Heteroarylamides useful as KIF18A inhibitors

Abstract

To provide a new class of compounds useful for modulating KIF18A protein alone or in a bound complex with microtubules, for treating KIF18A-mediated conditions and / or diseases, including cancer, inflammation, or ciliary body lesions.SOLUTION: Chemical compounds having the general formula (I) are provided. (In the formula: X1 is N or -CR6; X2 is N or CR7; X3 is N or CR8; X4 is N or CR9; and R6 to R9 are H, halo, or the like; provided that one, two or three of X1, X2, X3 and X4 are N.)SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Cancer is one of the most widespread diseases afflicting humankind and is a leading cause of death worldwide. Over the past 20-30 years, many groups have invested considerable time, effort, and resources in attempts to discover effective treatments or cures for one or more of the diverse types of cancer. However, to date, only a few of the available cancer treatments and therapies have achieved significant success.

[0003] Cancer is often characterized by uncontrolled cell proliferation. Damage to one or more genes that govern cellular pathways controlling proliferation throughout the cell cycle and centrosome cycle can lead to a loss of normal regulation of cell proliferation. These disordered genes may encode various tumor suppressor or oncogene proteins involved in the event cascade, resulting in uncontrolled cell cycle progression and cell proliferation. Various kinases and kinesin proteins have been identified that play crucial roles in cell cycle and mitotic regulation, as well as in the progression of normal dividing cells and cancer cells.

[0004] Kinesin is a molecular motor that plays a crucial role in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesin plays a role in spindle assembly, chromosome segregation, centrosome separation, and several aspects of dynamics (discussed 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," the ATPase activity of which drives unidirectional movement along microtubules (MTs). The non-motor domains of these proteins are responsible for cargo binding, which can include a wide variety of membrane organelles, signal transduction scaffolding systems, and chromosomes. Kinesin uses the energy from ATP hydrolysis to move cargo along polar microtubules. For this reason, kinesin is often called a "plus-terminus" or "minus-terminus" directional motor.

[0005] The KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end oriented motor. KIF18A is thought to influence the dynamics of the plus ends of kinetochore microtubules, which control correct chromosome positioning and spindle tension. Depletion of human KIF18A leads to longer spindles, increased chromosomal oscillations during metaphase mitosis, 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 treatment. KIF18A is overexpressed in various types of cancer, including but not limited to colorectal cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, uterine cancer, and ovarian cancer. Furthermore, gene deletion, knockdown, or inhibition of KIF18A induces mitotic spindle apparatus formation in cancer cell lines. Specifically, inhibition of KIF18A has been found to induce mitotic cell arrest, apoptosis-mediated mitotic cell death, known vulnerabilities, mitotic catastrophe, or polypolarity-driven lethality or death after mitotic slip in intermediate phase. Therefore, there is a strong interest in discovering inhibitors of the KIF18A protein.

[0006] Therefore, inhibiting 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 [Overview of the project]

Means for Solving the Problem

[0008] The present invention provides a novel class of compounds useful for regulating KIF18A protein, either alone or in a binding complex with microtubules, for treating KIF18A-mediated symptoms and / or diseases including cancer, inflammation, or ciliopathologies.

[0009] The compounds provided by the present invention have MT-based KIF18A regulatory activity, and particularly KIF18A inhibitory activity. For this purpose, the present invention also provides the use of these compounds, and their pharmaceutically acceptable salts, in the preparation and manufacture of pharmaceutical compositions or agents for the therapeutic, prophylactic, acute, or chronic treatment of KIF18A-mediated diseases and disorders, including but not limited to cancer. Thus, the compounds of the present invention are useful in the manufacture of anti-cancer agents. The present invention also provides a process for producing a compound of formula I, and intermediates useful in such processes.

[0010] In Embodiment 1, the present invention provides a compound of formula (I),

Chemical Formula

[0011] In Embodiment 1a, the present invention is [ka] The present invention provides compounds of formula (I) selected from the following.

[0012] In Embodiment 2, the present invention is expressed in the formula where L is -NR 3 -(C=O), X 1 is N, and X 2 CR 7 X 3 is N, and X 4 CR 9 And equation (Ia): [ka] The present invention provides compounds having the following properties.

[0013] In Embodiment 3, the present invention is expressed in the formula where L is -(C=O)-NR 3 - and X 1 CR 6 X 2 CR 7 X 3 CR 8 X4 CR 9 And equation (Ib): [ka] The present invention provides a compound having the following characteristics:

[0014] In Embodiment 4, the present invention is expressed in the formula where L is -(C=O)-NR 3 - and X 1 N is X 2 CR 7 X 3 CR 8 X 4 CR 9 And equation (Ic): [ka] The present invention provides a compound having the following characteristics:

[0015] In Embodiment 5, the present invention is expressed in the formula where L is -(C=O)-NR 3 - and X 1 N is X 2 CR 7 X 3 N is X 4 CR 9 And the formula (Id): [ka] The present invention provides compounds having the following properties.

[0016] In Embodiment 6, the present invention is R 3 The present invention provides compounds in which the element is H or methyl.

[0017] In Embodiment 7, the present invention provides a compound according to any one of Embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10jEach of them is H, Haro, C 1-6 alk, or C 1-4 It is Haloalk, R 10a and R 10b Each of these pairs combines with the carbon atom bonded to each of them, R x A saturated 3, 4, or 5-membered monocyclic ring is formed relative to the ring, and the ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S.

[0018] In sub-embodiment 7a, R x The ring is piperidinyl.

[0019] In Embodiment 8, the present invention provides a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R 10i , and R 10j Each of these is H, methyl, or ethyl, and R 10a and R 10b Each of these pairs combines with the carbon atom bonded to each of them, R x It forms a spiro-like cyclopropyl, cyclobutyl, or cyclopentyl ring on the ring.

[0020] In sub-embodiment 8a, R x The ring is piperidinyl.

[0021] In Embodiment 9, the present invention provides a compound according to any of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, R x teeth, [ka] Selected from.

[0022] In Embodiment 10, the present invention provides a compound according to any of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, Rx teeth, [ka] That is the case.

[0023] Embodiment 11 provides a compound according to any of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, where Z is absent, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, or -(C=O)NH-.

[0024] In Embodiment 12, the present invention provides a compound according to any of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, R 12 (a)H; (b)F, Cl, Br, -OH, -OCH3, or cyclopropyl is substituted with 0, 1, 2, or 3 groups selected from C 1-6 alk; or (c) F, Cl, Br, C 1-6 alk, C 1-4 Haloalk, -C 1-6 alkOH, -OH, -OCH3, -NH 2、 Alternatively, 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, which are substituted by 0, 1, 2, or 3 groups selected from oxo.

[0025] Embodiment 13 provides a compound according to any of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, R 12 This is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiadinyl.

[0026] Embodiment 14 provides a compound according to any of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CN, or base-ZR 12And Z is absent, -NH-, -NHSO2-, -SO2NH-, -N=S(=O)-(R 11 )2(In the formula, two R 11 The pairs are, in combination with the sulfur atoms alternately 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), -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, R 12 teeth, (a) H, (b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranil, oxetanil, tetrahydrofuranil, azetidinil, imidazolyl, morpholinil, pyrrolidinil, piperazinil, [ka] (Each ring is substituted with 0, 1, 2, or 3 OH, F, methyl, -CH2OH, -C(=O)OCH3, -C(=O)OC(CH3)3, NH2, CN, and oxo), or (c) C is substituted by 0, 1, 2, or 3 OH, F, -C(=O)OCH3, -NH2, -NH(CH3), or -N(CH3)2. 1-6 Selected from alk.

[0027] Embodiment 15 provides a compound according to any of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CN or base-ZR 12 And Z is absent, -NH-, -NHSO2-, -SO2NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO2-, -(C=O)-, or -(C=O)NH-, and R 12 teeth, (a) H; (b) Oxetanyl, cyclopropyl; or (c) C substituted with 0, 1, 2, or 3 OH groups1-6 It is an alk.

[0028] Embodiment 16 provides a compound according to any of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, with the group -ZR 12 -N=S(=O)-(R 12 )2, and in the formula, two R 12 The pairs of these combine with the sulfur atoms bonded to each of them alternately, [ka] A saturated or partially saturated 3, 4, 5, or 6-membered monocyclic ring can be formed containing 0, 1, 2, or 3 N atoms selected from, and 0, 1, or 2 atoms selected from, O and S.

[0029] Embodiment 17 provides a compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is, base-ZR 12 And Z is -NHSO2- or -SO2NH-, and R 12 is either oxetanyl, cyclopropyl, or R 12 C is substituted with 0, 1, 2, or 3 OH groups. 1-6 It is an alk.

[0030] Embodiment 18 provides a compound according to any of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 is base-ZR 12 And Z is -NHSO2- and R 12 It is -CH2-CH2-OH.

