Hz,1H),6.75(s,1H),6.60(d,J=8.2Hz,1H),4.87(br s,1H),4.19(d,J=13.2Hz,1H),4.02(d,J=12.7Hz,2H),3.83-3.99(m,2H),3.26-3.58(m,6H),3.09(m,4H) )2.82(dd,J=14.2,10.5Hz,1H),1.63(s,4H),1.17(d,J=6.1Hz,3H),0.35(s,4H).m / z(ESI):531.2(m+H) + .

[0330] Example 238: (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-6-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] A mixture of (R)-6-fluoro-N-(6-(2-methylmorpholino)pyridin-2-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (147A, 100 mg, 0.23 mmol) and sodium methanesulfinate (48 mg, 0.47 mmol) in DMF (2 mL) was heated in a microwave at 150° C. for 30 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 1-40% EtOAc in hexanes to give (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-6-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 238, 70 mg, 0.14 mmol, 61% yield) as a pale yellow solid. m / z ESI 486.3 (M+H). + .

[0331] [Table 22]

[0332] Example 243: (R)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] Step 1. A mixture of (R)-6-chloro-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (237D, 100 mg, 0.22 mmol), 4,4-dimethyloxazolidin-2-one (26 mg, 0.22 mmol), Cs2CO3 (74 mg, 0.22 mmol), Xantphos (131 mg, 0.22 mmol), and Pd2(dba)3 (207 mg, 0.22 mmol) in 1,4-dioxane (1 mL) was heated at 100° C. for 16 h. The reaction mixture was then filtered through a plug of Celite and the filter cake was rinsed with 2×25 mL of EtOAc. The filtrate was washed with water followed by brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 15% to 40% EtOAc in petroleum ether to give (R)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid (243A, 35 mg, 0.067 mmol, 30% yield). m / z (ESI): 521.2 (M+H). + .

[0333] Step 2. To a solution of (R)-6-(4,4-dimethyl-2-oxooxazolidin-3-yl)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (243A, 35 mg, 0.067 mmol) in methanol (0.3 mL) and water (0.3 mL) was added 10% NaOH solution (0.3 mL, 0.13 mmol) in one portion and the reaction mixture was heated at 60° C. for 4 h. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The concentrate was purified by flash column chromatography eluting with a gradient of 0% to 40% EtOAc in petroleum ether to give (R)-6-((1-hydroxy-2-methylpropan-2-yl)amino)-N-(6-(2-methylmorpholino)pyridin-2-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid (Example 243, 25 mg, 0.051 mmol, 75% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 11.60(s,1H),8.50(s,1H),7.45-7.64(m,2H),6.73(s,1H),6.51-6.59(m,1H),6.43(s ,1H),5.22(t,J=5.6Hz,1H),4.11-4.22(m,1H),4.01(d,J=12.8Hz,1H),3.90(dt,J=11 .0,2.0Hz,1H),3.45-3.71(m,5H),2.93(t,J=5.4Hz,4H),2.80(td,J=12.4,3.5Hz,1H) ,1.67(s,4H),1.27(s,6H),1.16(d,J=6.2Hz,3H),0.34(s,4H).m / z(ESI):495.3(m+H) + .

[0334] Example 244: N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-6-(1-(methylsulfonyl)ethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide. [ka] To a mixture of (R)-N-(6-(2-methylmorpholino)pyridin-2-yl)-6-((methylsulfonyl)methyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (Example 239, 0.55 g, 1.10 mmol) and potassium tert-butoxide (0.18 g, 1.65 mmol) in THF (10 mL) was added methyl iodide (0.10 mL, 1.65 mmol) at 0° C. After stirring at 0° C. for 1 h, the reaction was quenched with ice water (10 mL) and extracted with EtOAc (2×20 mL). The organic solution was concentrated under reduced pressure. The crude material was absorbed onto a plug of 60-120 mesh silica gel and purified by silica gel chromatography (0-10% EtOAc in DCM) to give N-(6-((R)-2-methylmorpholino)pyridin-2-yl)-6-(1-(methylsulfonyl)ethyl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white fluffy solid (Example 244, 50 mg, 9% yield). m / z ESI 514.3.