[0031] Embodiment 19 provides a compound according to any of Embodiments 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 2 is, base-YR 13 And Y is absent, -NH-, -NH-(CH2) 0-4 -, or -O-(CH2) 0-4 And, R 13 F, Cl, Br, C 1-6 alk, C 1-4 Halo-alk, -OH, -OC 1-4 Haloalk, CN, R 14 A saturated, partially saturated, or unsaturated 3, 4, 5, 6, or 7-membered monocyclic ring or a 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered bicyclic ring containing 0, 1, 2, or 3 N atoms substituted by 0, 1, 2, or 3 groups selected from oxo, and 0 or 1 atom selected from O and S, or, R 13 F, Cl, Br, -OH, -OC 1-4 C is substituted with 0, 1, 2, 3, 4, or 5 groups selected from haloalk or CN. 1-6 It is an alk.

[0032] In Embodiment 20, the present invention provides a compound according to any of Embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, R 2 The ring is a saturated 5 or 6-membered monocyclic ring, each of which contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and each of which contains F, Cl, Br, C 1-6 alk, C 1-4 Halo-alk, -OH, -OC 1-4 Haloalk, CN, R 14 It is substituted with 0, 1, 2, or 3 groups selected from the oxo.

[0033] Embodiment 21 provides a compound according to any of Embodiments 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2 teeth, (a) Base-YR 13 In the equation, Y is absent, and R 13 These include morpholinil, piperidinil, azetidinil, pyrrolidinil, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinil, tetrahydrofuranil, [ka] Each of the above rings is substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN, and oxo, the group -YR- 13 is or (b) Base-YR 13 In the formula, Y is NH, -O-, -O-(CH2)-, -O-(CH2)-(CH2)-, or -O-(CH2)-(CH2)-(CH2)-, and R 13 teeth [ka] Either or R 13 F, Cl, Br, methyl, CF 3、 -OH, or C, which is substituted with 0, 1, 2, 3, 4, or 5 groups selected from CN. 1-6 It is alk, base-YR 13 That is the case.

[0034] In Embodiment 22, the present invention provides a compound according to any of Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, R 2 It is a morpholinyl or piperidinyl compound substituted with 0, 1, 2, or 3 groups selected from F, Cl, Br, methyl, CF3, -OH, -OCHF2, CN, or oxo.

[0035] Embodiment 23 provides a compound according to any of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, R 2 This is morpholinyl substituted with one, two, or three methyl groups.

[0036] Embodiment 24 provides a compound according to any of Embodiments 1 to 23, or a pharmaceutically acceptable salt thereof, R 2 This is a piperidinyl compound substituted with one, two, or three fluoro groups.

[0037] Embodiment 25 provides a compound according to any of Embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, R 2 teeth, [ka] That is the case.

[0038] Embodiment 26 provides a compound according to any of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, R 4 It is methyl.

[0039] Embodiment 27 provides a compound according to any of Embodiments 1 to 26, or a pharmaceutically acceptable salt thereof, R 5 H is H.

[0040] Embodiment 28 provides a compound according to any of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, R 6 It is either H or F.

[0041] In Embodiment 29, the present invention provides a compound according to any of Embodiments 1 to 28, or a pharmaceutically acceptable salt thereof, R 7 It is either H or F.

[0042] In Embodiment 30, the present invention provides a compound according to any of Embodiments 1 to 29, or a pharmaceutically acceptable salt thereof, R 8 H is H.

[0043] In Embodiment 31, the present invention provides a compound according to any of Embodiments 1 to 30, or a pharmaceutically acceptable salt thereof, R 9 H is H.

[0044] In Embodiment 32, the present invention provides a compound selected from the following, or a pharmaceutically acceptable salt thereof, or any pharmaceutically acceptable salt thereof.

[0045] [Table 1]

[0046] [Table 2]

[0047] [Table 3]

[0048] Embodiment 33 provides a pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0049] Embodiment 34 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 32, or a composition described in Embodiment 33, to a patient in need thereof.

[0050] In Embodiment 35, the present invention provides the method of Embodiment 34, wherein the above symptoms are (a) solid or blood-derived tumors selected from cancers 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, ciliary cell lymphoma (c) Lymphoid hematopoietic malignancies selected from follicular lymphoma and Burkitt lymphoma; (d) Myeloid hematopoietic malignancies selected from acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia; (e) Mesenchymal tumors selected from fibrosarcoma and rhabdomyosarcoma; (e) Central and peripheral nervous system tumors selected from astrocytoma, neuroblastoma, glioma, and schwannoma; or (f) Cancers selected from the group consisting of melanoma, seminomas, teratomas, osteosarcomas, xeroderma pigmentosum, keratosacral cell carcinoma, follicular thyroid carcinoma, or Kaposi's sarcoma.

[0051] In sub-embodiment 35a, the present invention provides the method of embodiment 34, wherein the above symptoms are cancers 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.

[0052] Embodiment 36 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 to 32, or a composition described in Embodiment 33, to a subject in need thereof.

[0053] Embodiment 37 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 to 32, or a composition described in Embodiment 33, to a subject in need thereof.

[0054] Embodiment 38 provides a method for inhibiting KIF18A in cells, comprising contacting cells with a compound described in Embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, or a composition described in Embodiment 33.

[0055] Embodiment 39 provides a method for preparing a compound of formula (I) as described herein.

[0056] Embodiment 40 provides an intermediate compound used in a method for preparing a compound of formula (I) as described herein. [Modes for carrying out the invention]

[0057] The present invention comprises all pharmaceutically acceptable isotope-labeled compounds of the present invention, in which one or more atoms are substituted by atoms having the same atomic number but having an atomic mass or mass number different from the predominant atomic mass or mass number in nature.

[0058] Examples of isotopes suitable for inclusion in the compound of the present 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 Examples include sulfur isotopes such as ₂S, but are not limited to these.

[0059] The specific isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes, are useful in studies of drug and / or substrate tissue distribution. The radioactive isotope tritium, i.e. 3 H and carbon 14, that is14 C is particularly useful for this purpose in terms of ease of acquisition and ease of detection.

[0060] Deuterium, that is 2 Substitution with heavier isotopes, such as 1H, can be preferable in some situations because it can lead to certain therapeutic benefits, such as an extended in vivo half-life or a reduced required dose, resulting from increased metabolic stability.

[0061] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to investigate the receptor occupancy rate of substrates.

[0062] The isotope-labeled compounds of the present invention can generally be prepared by means of the prior art known to those skilled in the art, or by using a suitable isotope-labeling reagent instead of a previously used unlabeled reagent, in a manner similar to that described in the accompanying examples and preparations.

[0063] Examples of pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent can be substituted with an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0064] Specific embodiments of the present invention include the compounds exemplified in the following examples, as well as their pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs, and other derivatives.

[0065] Unless otherwise specified, the following definitions apply to terms found herein and in the claims.

[0066] "C α-β"alk" refers to an alkyl group that has a branched or linear relationship, or any combination of these three, containing a minimum of α and a maximum of β carbon atoms, where α and β are integers. Alkyl groups described in this section may also contain one or two double or triple bonds. The notation C0alk refers to a direct bond. 1-6 Examples of alkyl groups include, but are not limited to, the following: [ka]

[0067] The "benzo group," either alone or in combination, refers to a divalent radical C4H4=, one of which, when bonded adjacent to another ring, forms a benzene-like ring, such as tetrahydronaphthylene or indole, as -CH=CH-CH=CH-.

[0068] The terms "oxo" and "thioxo" represent the groups =O (as found in carbonyl groups) and =S (as found in thiocarbonyl groups), respectively.

[0069] "Halo" or "halogen" refers to a halogen atom selected from F, Cl, Br, and I.

[0070] "C α-β "Halo-alk" refers to the above-mentioned alk group in which any number (at least one) of the hydrogen atoms bonded to the alk chain are substituted with F, Cl, Br, or I.

[0071] Group N(R a )R a For example, two R a Examples include substituents in which both groups optionally form rings containing N, O, or S atoms, and these include: [ka] These are some examples of the basis for which this is based.

[0072] Group N(C α-β alk)C α-βalk (where α and β are as defined above) includes two C α-β alk groups, each optionally having a substituent that forms a ring containing an N, O, or S atom. Examples of such substituents include

Chemical formula

[0073] The term "bicyclic ring" means a group characterized by two joined rings. The bicyclic ring may be carbocyclic (all ring atoms are carbon) or heterocyclic (the ring atoms consist of, in addition to carbon atoms, for example, 1, 2, or 3 heteroatoms, such as N, O, or S). Both of the two rings may be aliphatic (e.g., decalin and norbornane), or aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin). Examples of bicyclic rings include (a) spiro ring compounds, where the two rings share only a single atom, which is usually a quaternary carbon atom, i.e., the spiro atom. Examples of spiro ring compounds include

Chemical formula

Chemical formula

Chemical formula

[0074] "Carbon ring" or "carbon ring formula" means, by itself or in combination with other terms, unless otherwise specified, "C α-β This refers to a ring that includes the cyclic version of "alk". Examples of carbocyclic rings include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, and cyclohexylene.

[0075] A "heterocyclic ring" or "heterocyclic formula" means a ring comprising at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocyclic rings that may be found in the claims include: [ka] These are some possible examples, but are not limited to them.

[0076] "Pharmacologically acceptable salts" means salts prepared by conventional means, which are well known to those skilled in the art. Examples of "pharmacologically acceptable salts" include, but are not limited to, basic salts of inorganic and organic acids such as 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, and mandelic acid. When the compounds of the present invention contain acidic functional groups such as carboxyl groups, suitable pharmaceutically acceptable cation pairs for carboxyl groups are well known to those skilled in the art, and include alkalis, alkaline earth elements, ammonium, and quaternary ammonium cations. For additional examples of "pharmacologically acceptable salts," see below and Berge et al., J. Pharm. Sci. 66:1 (1977).

[0077] "Saturated, partially saturated, or unsaturated" includes substituents saturated with hydrogen, substituents not saturated with hydrogen at all, and substituents partially saturated with hydrogen.

[0078] A "detaching group" generally refers to a group that can be readily substituted by a nucleophile, such as an amine, thiol, or alcohol nucleophile. Such detaching groups are well known in the art. Examples of such detaching groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, and tosylates. Preferred detaching groups are shown herein as needed.

[0079] A “protecting group” generally refers to a group well known in the art that is used to prevent selected reactive groups, such as carboxy, amino, hydroxy, and mercapto, from undergoing undesirable reactions such as nucleophilic, electrophilic, oxidation, and reduction reactions. Preferred protecting groups are shown 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, and silyl. Examples of aralkyl groups include, but are not limited to, benzyl, orthomethylbenzyl, trityl, and benzhydryl, which can be optionally substituted with halogens, alkyl, alkoxy, hydroxy, nitro, acylamino, and acyl, as well as salts of phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenantrenyl, and durenyl. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals having 6 to 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, and phthaloyl. A mixture of protecting groups can be used to protect the same amino group, such as when a primary amino group is protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups, together with the nitrogen to which they are bonded, can also form heterocyclic rings such as 1,2-bis(methylene)benzene, phthaliumidyl, succinimidyl, and maleimidyl, and these heterocyclic groups may further contain adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups may be monosubstituted, disubstituted, or trisubstituted, such as nitrophthaliumidyl. The amino group can also be protected from undesirable reactions such as oxidation by forming addition salts of hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid, etc.Many amino acid protecting groups are also suitable for protecting carboxyl, hydroxyl, and mercapto groups. For example, aralkyl groups. Alkyl groups such as tert-butyl are also suitable for protecting hydroxyl and mercapto groups.

[0080] A silyl protecting group is a silicon atom optionally substituted with one or more alkyl, aryl, and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane, and diphenylmethylsilyl. Silylation of an amino group yields a mono- or disilylamino group. Silylation of an amino alcohol compound can yield N,N,O-trisilyl derivatives. Removal of the silyl functional group from a silyl ether functional group is easily achieved as a separate reaction step or in situ during the reaction with the alcohol group, for example, by treatment with a metal hydroxide or ammonium fluoride reagent. Suitable silylation agents include, for example, trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride, or combination products thereof with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Furthermore, methods for preparing these amine derivatives from corresponding amino acids, amino acid amides, or amino acid esters are well known to those skilled in organic chemistry, including amino acid / amino acid ester chemistry, or amino alcohol chemistry.

[0081] 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 and hydrolysis. Preferred methods involve the removal of protecting groups, such as the removal of benzyloxycarbonyl groups by hydrolysis using palladium carbon in a suitable solvent system such as alcohol, acetic acid, or mixtures thereof. t-Butoxycarbonyl protecting groups can be removed using inorganic or organic acids such as HCl or trifluoroacetic acid in a suitable solvent system such as dioxane or methylene chloride. The resulting amino salt can be readily neutralized to obtain a free amine. Carboxylated protecting groups such as methyl, ethyl, benzyl, tert-butyl, and 4-methoxyphenylmethyl can be removed under hydrolysis and hydrolysis conditions well known to those skilled in the art.

[0082] The compounds of the present invention may contain tautomerizable groups such as cyclic and acyclic amidine and guanidine groups, and heteroatom-substituted heteroaryl groups (Y'=O, S, NR), as illustrated in the following examples: [ka] In this specification, one form is named, described, indicated, and / or claimed, but it should be noted that all tautomers are essentially included in such naming, description, indication, and / or claims.

[0083] Prodrugs of the compounds of the present invention are also investigated in accordance with the present invention. Prodrugs are active or inactive compounds that, after administration to a patient, are chemically modified by in vivo physiological actions such as hydrolysis and metabolism to become the compounds of the present invention. The suitability and techniques for the manufacture and use of prodrugs are well known to those skilled in the art. For an overview of ester-containing prodrugs, 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). The amines are masked as arylcarbonyloxymethyl-substituted derivatives that are cleaved in vivo by esterase, releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Furthermore, drugs containing acidic NH groups, such as imidazoles, imides, and indoles, are masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups are masked as esters and ethers. European Patent No. 039,051 (Sloan and Little, 4 / 11 / 81) discloses Mannich base hydroxamic acid prodrugs, their preparation, and use.

[0084] This specification and the claims include enumerations of chemical species using the expressions “selected from ~ and ~” and “or ~” (sometimes referred to as Markush groups). When used in this application, unless otherwise specified, this term is intended to include the entire group, any single component thereof, or any subgroup thereof. The use of this expression is solely for abbreviated purposes and does not in any way limit the exclusion of individual elements or subgroups as necessary.

[0085] Pharmaceutical Composition, Administration, and Administration Route Furthermore, this specification also provides a pharmaceutical composition comprising a compound disclosed herein together with a pharmaceutically acceptable excipient such as a diluent or a carrier. Suitable compounds and pharmaceutical compositions for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. The administration of the compound will be described in more detail below.

[0086] Suitable pharmaceutical formulations can be determined by those skilled in the art according to the administration route and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). The formulation can affect the physical state, stability, in vivo release rate, and in vivo clearance rate of the administered drug. Depending on the administration route, the suitable dosage can be calculated according to body weight, body surface area, or organ size. Further fine-tuning of the calculations necessary to determine the appropriate therapeutic dosage can be mechanically performed by those skilled in the art without performing more experiments than necessary, especially in light of the dosage information and assays disclosed herein and the pharmacokinetic data obtained from animal or human clinical trials.

[0087] The terms “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce adverse allergic or other undesirable reactions when administered to animals or humans. As used herein, “pharmaceutically acceptable excipients” include all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, etc. The use of such excipients with pharmaceutically active substances is known in the art. Their use in a therapeutic composition is considered unless any conventional medium or agent is incompatible with the therapeutic composition. Auxiliary active ingredients may also be incorporated into the composition. In exemplary embodiments, the formulation contains 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, dicatrix 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, and L-cystine dihydrochloride. It may contain 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 selenite, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0088] The compounds may be present in pharmaceutical compositions as pharmaceutically acceptable salts. Examples of "pharmaceutically acceptable salts" as used herein include base addition salts and acid addition salts.

[0089] pharmaceutically acceptable base addition salts can be formed with metals or amines such as alkali metals, alkaline earth metals, or organic amines. pharmaceutically acceptable salts of compounds can also be prepared with pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali, 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.

[0090] Examples of pharmaceutically acceptable acid addition salts include salts of inorganic or organic acids. Suitable examples of salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art, and include, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; organic carboxylic acids, sulfonic acids, sulfoacids or phosphoacids or N-substituted sulfamic acids, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, Examples include salts with embonic acid, nicotinic acid or isonicotinic acid; with 20 alpha amino acids involved in the synthesis of natural proteins, such as glutamic acid or aspartic acid; and salts with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with cyclamate formation), or other acidic organic compounds such as ascorbic acid.

[0091] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured by conventional methods, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet manufacturing, powdering, emulsification, encapsulation, encapsulation, or lyophilization processes. The appropriate formulation depends on the selected route of administration.

[0092] Suitable compositions for oral administration can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients such as carriers well known in the art. Such excipients and carriers enable the compounds of the present invention to be formulated as tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by patients being treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds disclosed herein together with a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants as needed to obtain a tablet or coated tablet core. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants may be added as needed. Pharmaceutically acceptable components are well known for various types of formulations and may include, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavorings, coatings, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various types of formulations.

[0093] When a therapeutically effective amount of the compounds disclosed herein is administered orally, the compositions are typically in the form of solids (e.g., tablets, capsules, pills, powders, or lozenges) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0094] When administered in tablet form, the composition may further contain a functional solid and / or a functional solid carrier, such as gelatin or an adjuvant. Tablets, capsules, and powders may contain about 1 to about 95% of the compound, preferably about 15 to about 90%.