[0335] Example 245: N-(2-(6-azaspiro[2.5]oct-6-yl)-3-pyridinyl)-6-(4-morpholinyl)-2-pyridinecarboxamide. [ka] Step 1. 6-Azaspiro[2.5]octane (0.58 g, 5.18 mmol, Wuxi AppTech) was added to a solution of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol, Aldrich) and DIPEA (1.00 mL, 5.70 mmol) in THF (15 mL) at 0 °C. The mixture was stirred for 2 h, followed by the addition of EtOAc and water. The resulting biphasic mixture was separated and the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil. The oil was fused to silica gel and purified by silica gel chromatography eluting with a 0% to 20% EtOAc / heptane gradient to give 6-(6-chloro-3-nitropyridin-2-yl)-6-azaspiro[2.5]octane as a yellow solid (245A, 1.16 g, 4.33 mmol, 84% yield). 1 H NMR(400MHz,DMSO-d6)δ ppm 8.27(d,J=8.41Hz,1H)6.87(d,J=8.22Hz,1H)3.36-3.43(m,4H)1.41-1.47(m,4H)0.38(s,4H).m / z(ESI):268.1(m+H) + .

[0336] Step 2. Concentrated HCl (2 mL) was added dropwise to a mixture of 6-(6-chloro-3-nitropyridin-2-yl)-6-azaspiro[2.5]octane (245A, 1.16 g, 4.33 mmol) and iron (0.97 g, 17.3 mmol) in EtOH (15 mL) and water (3 mL). The mixture was heated to 80° C. for 4 h and then cooled to RT. The resulting suspension was filtered through Celite and the filtrate was partitioned between EtOAc and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (2×), dried over anhydrous MgSO4, filtered and concentrated to give a red oil. The oil was purified by silica gel chromatography eluting with a 0-50% EtOAc / heptane gradient to give 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-amine (245B, 0.76 g, 3.21 mmol, 74% yield) as a red solid. 1H NMR(400MHz,chloroform-d)δ ppm 6.90(d,J=8.02Hz,1H)6.81(d,J=8.02Hz,1H)3.76(br s,2H)3.11(t,J=5.48Hz,4H)1.51(br s,4H)0.34(s,4H).m / z(ESI):238.1(m+H) + .

[0337] Step 3. A mixture of 6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-amine (245B, 0.89 g, 3.75 mmol), 6-morpholinopicolinic acid (0.78 g, 3.75 mmol, Apollo Scientific), DIPEA (1.96 mL, 11.2 mmol), and HATU (4.27 g, 11.2 mmol) in DMA (10 mL) was heated to 60° C. for 16 h, then cooled to RT. EtOAc was added and the mixture was washed twice with water, then concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography eluting with a 50% EtOAc / heptane gradient to give N-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide as an off-white solid (245C, 0.58 g, 1.35 mmol, 35.9% yield). m / z (ESI): 428.1 (M+H). + .

[0338] Step 4. A mixture of N-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide (245C, 50 mg, 0.12 mmol), palladium (10 wt% on activated carbon, 50 mg, 0.047 mmol), and ammonium formate (74 mg, 1.17 mmol) in EtOH (2 mL) under argon was heated to 60° C. for 30 min and then cooled to RT. The mixture was filtered through Celite and the filtrate was diluted with EtOAc and water. The resulting biphasic mixture was separated and the organic layer was washed with water (1x), dried over anhydrous MgSO4, filtered, and concentrated to give N-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide (Example 245, 45 mg, 0.11 mmol, 98% yield) as an off-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 10.57(br s,1H)8.82(dd,J=8.12,1.66Hz,1H)8.12(dd,J=4.79,1.66Hz,1H)7.68-7.75(m,2H)7.09(dd,J=8.02,4.89Hz,1H)6.84(d ,J=7.63Hz,1H)3.88-3.94(m,4H)3.67-3.74(m,4H)3.10(t,J=5.38Hz,4H)1.57(s,4H)0.39(s,4H).m / z(ESI):394.1(m+H) + .

[0339] Example 246: N-(2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl)-6-morpholinopicolinamide. [ka] Step 1. A mixture of N-(6-chloro-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide (245C, 0.28 g, 0.65 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (92 mg, 0.130 mmol), and tributyl(1-ethoxyvinyl)stannane (0.35 g, 0.98 mmol) in toluene (3 mL) was heated at 90° C. under argon for 16 h, then cooled to RT. 4N HCl in dioxane (0.75 mL) was added and the mixture was stirred for 2 days. EtOAc and saturated aqueous NaHCO3 were added and the resulting biphasic mixture was separated. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give an oil. The oil was purified by silica gel chromatography (0% to 100% EtOAc / heptane) to give N-(6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide (246A, 103 mg, 0.24 mmol, 36% yield) as an orange solid. 1 H NMR(400MHz,chloroform-d)δ ppm 10.70(s,1H)8.92(m,J=8.41Hz,1H)7.87(m,J=8.22Hz,1H)7.67-7.76(m,2H)6.86(dd,J=8.22,0.98Hz,1H)3.88-3. 95(m,4H)3.64-3.77(m,4H)3.14(t,J=5.48Hz,4H)2.68(s,3H)1.49-1.70(m,4H)0.42(s,4H).m / z(ESI):436.2(m+H) + .

[0340] Step 2. A mixture of N-(6-acetyl-2-(6-azaspiro[2.5]octan-6-yl)pyridin-3-yl)-6-morpholinopicolinamide (246A, 103 mg, 0.24 mmol), tetramethylammonium fluoride (33 mg, 0.36 mmol), and trimethyl(trifluoromethyl)silane (0.052 mL, 0.355 mmol) in THF (1.5 mL) was stirred at RT for 16 h. The solvent was removed under reduced pressure and the resulting oil was purified by silica gel chromatography (40% EtOAc / heptane) to give N-(2-(6-azaspiro[2.5]octan-6-yl)-6-(1,1,1-trifluoro-2-hydroxypropan-2-yl)pyridin-3-yl)-6-morpholinopicolinamide (246A, 8.5 mg, 0.017 mmol, 7% yield) as a pale yellow oil. 1 H NMR(400MHz,chloroform-d)δ ppm 10.49(s,1H)8.90(d,J=8.22Hz,1H)7.64-7.76(m,2H)7.24-7.26(m,1H)6.79-6.89(m,1H)6.08(s,1H)3.82-3. 96(m,4H)3.58-3.74(m,4H)3.05-3.22(m,4H)1.73(s,3H)1.58(s,4H)0.36-0.45(m,4H)m / z(ESI):506.3(m+H) + .

[0341] Example 247: 2-(6-azaspiro[2.5]octan-6-yl)-N-(5-fluoro-6-((2R)-2-methyl-4-morpholinyl)-2-pyridinyl)-6-((1-hydroxy-2-methyl-2-propanyl)amino)-3-pyridinecarboxamide. This compound was prepared in a manner similar to that described above for Example 104. 1H NMR(400MHz,DMSO-d6):δ ppm 12.51(s,1H),7.95(d,J=8.7Hz,1H),7.72(dd,J=8.5,2.4Hz,1H),7.53(dd,J=12.8,8.5Hz ,1H),6.82(s,1H),6.44(d,J=8.7Hz,1H),4.82(t,J=5.7Hz,1H),3.79-3.94(m,3H),3.62-3 .73(m,2H),3.60(d,J=5.7Hz,2H),3.05(t,J=5.5Hz,4H),2.91-2.99(m,1H),2.60-2.70(m ,1H),1.70(s,4H),1.36(s,6H),1.16(d,J=6.2Hz,3H),0.37(s,4H).m / z(ESI):513.3(m+H) + . [ka]