[0095] When administered in liquid or suspension form, functional liquids and / or functional liquid carriers, such as water, petroleum, or animal or plant-derived oils, may be added. The liquid form of the composition may further contain physiological saline solution, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in liquid or suspension form, the composition may contain about 0.5 to about 90% by weight of the compounds disclosed herein, preferably about 1 to about 50% of the compounds disclosed herein. In one possible embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. When administered in liquid form, the composition may be supplied as a rapidly soluble solid formulation that dissolves or suspends immediately before administration.

[0096] When a therapeutically effective dose 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. The preparation of such parenterally acceptable solutions, with due consideration to pH, isotonicity, stability, etc., is within the scope of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compounds disclosed herein. Such compositions may be prepared for administration as a solution of a free base or pharmacokinetically acceptable salt in water, appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as in oil. Under normal storage and use conditions, these preparations may optionally contain preservatives to prevent microbial growth.

[0097] The injectable composition may include sterile aqueous solutions, suspensions or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions, suspensions or dispersants. In all embodiments, this form must be sterile and fluid enough to allow for easy needle penetration. It must be stable under manufacturing and storage conditions and, optionally, withstand contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one possible embodiment, the carrier is non-aqueous or substantially non-aqueous. Adequate fluidity can be maintained, for example, by the use of coating agents such as lecithin, maintaining the particle size of the compounds required in the dispersion embodiment, and the use of surfactants. Prevention of microbial activity can be provided by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many embodiments, it is preferable to include an isotonic agent, such as sugar or sodium chloride. Sustained absorption of an injectable composition can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0098] Sterile injectable solutions are prepared by incorporating the required amount of the active compound, along with the various other necessary components listed above, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other desired components from the components listed above. In embodiments of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, in which a powder containing the active ingredient plus any additional desired components is obtained from a pre-sterilized filtered solution thereof.

[0099] Sustained-release or sustained-release formulations can also be prepared to provide controlled release of active compounds in contact with bodily fluids in the gastrointestinal tract and to deliver substantially constant and effective levels of the active compound in plasma. For example, release can be controlled by one or more of the following: dissolution, diffusion, and ion exchange. Furthermore, the sustained-release approach can enhance absorption via saturable or restricted pathways in the gastrointestinal tract. For example, for this purpose, the compound can be embedded in a polymer matrix with 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 into the polymer matrix. Controlled-release formulations can also be obtained by encapsulation of dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0100] For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant. In the pressurized aerosol embodiment, the dose unit can be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, gelatin capsules and cartridges for use in inhalers or injectors, can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0101] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). The injectable formulations can be provided in unit dosage forms (e.g., ampoules or multi-dose containers) with added preservatives. The compositions can take the form of suspensions, liquids or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers and / or dispersants.

[0102] Pharmaceutical formulations for parenteral administration include aqueous solutions of the compound in a water-soluble form. Furthermore, suspensions of the compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and enable the preparation of highly concentrated solutions. Alternatively, the composition of the present invention may be in powder form for configuration with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0103] The compounds disclosed herein can also be formulated in rectal compositions such as suppositories or retained enemas (e.g., those containing conventional suppository bases). In addition to the formulations described herein, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by injection (e.g., subcutaneous or intramuscular) or by intramuscular injection. Accordingly, for example, the compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion-exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts.

[0104] In particular, the compounds disclosed herein may be administered orally, orally, or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules alone or in mixtures with excipients, or in the form of elixirs or suspensions containing flavoring agents or coloring agents. Such liquid formulations may be prepared using pharmaceutically acceptable additives such as suspending agents. The compounds may also be administered parenterally, for example, by intravenous, intramuscular, subcutaneous, or coronary artery injection. For parenteral administration, the compounds are most commonly used in the form of sterile aqueous solutions that may contain other substances, such as salts or sugar alcohols such as mannitol or glucose, to make the solution isotonic with blood.

[0105] For veterinary use, the compounds disclosed herein are administered as appropriately acceptable formulations in accordance with normal veterinary practice. Veterinarians can easily determine the most appropriate administration plan and route for a particular animal.

[0106] In some embodiments, in the treatment of KIF18A-related disorders, all components necessary for such treatment, either using the compounds disclosed herein alone or in combination with other conventionally used drugs or interventions for the treatment of such disorders, can be packaged in a kit. Specifically, the present invention provides a kit for use in a treatment intervention for a disorder, comprising a drug comprising the compounds disclosed herein, as well as buffers and other components for preparing a deliverable form of the drug, and / or an instrument for delivering such drug, and / or any drug used in combination therapy with the compounds disclosed herein, and / or a packaged set of instructions for the treatment of the disorder packaged together with the drug. The instructions may be fixed on printed paper or any tangible medium such as computer-readable magnetic or optical media, or may refer to a data source on a remote computer, such as a page on the World Wide Web accessible via the Internet.

[0107] "Therapeutic dose" means an amount effective in treating, preventing the progression of, or alleviating the existing symptoms of the subject being treated. Determining the effective dose is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure provided herein. Generally, "therapeutic dose" refers to the amount of compound that produces the desired effect. For example, in one preferred embodiment, a therapeutic dose of the compound disclosed herein reduces KIF18A activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0108] The amount of compound administered may depend on the subject being treated, their age, health, sex, and weight, the type of concurrent treatment (if any), the severity of the disease, the nature of the desired effect, the mode and frequency of treatment, and the judgment of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen pressure. Individual needs vary, but determining the optimal range of effective amounts of the compound is within the scope of the art. Such doses may be administered as a single dose or divided into multiple doses.

[0109] As used herein, the terms “cancer” and “cancerous” refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, sarcomas, blastomas, and leukemias. More specific examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, and head and neck cancers, ovarian cancer, and endometrial cancer. As used herein, the term “cancer” is not limited to any specific form of any disease, but the methods of the present invention appear to be particularly effective for cancers that are accompanied by uncontrolled levels of KIF18A, or that have been found to be dependent on KIF18A for proper chromosome segregation and survival in mammals.

[0110] As used herein, the terms “treat,” “treating,” and “treatment” refer to therapies including, but not limited to, curative, prophylactic, and preventive therapies. Prophylactic treatment generally consists of either preventing the onset of the entire disorder in an individual, or delaying the onset of a stage before the disorder becomes clinically apparent.

[0111] As used herein, the terms “patient,” “subject,” or “mammal” refer to any “patient,” “subject,” or “mammal,” including humans, cattle, horses, dogs, and cats. In one embodiment of the present invention, the mammal is a human.

[0112] The term "includes" means that it is open-ended, including the listed components but not excluding other elements.

[0113] The term "Formula I" includes any sub-formulas.

[0114] Method using KIF18A inhibitors This disclosure provides compounds that generally have MT-based KIF18A modulating activity, specifically inhibitory activity. One embodiment of the present invention provides a method for modulating the KIF18A protein in a subject, the method comprising administering an effective dose of the compound of formula I to the subject. Thus, the compounds of the present invention may be used to treat cell proliferation disorders, including uncontrolled cell growth, abnormal cell cycle regulation, and centrosome abnormalities (structural and / or numerical). Other diseases or disorders involving the accumulation of excess centrosomes (>2) include HPV infections, including human papillomavirus (HPV)-associated neoplasm formation. The compounds are also useful for ciliary disorders and for ablating haploid germ cell populations, which may be used as male contraceptives.

[0115] In addition, the compounds of the present invention are useful in preventing or treating cancer and other KIF18A-mediated diseases or disorders, though not limited to these. For example, the compounds of the present invention are useful in various solid and hematopoietic 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, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphatic system (leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, It is useful in the treatment of: pilocytic cell lymphoma and Burkitt lymphoma; myeloid hematopoietic malignancies (including acute and chronic myeloid leukemia, myelodysplastic syndromes, and promyelocytic leukemia); mesenchymal tumors (fibrosarcomas and rhabdomyosarcomas, and other sarcomas, such as those of soft tissue and bone); tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma, and schwannoma); and other tumors (including melanoma, seminomas, teratomas, osteosarcomas, xeroderma pigmentosum, keratosacral cell tumors, follicular thyroid carcinoma, and Kaposi's sarcoma).

[0116] The compounds of the present invention are also useful in treating 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 effusion, and malignant ascites.

[0117] 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 disorders. Specifically, these compounds can be used to treat various inflammatory rheumatoid-like diseases, particularly symptoms in the musculoskeletal system, especially chronic polyarthritis including rheumatoid arthritis, juvenile arthritis, or psoriatic arthritis; paraneoplastic syndromes or tumor-induced inflammatory diseases, turbid exudates, collagen diseases, such as systemic lupus erythematosus, polymyositis, dermatomyositis, systemic scleroderma, or mixed collagen diseases; post-infectious arthritis (where no pathogens are found to be surviving in or within the affected part of the body), seronegative spondyloarthritis such as ankylosing spondylitis; vasculitis, sarcoidosis, or arthropathy; or any further combination thereof.