[0342] Example 248: 6-(4,4-difluoropiperidin-1-yl)-N-(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)picolinamide. [ka] Step 1. A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.41 mmol, Combi-blocks), 6-azaspiro[2.5]octane hydrochloride (2.447 g, 16.57 mmol, AstaTech), and potassium carbonate (5.97 g, 43.2 mmol, Aldrich) in 12 mL DMSO was heated in a 60° C. oil bath for 10 min, followed by a 90° C. oil bath for 1 h. The mixture was cooled to RT, treated with 20 mL water, and extracted with 2×50 mL EtOAc. The combined organic extracts were washed with 2×5 mL water and concentrated. The residue was purified on a silica gel column (15% to 45% EtOAc in heptane) to give 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane as an orange solid (4.26 g, 13.69 mmol, 95% yield). m / z (ESI): 311.0 / 313.0 (M+H).+ .

[0343] Step 2. To a mixture of 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane (2.91 g, 9.35 mmol) and ammonium chloride (1.50 g, 28.1 mmol, Aldrich) in EtOH (16 mL) and water (4.00 mL) was added iron powder (3.13 g, 56.1 mmol, Aldrich). The heterogeneous mixture was heated in an oil bath at 85° C. for 2 h. The dark mixture was diluted with 50 mL of MeOH and filtered through a pad of Celite. The filter cake was rinsed with 2×5 mL of MeOH. The filtrate was concentrated. The residue was partitioned between 10 mL of water and 75 mL of water. The organic layer was dried over Na2SO4 and concentrated to give 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (248A, 2.23 g, 7.95 mmol, 85% yield) as a brown oil, which was used in the next step without further purification. 1 H NMR(400MHz, methanol-d4)δ 6.87(d,J=2.28Hz,1H),6.77(dd,J=2.18,8.40Hz,1H),6.48(d,J=8.50Hz,1H), 4.65(s,4H),1.23-1.50(br.s,4H),0.18(s,4H).m / z(ESI):281.0 / 283.0(m+H) + .

[0344] Step 3. To a solution of 6-fluoropicolinic acid (242 mg, 1.71 mmol, Aldrich), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline (248A, 455 mg, 1.61 mmol), and DIPEA (565 μL, 3.24 mmol) in 12 mL of DCM was added T3P (50 wt% in ethyl acetate, 1.44 mL, 2.43 mmol) at 0° C. The mixture was stirred at RT for 1 h, then diluted with 50 mL of DCM and washed with 10 mL of water followed by 10 mL of 0.5 N NaOH. The organic solution was concentrated and the residue was purified on a silica gel column (10% to 25% EtOAc in heptane) to give N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-6-fluoropicolinamide (248B, 539 mg, 1.33 mmol, 82% yield) as a brown solid. m / z (ESI): 404 / 406 (M+H). + .

[0345] Step 4. A solution of 4,4-difluoropiperidine hydrochloride (136 mg, 0.86 mmol, Matrix Scientific), N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-6-fluoropicolinamide (248B, 290 mg, 0.72 mmol), and DIPEA (0.37 mL, 2.15) in 3 mL DMSO was heated in a microwave at 185° C. for 2.5 h, followed by 200° C. for 0.5 h. The mixture was cooled to RT and partitioned between water (10 mL) and EtOAc (50 mL). The layers were separated and the organic layer was dried over MgSO4 and concentrated. The residue was purified by ISCO (0% to 30% EtOAc in heptane) to give N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-6-(4,4-difluoropiperidin-1-yl)picolinamide (248C, ca. 65%, m / z (ESI): 505 / 507 (M+H)). + ) and N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-6-fluoropicolinamide (248B, ca. 35%, m / z (ESI): 404 / 406 (M+H) +) to give 310 mg of a brown solid, which was used without further purification.

[0346] Step 5. A mixture of N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-6-(4,4-difluoropiperidin-1-yl)picolinamide (248C, 155 mg, approx. 65% purity), 2-hydroxyethane-1-sulfonamide (89 mg, 0.71 mmol, Enamine), potassium phosphate (377 mg, 1.77 mmol, Aldrich), dimethylglycine (36.6 mg, 0.355 mmol, Oakwood), and copper(I) iodide (34 mg, 0.18 mmol, Strem) in 4 mL DMF was degassed for 3 min. The mixture was heated at 130° C. for 6 h, then cooled to RT and partitioned between 5 mL water and 50 mL EtOAc. The layers were separated and the organic layer was washed with 3 mL brine and concentrated. The residue was purified by reverse phase HPLC (10% to 90% (CH) in (0.1% TFA in water) 3 0.1% TFA in CN) to give 6-(4,4-difluoropiperidin-1-yl)-N-(4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)picolinamide bis(2,2,2-trifluoroacetate) as a brown solid (248, 25 mg). 1 H NMR(400MHz, methanol-d4)δ 8.14-8.27(m,1H),7.68(t,J=7.93Hz,1H),7.48(d,J=7.26Hz,1H),7.11-7.24(m,1H),6.95-7.09(m,2H),4.74(s,14H),4.65(br t,J=5.70Hz,1H),3.84(m,6H),3.18(m,2H),2.90(s,4H),1.93-2.12(m,4H),1.42-1.69(m,4H),0.33(s,4H). 19 F NMR (376 MHz, methanol-d4) δ-77.72 (s, 6F), -99.15 (s, 2F). m / z (ESI): 550.2 (m+H) + ..

[0347] Example 249: The following compounds have the formula: [ka] can be prepared according to the methods described in the examples above.

[0348] [Table 23]

[0349] [Table 24]

[0350] [Table 25]

[0351] [Table 26]

[0352] 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.

[0353] 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 m Add 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.

[0354] 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.

[0355] [Table 27]

[0356] [Table 28]

[0357] [Table 29]

[0358] [Table 30]

[0359] [Table 31]

[0360] [Table 32]

[0361] [Table 33]

[0362] [Table 34]

[0363] [Table 35]

[0364] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. Those skilled in the art will recognize that changes and modifications may be practiced within the scope of the appended claims. It is therefore to be understood that the above description is intended to be illustrative, and not limiting. The scope of the invention should, therefore, be determined not with reference to the above description, but with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0365] 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 individually indicated.