[0118] The compounds of the present invention can also be used as activators against conditions such as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and collateral artery disease, ischemic limb angiogenesis, wound healing, peptic ulcers, Helicobacter-associated diseases, fractures, cat-scratch fever, rubeosis, neovascular glaucoma, and retinopathy, including those associated with diabetic retinopathy or macular degeneration. In addition, some of these compounds can be used as activators against solid tumors, malignant ascites, hematopoietic carcinomas and hyperproliferative disorders, such as thyroid hyperplasia (especially Graves' disease), and cysts (e.g., hypervascularization of ovarian bronchus, a characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome)), because these diseases require the proliferation of vascular cells for growth and / or metastasis.

[0119] In addition to their usefulness in human treatment, these compounds are also useful in the veterinary treatment of companion animals, including mammals and rodents, as well as exotic animals and livestock. For example, animals including horses, dogs, and cats can be treated with the compounds provided by this invention.

[0120] The compounds of the present invention can be taken or administered as single active pharmaceutical agents, but they may also be used in combination with one or more of the compounds of the present invention, or in combination with other agents. When administered as a combination agent, the therapeutic agents may be formulated as separate compositions to be administered simultaneously or sequentially at different time points, or the therapeutic agents may be given as a single composition.

[0121] The term "co-therapy" (or "combination-therapy") used to define the use of the compounds of the present invention and other pharmaceutical products encompasses the sequential administration of each drug in a dosing plan that provides the beneficial effects of drug combination, and also encompasses substantially simultaneous co-administration of these drugs, such as in a single capsule having a fixed ratio of these active drugs or in individual capsules of each drug.

[0122] Specifically, the administration of the compounds of the present invention may be combined with additional therapies known to those skilled in the art in the field of cancer prevention or treatment, such as radiotherapy, small molecule targeted agents (e.g., PARP inhibitors, kinase inhibitors), therapeutic antibodies (e.g., naked and drug conjugates), immunotherapy antibodies (checkpoint inhibitors, bispecific T cell enhancers), and antineoplastic or cytotoxic agents.

[0123] When formulated as a fixed dose, such combination products use the compounds of the present invention within an acceptable dose range. If a combination formulation is unsuitable, the compounds of formula I may also be administered sequentially with known anticancer or cytotoxic agents. The present invention is not limited to the order of administration, and the compounds of the present invention may be administered before, concurrently with, or after the administration of known anticancer or cytotoxic agents.

[0124] Numerous anticancer drugs are available for commercial use, clinical evaluation, and preclinical development for the treatment of neoplasm formation with combination chemotherapy. These drugs can be divided into several main classifications, including antibiotics, alkylating and alkylating-like agents, antimitotic agents, targeted small molecule agents, antimetabolites, hormones, immunological agents, anti-angiogenic agents, interferon-type agents, and other agents.

[0125] The disclosure also provides methods of combination therapy in which agents known to modulate other pathways or other components of the same pathway, or further overlapping sets of target enzymes, are used in combination with the compounds of the disclosure or pharmaceutically acceptable salts thereof. In one embodiment, such a therapy includes, but is not limited to, a combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, targeted small molecule agents, and radiotherapy to provide a synergistic or additive therapeutic effect.

[0126] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of this disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormone agents, angiogenesis inhibitors, and antiandrogens. Non-limiting examples include 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 hosts of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; benzodopa, carboquan, metsuredo Aziridines such as super and uredopa; ethyleneimines and methylameamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomellamine; chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, oxidized mechloretamine hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trophosphamide, uracil mustard and other nitrogen mustards; nitrosoureas such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine;Acrasinomycin, Actinomycin, Ausramycin, Azaserin, Bleomycin, Kakutinomycin, Calicheamycin, Carabicin, Carminomycin, Cardinophilin, Casodex (trademark), Chromomycin, Dactinomycin, Daunorubicin, Detrubicin, 6-Diazo-5-Oxo-L-Norleucine, Doxorubicin, Epirubicin, Esolubicin, Idarubicin, Marcelomycin, Mitomycin, Mycophenolic Acid, Nogaramycin, Olibomycin, Peplomycin, Potophyllomycin, Puromycin Antibiotics such as keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folate analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and enosyl Pyrimidine analogs such as Tabin and furoxiuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; acegraton; aldofsphamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisantren; edatraxate; defofamine; demecolsin; diazicone; elfornithine; eriptinium acetate; etogluside; gallium nitrate; hydroxy Urea; Lentinan; Ronidamin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Lazoxane; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadiquan; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;Taxanes, such as paclitaxel and docetaxel, nab-paclitaxel; retinoic acid; esperamycin; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the above.

[0127] Furthermore, suitable chemotherapy cell conditioners include anti-estrogens such as tamoxifen (Nolvadex®), raloxifen, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY 117018, onapristone, and toremifene (Fareston), which act to modulate or inhibit hormonal effects on tumors; as well as anti-androgens such as flutamide, nilutamide, bicalutamide, luprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin, and carboplatin; etoposide (VP-16); ifosfamide; and mitomycin. C; Mitoxantrone; Vinblastine; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; Topotecan; Camptothecin-11 (CPT-11); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO).

[0128] If necessary, the compounds or pharmaceutical compositions disclosed herein include Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Abraxane, Arimidex®, Taxotere®, ABVD, AVICINE, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfa-lazine, arbocidib, 3-aminopyridine-2-carbocidib. Ruboxialdehydothiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antineoplastic agent, antitumor herb, apadiquon, atiprimod, azathioprine, berothecan, bendamustine, BIBW2992, bilicodal, brostarisin, bryostatin, butionine sulfoximine, CBV (chemotherapy), kallikrin, cell cycle nonspecific antineoplastic agent, dichloroacetic acid, discodermorid, erusamitrusin, enocitabine, epotilon, eribulin, everolimus, exateca Exislind, Ferginol, Forodesine, Phosfestrol, ICE chemotherapy regimen, IT-101, Imexon, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Larotaxel, Lenalidomide, Lucanton, Luutecan, Mafosfamide, Mitozolomide, Nafoxidin, Nedaplatin, Olaparib, Talazoparib, Niraparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome inhibitors, Rebeccamycin, Reximod, Rubitecan, SN-3 8. It can be used in combination with commonly prescribed anticancer drugs such as salinosporamide A, sapacitabine, Stanford V, swinesonin, talaporfin, talikidal, tegaflu-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, bajimezan, vinflunin, ZD6126 or zoskidal, and CDK4 / 6 inhibitors (palbociclib, Ibrance; ribociclib, Kisqali; abemaciclib, Verzenio).

[0129] This disclosure further relates to a method of using a compound or pharmaceutical composition provided herein in combination with radiotherapy to inhibit abnormal cell growth in mammals or to treat hyperproliferative disorders. Methods for administering radiotherapy are known in the art and can be used in the combination therapy described herein. The administration of the compounds of this disclosure in this combination therapy can be determined as described herein.

[0130] Radiotherapy can be administered by one of several methods, or a combination thereof, including external beam therapy, internal radiation therapy, brachytherapy, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary intratissue brachytherapy. As used herein, the term “brachytherapy” refers to radiotherapy delivered by spatially restricted radioactive material inserted into or near a tumor or other proliferative tissue disease site. This 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 radioactive sources for use as cell conditioners in this disclosure include both solid and liquid sources. As a non-limiting example, a radiation source may be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, or another radionuclide that emits photons, beta particles, gamma rays, or other therapeutic rays. The radioactive material may be a fluid prepared from any solution of a radionuclide, for example, a solution of I-125 or I-131, or the radioactive fluid may be prepared using a suitable fluid slurry containing fine particles of solid radionuclides such as Au-198 and Y-90. Furthermore, radionuclides can be embodied as gels or radioactive microspheres.

[0131] The compounds or pharmaceutical compositions disclosed herein can be used in combination with a certain amount of one or more substances selected from anti-angiogenic agents, signaling inhibitors, antiproliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0132] Anti-angiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in conjunction with the disclosed compounds and pharmaceutical compositions described herein. Examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are found in International Publication No. 96 / 33172, International Publication No. 96 / 27583, European Patent No. 0818442, European Patent No. 1004578, International Publication No. 98 / 07697, International Publication No. 98 / 03516, International Publication No. 98 / 34918, International Publication No. 98 / 34915, International Publication No. 98 / 33768, International Publication No. 98 / 30566, European Patent No. 606046, and European Patent No. 931788. These are described in the specifications, International Publication No. 90 / 05719, International Publication No. 99 / 52910, International Publication No. 99 / 52889, International Publication No. 99 / 29667, International Publication No. 1999007675, European Patent No. 1786785, European Patent No. 1181017, U.S. Patent Application Publication No. 20090012085, U.S. Patent No. 5863949, U.S. Patent No. 5861510, and European Patent No. 0780386, all of which are incorporated herein by reference as a whole. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More preferably, it selectively inhibits MMP-2 and / or AMP-9 with respect 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 this disclosure are AG-3340, RO32-3555, and RS13-0830.