Claims

1. Compounds of Formula I: 【Chemistry 1】 or any pharma- ceutically acceptable salt thereof, wherein: X １ is N or CR ６ and X ２ is N or CR ７ and X ３ is N or CR ８ and X ４ is N or CR ９ and X １ , X ２ , X ３ , and X ４ 3 or less of the X ２ , X ３ , and X ４ When any of is N, L is -NR ３ -(C=O)-, X ２ , X ３ , and X ４ When all of are not N, L is -(C=O)-NR ３ - and R １ is a group -Z-R １２ and wherein, Z is -C ０－４ alk-, -NR １１ -, -NR １１ SO ２ -C ０－４ alk-, -SO ２ NR １１ -C ０－４ alk-, -NR １１ SO ２ NR １１ -, -NR １１ SO ２ NR １１ -C(=O)-O-, -C ０－４ alk-S(=O)(=NH)-, C ０－４ alk-NR １１ -S(=O)(=NH), -C ０－４ alk-S-, -C ０－４ alk-S(=O)-, -C ０－４ alk-SO ２ -, -O-, -P-, -P(=O), -P(=O) ２ , -(C=O)-, -(C=O)NR １１ -, or -NR １１ (C=O), and R ２ is a halo or a group -Y-R １３ wherein Y is -C ０－４ alk-, -N(C ０－１ alk)-C ０－４ alk-, -C(=O)NR ａ R ａ (C １－４ alk)-, -O- ０－４ alk-, -S-, -S=O, -S(=O) ２ -, -SO ２ N (C ０－１ alk)-C ０－４ alk-, -N(C ０－１ alk)-SO ２ -C ０－４ alk-, -C ０－４ alk-S(=O)(=NH)-, -(C=O)-, -C ０－４ alk-(C═O)—O—; or Group -Y-R １３ is -N=S(=O)-(R １３） ２ In the formula, two R １３ can alternatively combine with their respective bonded sulfur atoms to form a saturated or partially saturated 3-, 4-, 5-, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; R ３ is H, methyl, or ethyl; R ４ H, halo, C １－４ alk or C １－４ Helloalk, R ５ H, halo, C １－８ alk or C １－４ Helloalk, R ６ H, halo, CN, R ６ａ Or R ６ｂ and R ７ H, halo, C １－４ alk or C １－４ Helloalk, R ８ H, halo, C １－８ alk or C １－４ Helloalk, R ９ H, halo, C １－４ alk or C １－４ Helloalk, R x is 【Chemistry 2】 and R １１ is H or C １－８ alk, R １２ H, halo, R １２ａ , or R １２ｂ and R １３ is R １３ａ Or R １３ｂ and R ６ａ , R 12a, and R １３ａ is independently, at each occurrence, 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 １４ and oxo; R ６ｂ , R 12b, and R １３ｂ is independently, at each occurrence, F, Cl, Br, -C(=O)OR ａ , -OR ａ , -C １－２ Haloalk, -OC １－１ Haroalk, CN, NH ２ , NH(CH ３ ), or N(CH ３ ) ２ C is substituted by 0, 1, 2, 3, 4, or 5 groups selected from １－６ alk is selected from the group consisting of R １４ は、F、Cl、Br、C １－６ alk、C １－４ ハロalk、-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 , -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 １－６ 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 by 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 The compounds of formula I or any pharma- ceutically acceptable salt thereof, wherein the compounds are substituted by 0, 1, 2 or 3 substituents selected from alk.

2. R ３ is H or methyl.

3. Z is absent, -NH-, -NHSO ２ -, -O-, -SO ２ NH-, -S(=O)(=NH)-, -CH ２ -S(=O)(=NH)-, -SO ２ --, --CH ２ -SO ２ , or C.H. ３ (CH)-SO ２ and R １２ is (a) H, (b) F, (c) F, Cl, Br, -CF ３ , C(=O)CH ３ , -OH, -OCH ３ , N.H. ２ , cyclopropyl, cyclopropylmethanol, or 3-(trifluoromethyl)-3H-diazirinyl; １－６ alk, or (d) F, Cl, Br, methyl, ethyl, -CF ３ , -C １－６ alkOH, -OH, -OCH ３ , N.H. ２ or oxo; or R １２ The compound according to any one of claims 1 to 2, wherein is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, oxazolidinyl, 1,3-dioxolanyl, or pyrrolidinyl.

4. R １ is a group -Z-R １２ where Z is -NHSO ２ -or-SO ２ NH- and R １２ is cyclopropyl, or R １２ is C substituted by 0, 1, 2 or 3 OH groups １－６ alk or R １ is a group -Z-R １２ where Z is -NHSO ２ - and R １２ is -CH ２ -CH ２ The compound according to any one of claims 1 to 3, wherein said compound is -OH.