[0133] The compounds of the present invention include acemannan, acralubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amiphostin, aminolevulinic acid, amrubicin, amsacrin, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenite, BAM002 (Novelos), bexarotene, bicalutamide, proxuridine, capecitabine, cermoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphonate, DA3030 (Dong-A), daclizumab, and denileukin. Difutitex, Deslorerin, Dexrazoxane, Dilazep, Docetaxel, Docosanol, Doxelcalciferol, Doxifluridine, Doxorubicin, Bromocriptine, Carmustine, Cytarabine, Fluorouracil, HIT Diclofenac, Interferon Alpha, Daunorubicin, Doxorubicin, Tretinoin, Edelfosine, Edrecolomab, Eflornithine, Emiteflu, Epirubicin, Epoetin Beta, Etoposide Phosphate, Exemestane, Exislind, Fadrozol, Filgrastim, Finasteride, F Rudarabine phosphate, Formestan, Fotemustine, Gallium nitrate, Gemcitabine, Gemtuzumabuzogamicin, Gimeracil / Oteracil / Tegaflu combination, Glycopine, Goserelin, Heptaplatin, Human chorionic gonadotropin, Human fetal alpha-fetoprotein, Ibandronate, Idarubicin, (Imiquimod, Interferon Alpha, Interferon Alpha, Natural, Interferon Alpha-2, Interferon Alpha-2a, Interferon Alpha-2b, Interferon Alpha-N1, Interferon Lonalpha-n3, Interferon Alphacon-1, Interferon Alpha, Natural, Interferon Beta, Interferon Beta-1a, Interferon Beta-1b, Interferon Gamma, Natural Interferon Gamma-1a, Natural Interferon Gamma-1b, Interleukin-1 Beta, Iobenguan, Irinotecan, Ilsogladine, Lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Leucosite Alpha Interferon, Leuprorelin,Lebamisol + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masopropyl, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mismatch Double-Stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltograstim, Nedaplatin, Niltamide, Noscapine, Novel Erythropoiesis-Promoting Protein, NSC 631570 Octreotide, Oprelbequin, Osateron, Oxaliplatin, Paclitaxel, Pamidronic acid, Pegasparagase, Peginterferon alpha-2b, Pentosan polysulfate sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit anti-thymocyte polyclonal antibody, Polyethylene glycol interferon alpha-2a, Porfimer sodium, Raloxifene, Larcitrexed, Rasbrand Reenbodyment, Rhenium Re186 etidronate, RII retinamide, rituximab, romultide, samarium (153Sm) lexidonam, salglamostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegaflu, temoporfin, temozolomide, teniposide, tetrachlorodecoxide, thalidomide, thymalfacin, thyrotropin alpha, topote Can, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tretinoin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, barbicin, verteporfin, vinorelbine, virulizin, dinostatin stimalamer or zoledronic acid; abalelix; AE941 (Aet erna), ambamustine, antisense oligonucleotides, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diazicon, EL532 (Elan), EM800 (Endorecherche), enyluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, gallocitabine, gastrin-17 immunogene,HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilostat, IM862 (Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125MAb (Biomira), cancer MAb (Nippon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), Idiotic 105AD7MAb (CRC Technology), Idiotic CEA MAb (Trilex), LYM-1-iodine-131 MAb (Techniclone), polymorphic epithelial mucin yttrium 90 MAb (Antisoma), marimast, menogalil, mitumomab, motexafingadolinium, MX6 (Galderma), nelarabine, noratexed, P30 protein, pegvisomant, pemetrexed, porphyromycin, prinomast, RL0903 (Shire), rubitecan, satoraplatin, sodium phenylacetate, sparphosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, taliblastin, thrombopoietin, tin ethylethiopurine, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering It can also be used in combination therapy with other antineoplastic agents such as the Institute, melanoma tumor lysate vaccine (New York Medical College), viral melanoma cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

[0134] The compounds of the present invention may be further used in combination with VEGFR inhibitors. Other compounds described in the following patents and patent applications may be used in combination therapy: U.S. Patent No. 6,258,812, U.S. Patent Publication No. 2003 / 0105091, International Publication No. 01 / 37820, U.S. Patent No. 6,235,764, International Publication No. 01 / 32651, U.S. Patent No. 6,630,500, U.S. Patent No. 6,515,004, U.S. Patent No. 6,713,485, U.S. Patent No. 5,521,184, U.S. Patent No. 5,770,599, U.S. Patent No. 5,747,498, International Publication No. 02 / 68406, International Publication No. 02 / 6 Pamphlet No. 6470, Pamphlet No. 02 / 55501, Pamphlet No. 04 / 05279, Pamphlet No. 04 / 07481, Pamphlet No. 04 / 07458, Pamphlet No. 04 / 09784, Pamphlet No. 02 / 59110, Pamphlet No. 99 / 45009, Pamphlet No. 00 / 59509, Pamphlet No. 99 / 61422, U.S. Patent No. 5,990,141, International Publication Pamphlet No. 00 / 12089 and International Publication Pamphlet No. 00 / 02871.

[0135] In some embodiments, the combination agent comprises a composition of the present invention combined with at least one anti-angiogenic agent. The agent includes, but is not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, prepared by synthesis in vitro. The agent may be an agonist, antagonist, allosteric regulator, toxin, or more generally, may act to inhibit or stimulate its target (e.g., by activating or inhibiting a receptor or enzyme), thereby promoting cell death or halting cell growth.

[0136] Exemplary anti-angiogenic 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 soluble VEGF receptors or their ligand-binding regions), anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind thereto), EGFR inhibitors such as Vectibix (panitumumab), IRESSA® (gefitinib), and TARCEVA® (erlotinib) (e.g., antibodies or antigen-binding regions that specifically bind thereto), anti-Ang1 and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to them or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical compositions of the present invention may also include one or more agents (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to and inhibit the activity of growth factors, such as an antagonist of hepatocyte growth factor (HGF, also known as a scattering factor) that specifically binds to the receptor "c-met," and an antibody or antigen-binding domain.

[0137] 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., antibody or antigen-binding domains that specifically bind, or soluble Tweak receptor antagonists; see 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), and anti-ep that specifically bind. Examples include the h receptor and / or anti-ephrin antibodies or antigen-binding regions (U.S. Patent Nos. 5,981,245; Nos. 5,728,813; Nos. 5,969,110; Nos. 6,596,852; Nos. 6,232,447; Nos. 6,057,124, and members of their respective patent families), anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind to them), antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to them).

[0138] Further anti-angiogenic / antinomatous agents include: SD-7784 (Pfizer, USA); Silendide (Merck KGaA, Germany, EPO 770622); Pegabutanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S. Patent No. 5712291); Ilomast (Arriva, USA, U.S. Patent No. 5892112); Emaxanib (Pfizer, USA, U.S. Patent No. 5792783); Batalanib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecoltab Acetate (Alcon, USA); α-D148Mab (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 Inhibitor (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 Company Limited, Japan); FR-111142 (Fujisawa Pharmaceutical Co., Ltd., Japan, Japanese Patent Publication No. 02233610);Platelet factor 4 (RepliGen, USA, European Patent No. 407122); 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-inducing anti-angiogenic agents (XOMA, USA); PI88 (Progen, Australia); Silengitide (pINN), (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); Cetuximab (INN), (Aventis, France); AVE8062 (Ajinomoto, Japan); AS1404 (Cancer Research Laboratory, New Zealand); SG292 (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN161 (Attenuon, USA); Angiostatin (Boston Childrens Hospital, USA); 2-Methoxyestradiol (Boston Childrens ZD6474 (AstraZeneca, UK); ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK);Batalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA); Pegaptanib (Pinn) (Gilead Sciences, USA); Xantrizole (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); Vaccine, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1 Alpha Inhibitor (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 Minnesota University, 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); Ilsogladine (INN) (Nippon Shinyaku, Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany);Squalamine (pINN) (Genaera, USA); RPI4610 (Sirna, USA); Cancer therapy (Marinova, Australia); Heparanase inhibitor (InSight, Israel); KL3106 (Kolon, South Korea); Fountainhead (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (ZK Angio) (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho Pharmaceutical, Japan); VEGF receptor modulator (Pharmacopeia, USA); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Vaccine, Flk-1 (ImClone Systems, USA; TZ93 (Tsumura, Japan); Tamstatin (Beth Israel Hospital, USA); Sclerolytic soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin 1 inhibitors (Allegheny Health, Education and Research Foundation, USA).