5. R ２ is a group -YR １３ In the formula, Y is absent, -NH-, or -NHSO ２ - and R １３ is F, Cl, Br, methyl, ethyl, CF ３ , C.H. ２ OH, -OH, -OCH ３ , -NH ２ , NH(CH ３ a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or an 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2, or 3 groups selected from aryl, aryloxy ... R １３ is F, Cl, Br, -OH, -OC １－４ substituted by 0, 1, 2, 3, 4, or 5 groups selected from haloalk, or CN; １－６ alk or R ２ is a saturated 5- or 6-membered monocyclic ring, each of said rings containing 1 or 2 N atoms and 0 or 1 O atoms, 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. １４ and oxo; or R ２ teeth, (a) F, Br; (b) a group -YR １３ wherein Y is absent or SO ２ and R １３ is morpholinyl, oxazolidinyl, oxazolyl, pyrrolidinyl, piperidinyl, azetidinyl, dihydropyranyl, dihydropyridinyl, piperazinyl, or tetrahydropyranyl. and each of said rings is selected from the group consisting of F, Cl, Br, methyl, ethyl, —OH, —OCH ３ , C.H. ２ O.H., N.H. ２ , NH(CH ３ the group -YR substituted by 0, 1, 2 or 3 group(s) selected from １３ or (c) a group -YR １３ In the formula, Y is NH or -SO ２ NH- and R １３ is F, Cl, Br, methyl, CF ３ or OH; １－６ The group -YR １３ or R ２ is a group -YR １３ wherein Y is absent and R １３ is morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl, or tetrahydrofuranyl; and each of said rings is selected from the group consisting of F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ the group -YR being substituted by 0, 1, 2 or 3 groups selected from , CN, and oxo; １３ or (c) a group -YR １３ In the formula, Y is NH, —O—, —O—(CH ２ ) -, -O-(CH ２ )-(CH ２ )-, or -O-(CH ２ )-(CH ２ )-(CH ２ )-, and R １３ is F, Cl, Br, methyl, CF ３ , -OH, or CN; １－６ The group -YR １３ and R ２ is F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ , CN, or oxo; or R ２ is morpholinyl substituted by one, two or three methyl groups; or R ２ is piperidinyl substituted by 1, 2 or 3 fluoro groups; The compound according to any one of claims 1 to 4.

6. R ４ The compound according to any one of claims 1 to 5, wherein is H or halo.

7. R ５ The compound according to any one of claims 1 to 6, wherein is H.

8. R ６ The compound according to any one of claims 1 to 7, wherein is H or F.

9. R ７ (a) H; (b) F, Cl, Br, -OH, -OCH ３ or cyclopropyl; １－６ alk; or (c) F, Cl, Br, C １－６ alk, C １－４ Haloalk, -C １－６ alkOH, -OH, -OCH ３ , -NH ２ 9. The compound according to any one of claims 1 to 8, wherein the ring is selected from a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, substituted by 0, 1, 2 or 3 groups selected from N, C, H, NH, NH2, or NH3.

10. R ６ The compound according to any one of claims 1 to 9, wherein is H.

11. R ７ The compound according to any one of claims 1 to 10, wherein is H.

12. R ８ The compound according to any one of claims 1 to 11, wherein is H.

13. R ９ The compound according to any one of claims 1 to 12, wherein is H.

14. 【Table 1】 【Table 2】 【Table 3】 2. The compound of claim 1 selected from:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

16. A medicament for use in a method of treating a condition that can be treated with a KIF18A inhibitor, the medicament comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a composition according to claim 15, the method comprising administering the compound or composition to a patient in need thereof, the condition being selected from (a) a solid or blood-borne tumor selected from the group consisting of 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 ... (c) hematopoietic tumors of the lymphatic system selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia; (d) tumors of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma; (e) tumors of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) cancer selected from the group consisting of melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, follicular thyroid cancer, and Kaposi's sarcoma.

17. 16. A method for reducing the size of a solid tumor in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a composition according to claim 15.

18. 19. A medicament for use in a method of treating a cell proliferation disorder in a subject, the medicament comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a composition according to claim 15, the method comprising administering the compound or composition to the subject in need thereof.

19. 17. A method for inhibiting KIF18A in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharma- ceutical acceptable salt thereof, or a composition according to claim 15, the method comprising contacting the cell with the compound, or a pharma- ceutical acceptable salt thereof, or the composition comprising the compound.

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