[0139] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), bafilomycin A1, 5-amino-4 imidazole carboxamido riboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense or siRNAs that inhibit protein expression, including but not limited to ATG5 (which is involved in autophagy), may also be used.

[0140] Additional pharmaceutically active compounds / agents that can be used in the treatment of cancer and in combination with one or more compounds of the present invention include epoetin α; darbepoetin α; panitumumab; pegfilbrastim; palifermin; filgrastim; denosumab; ancestim; AMG102; AMG386; AMG479; AMG655; AMG745; AMG951; and AMG706, or pharmaceutically acceptable salts thereof.

[0141] In certain embodiments, the compositions provided herein are administered in combination with chemotherapeutic agents. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorerbin), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mitramycin), mitomycin, and enzymes (e.g., L-asparagine). L-asparaginase, which systemically metabolizes asparagine and removes cells that lack the ability to synthesize their own asparagine; antiplatelet agents; antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and analogs, melphalan and chlorambucil); ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa); CDK inhibitors (e.g., sericiclib, UCN-01, P1446A-05, PD-0332991, d Antiproliferative / antimitotic antimetabolites such as naciclib (P27-00, AT-7519, RGB286638 and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and its analogs, as well as streptozocin), trazene-dacarbazinine (DTIC), folate analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, phloxuridine, and cytarabine), purine analogs, and related inhibitors. Harmful agents (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum-coordinate complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215 and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridaflorimus and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalipsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multi-kinase inhibitors (e.g., TG02 and sorafenib), hormone agonists such as hormones (e.g., estrogen) and 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., Perifosin), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., Enzastaurin), FTI (e.g., Zanestra®), 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., Other possible chemotherapeutic agents include ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib, talazoparib, niraparib, veliparib (ABT-888)), and BCL-2 antagonists. Other possible chemotherapeutic agents include mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analog or derivative of the above.

[0142] The compounds of the present invention may also be used in combination with radiotherapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0143] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with steroids. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortivazole, deflazacort, desonide, desoxymethasone, dexamethasone, diflorasone, diflucortol, difluprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolidide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulandre. The compounds may include, but are not limited to, nolid, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and their salts and / or derivatives. In certain embodiments, the compounds of the present invention may also be used in combination with additional pharmaceutically active agents for treating nausea. Examples of drugs that may be used to treat nausea include: dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharmaceutically acceptable salts thereof.

[0144] The compounds or pharmaceutical compositions of this disclosure may also be used in combination with a certain amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, and immunosuppressive therapies (including PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents), GITR agonists, CAR-T cells, and BiTE.

[0145] 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), zaltumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently, lapatinib (TykerB). For example, see 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.

[0146] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors and all pharmaceutically acceptable salts and solvates thereof described in the following patent publications: European Patent Application Publication No. 520722, published on 30 December 1992; European Patent Application Publication No. 566226, published on 20 October 1993; International Publication No. 96 / 33980, published on 31 October 1996; U.S. Patent No. 5,747,498, issued on 5 May 1998; International Publication No. 96, published on 3 October 1996. Brochure No. / 30347; Specification of European Patent Application Publication No. 787772, published August 6, 1997; Brochure of International Publication No. 97 / 30034, published August 21, 1997; Brochure of International Publication No. 97 / 30044, published August 21, 1997; Brochure of International Publication No. 97 / 38994, published October 23, 1997; Brochure of International Publication No. 97 / 49688, published December 31, 1997; Specification of European Patent Application Publication No. 837063, published April 22, 1998; Brochure of International Publication No. 98 / 02434, published January 22, 1998; October 1997 Pamphlet No. 97 / 38983 published on the 23rd; Pamphlet No. 95 / 19774 published on July 27, 1995; Pamphlet No. 95 / 19970 published on July 27, 1995; Pamphlet No. 97 / 13771 published on April 17, 1997; Pamphlet No. 98 / 02437 published on January 22, 1998; Pamphlet No. 98 / 02438 published on January 22, 1998; Pamphlet No. 97 / 32881 published on September 12, 1997; Specification of German Patent Application Publication No. 19629652 published on January 29, 1998; 1998 International Publication No. 98 / 33798, published on August 6; International Publication No. 97 / 32880, published on September 12, 1997; International Publication No. 97 / 32880, published on September 12, 1997; Specification of European Patent Application Publication No. 682027, published on November 15, 1995; International Publication No. 97 / 02266, published on January 23, 1997; International Publication No. 97 / 27199, published on July 31, 1997; International Publication No. 98 / 07726, published on February 26, 1998; International Publication No. 97 / 34895, published on September 25, 1997;Pamphlet No. 96 / 31510 released on October 10, 1996; Pamphlet No. 98 / 14449 released on April 9, 1998; Pamphlet No. 98 / 14450 released on April 9, 1998; Pamphlet No. 98 / 14451 released on April 9, 1998; Pamphlet No. 95 / 09847 released on April 13, 1995; Pamphlet No. 97 / 19065 released on May 29, 1997; Pamphlet No. 98 / 17662 released on April 30, 1998; August 4, 1998 U.S. Patent No. 5,789,427 issued; U.S. Patent No. 5,650,415 issued on 22 July 1997; U.S. Patent No. 5,656,643 issued on 12 August 1997; International Publication No. 99 / 35146 published on 15 July 1999; International Publication No. 99 / 35132 published on 15 July 1999; International Publication No. 99 / 07701 published on 18 February 1999; and International Publication No. 92 / 20642 published on 26 November 1992. Additional non-exclusive examples of small molecule EGFR inhibitors include any of the EGFR inhibitors listed in Traxler, P., 1998, Exp. Opin.Ther. Patents 8(12):1599-1625.

[0147] 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-exclusive 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. Therefore, EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, cited above), or Mab C225 (ATCC accession number HB-8508), or antibodies or antibody fragments having binding specificity thereto.

[0148] Examples of MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0149] PI3K inhibitors include wartmannin, a 17-hydroxywartmannin analog described in International Publication No. 06 / 044453, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as GDC 0941, described in International Publication Nos. 09 / 036,082 and International Publication Nos. 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propionitrile (BEZ 235 or NVP-BEZ) Also known as 235, as described in International Publication No. 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (as described in International Publication No. 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]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (Axon N'-[(1E)-(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-N,2-dimethyl-5-nitrobenzene sulfon-hydrazide hydrochloride) available from Medchem, PIK 90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazoline-5-yl)-nicotinamide) available from Axon Medchem, GDC-0941 bismesylate (2-(1H-indazole-4-yl)-6-(4-methanesulfonylpiperazine-1-ylmethyl)-4-morpholine-4-ylthieno[3,This includes, but is not limited to, 2-d]pyrimidine bismesylate), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidin-2,4-dione, available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidine-4-one, available from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxypyridine, perifosin, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, paromide 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0150] Examples of 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., International Publication No. 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. 134 (12) Examples include, but are not limited to, Suppl), 3493S-3498S; perifosin (e.g., inhibits the 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 trisirivine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0151] Examples of TOR inhibitors include, but are not limited to, AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, and ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Trin 1). Other TOR inhibitors in FKBP12 enhancers; rapamycin and its derivatives, including: CCI-779 (temsirolimus), RAD001 (everolimus; International Publication No. 9409010) and AP23573; rapagnologs, e.g., those disclosed in International Publication No. 98 / 02441 and International Publication No. 01 / 14387, e.g., 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-pentinyloxy-32(S)-dihydrorapanycin, and other derivatives disclosed in International Publication No. 05005434; U.S. Patent 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 Derivatives disclosed in Brochure 23, International Publication 94 / 02136, International Publication 95 / 16691, International Publication 96 / 41807, International Publication 96 / 41807 and U.S. Patent No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., Brochure 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0152] Immunotherapy includes, but is not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents. Exemplary anti-PD-1 antibodies and their uses 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 (Brochure International Publication No. 2006 / 121168A1), which are expressly incorporated herein by reference, respectively. These include: Yervoy® (ipilimumab) or tremelimumab (for CTLA-4), galiximab (for B7.1), BMS-936558 (for PD-1), MK-3475 (for PD-1), AMP224 (for B7DC), BMS-936559 (for B7-H1), MPDL3280A (for B7-H1), MEDI-570 (for ICOS), AMG557 (for B7H2), MGA271 (for B7H3), IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to OX40L), atacicept (to TACI), CP-870893 (to CD40), lucatumumab (to CD40), dacetuzumab (to CD40), muromonab-CD3 (to CD3), ipilimumab (to CTLA-4). Immunotherapy also includes genetically modified T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

[0153] Examples of GITR agonists include GITR fusion proteins described in U.S. Patent No. 6,111,090box.c, European Patent No. 090505B1, U.S. Patent No. 8,586,023, International Publication No. 2010 / 003118 and International Publication No. 2011 / 090754, or, for example, U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, European Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. 1866339, International Publication No. 2011 / 028683 and International Publication No. 2013 / 03 Examples of GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) described in Pamphlet No. 9954, Pamphlet No. 2005 / 007190, Pamphlet No. 2007 / 133822, Pamphlet No. 2005 / 055808, Pamphlet No. 99 / 40196, Pamphlet No. 2001 / 03720, Pamphlet No. 99 / 20758, Pamphlet No. 2006 / 083289, Pamphlet No. 2005 / 115451, U.S. Patent No. 7,618,632, and International Publication No. 2011 / 051726 include, but are not limited to, anti-GITR antibodies.

[0154] The compounds described herein may be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more of the compounds disclosed herein will be administered concurrently with the other agents described above. When used in combination therapy, the compounds described herein may be administered concurrently with or separately from the second agent. This concurrent administration may include concurrent administration of two agents in the same dosage form, concurrent 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 concurrently. Alternatively, the compounds disclosed herein and any of the agents described above may be administered concurrently, where both agents are present in separate formulations. Another alternative is that the compounds disclosed may be administered followed by any of the agents described above, or in the reverse order. In some embodiments of the individual administration protocols, the compounds disclosed and any of the agents described above may be administered at intervals of several minutes, several hours, or several days.

[0155] As one aspect of the present invention involves considering the treatment of a disease / condition by a combination of pharmaceutically active compounds that can be administered individually, the present invention further relates to combining individual pharmaceutical compositions into a kit. The kit comprises two individual pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for housing the individual compositions, such as a divided bottle or a divided metal foil bag. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for the use of the individual components. The kit form is particularly advantageous when the individual components are preferably administered in different forms of dosing (e.g., orally and parenterally), at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing healthcare professional.

[0156] experiment Abbreviations: The following abbreviations may be used in this specification:

[0157] [Table 4]

[0158] [Table 5]

[0159] Unless otherwise noted, all substances were obtained from commercial suppliers and used without further purification. Unless otherwise indicated, all values ​​are by weight, and temperatures are in Celsius. All microwave-assisted reactions were performed 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 were not corrected. Mass spectral data were measured using electrospray ionization techniques. All examples were purified to >90% by high-performance liquid chromatography. Unless otherwise specified, reactions were carried out at room temperature.

[0160] In the synthesis of the compounds of the present invention, the use of specific leaving groups may be desirable. The term “leaving group” (“LG”) generally refers to a group that can be substituted 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, etc. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, and anionic species (e.g., alkoxides, amides, carbanions).

[0161] The following embodiments illustrate specific examples of the present invention. These embodiments are representative and are not intended to limit the scope of the claims in any way.

[0162] Note that when percentages (%) are used for liquids, this refers to the volume percentage relative to the solution. When used for solids, this refers to the solid composition percentage. Materials obtained from commercial suppliers were typically used without further purification. Reactions involving reagents sensitive to air or moisture were typically carried out under a nitrogen or argon atmosphere. Purity was measured using a high-performance liquid chromatography (HPLC) system with UV detection at 254 nm and 215 nm (System A: Agilent Zorbax Eclipse XDB-C8 4.6 × 150 mm, 5 μm, 5–100% CH3CN in H2O containing 0.1% TFA, 1.5 mL / min for 15 minutes; System B: Zorbax SB-C8, 4.6 × 75 mm, 10–90% CH3CN in H2O containing 0.1% formic acid, 1.0 mL / min for 12 minutes) (Agilent Technologies, Santa Clara, CA). Silica gel chromatography was generally performed using pre-packed silica gel cartridges (Biotage, Uppsala, Sweden, or Teledyne-Isco, Lincoln, NE). 1 ¹H NMR spectra were recorded at ambient temperature using 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) low magnetic field from tetramethylsilane (TMS) or other internal standards in a specified appropriate solvent. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quadruplet, br=broad, m=multilet), coupling constant, and number of protons. Low-resolution mass spectral (MS) data were determined on an Agilent 1100 Series (Agilent Technologies, Santa Clara, CA) LC / MS with UV detection at 254 nm and 215 nm, and low-resonance electrospray mode (ESI).

[0163] Unless otherwise specified, the starting materials and reagents used to prepare these compounds are either available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or prepared by methods known to those skilled in the art, following the 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 merely illustrate some methods by which the compounds of the present invention can be synthesized, and various modifications to these schemes are possible and will be suggested to those skilled in the art who have referenced this disclosure. The starting materials and intermediates of the reaction, as well as the final product, can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography, as desired. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0164] General synthesis scheme Unless otherwise indicated, the reactions described herein occur under 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 at room temperature (or ambient temperature), for example, about 20°C.

[0165] For clarity in this general synthesis section, the compound of formula (I) is the following ring Ar 1 and ring Ar 2 It can be roughly described as including: [ka] In the formula, the base L is a linker as defined in the outline of the invention, and the ring Ar 1 It is located to the left of the linker, ring Ar 2 It is located to the right of the linker.

[0166] Generally, compounds of formula (I) can be synthesized through the following three general steps: Step 1: Ring Ar 1 Preparation of compounds. Step 2: Ring Ar 2 Preparation of compounds. Step 3: Ring Ar 1 The compound's ring Ar 2 Coupling into compounds.

[0167] The general schemes A and B below are intended to provide guidance to synthetic chemists of ordinary ability who readily understand that solvents, concentrations, reagents, protecting groups, sequence of synthesis steps, time, temperature, etc., can be modified as needed within the scope of the skill and judgment of those skilled in the art.

[0168] Scheme A In one embodiment, the general formula (IA): [ka] Compounds of formula (I) having can be synthesized according to scheme A.

[0169] Step A-1a: Ring Ar 1 Preparation of compounds: [ka] In step A-1a, compound A-1 (wherein W is used in the formula) 1(where is a halogen, for example fluoro or chloro) is used in the presence of a suitable base in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc. 2 Compound A-2 can be formed by reacting it with a drug containing the group. Compound A-1 is commercially available or can be synthesized by methods known to those skilled in the art. Examples of compound A-1 include, but are not limited to, 2-chloropyrimidine-4-amine, 2-chloro-6-methylpyrimidine-4-amine, 2-fluoro-6-methylpyridine-4-amine, 2-chloropyridine-4-amine, 2-chloro-6-methylpyridine-4-amine, 2-chloro-6-ethylpyrimidine-4-amine, or 2-chloro-6-cyclopropylpyrimidine-4-amine. 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, (3) 3,3-difluoroazetidine hydrochloride, or (4) 3,3,3-trifluoropropan-1-ol. Examples of bases include, but are not limited to, diisopropylethylamine, potassium carbonate, or sodium hydride.

[0170] Step A-1b: Ring Ar 1 Preparation of compounds: [ka] Alternatively, in step A-1b, compound A-1 defined in step 1a is a suitable organoboron R 2 Reagent (R 2Compound A-2, as defined in step 1a, can also be converted to compound A-2 via a Suzuki cross-coupling reaction using a suitable palladium catalyst and base, such as PdCl2(dppf)-DCM adduct and tribasic potassium phosphate, for example, 2-(4,4-difluorocyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane or 2-(4-fluorocyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and a suitable palladium catalyst and base, such as PdCl2(dppf)-DCM adduct and tribasic potassium phosphate. Following this step, compound A-2 is formed by reduction with a suitable palladium catalyst and hydrogen source, such as Pd / C, in the presence of hydrogen gas. This alternative Suzuki reaction involves group R 2 Ar 1 It can be used when connected to a ring.

[0171] Step A-2a: Ring Ar 2 Preparation of compounds: [ka] In step A-2a, compound A-3 (wherein W) 2 and W 3 Each of these is independently a halogen, e.g., fluoro, chloro, bromo, or iodine), and in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or DMSO, (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride, etc. x Compound A-4 can be formed by reacting it with a reagent.

[0172] Step A-3a: Ring Ar 1 The compound's ring Ar 2 Coupling to the compound, and the subsequent R 1 Introduction: [ka] In step A-3a, compound A-4 obtained from step A-2a can be reacted with an activator such as an acid chloride (COCl)2 or SOCl2 in a suitable organic solvent such as tetrahydrofuran or methylene chloride to form an acid chloride derivative, which can then be reacted with compound A-2 to form compound A-5. Alternatively, compound A-2 may be directly coupled with compound A-4 obtained from step A-2a in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, or methylene chloride, in the presence of a coupling reagent such as N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyldiimidazole, and polyphosphonic anhydride. A synthetic chemist of normal ability will readily understand that other coupling agents may be used. In a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, or DMF, a metal catalyst such as (1) 1-methylcyclopropane-1-sulfonamide, (2) 3-methyloxetane-3-amine, (3) tert-butyl 3-mercaptoazetidine-1-carboxylate, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) ethyl iodoethyl, (8) 2-mercaptopropane-1-ol, (9) 2-mercapto-2-methylpropane-1-ol, (10) 2-aminoethane-1-ol, or (11) cyclopropanechiol and R 1 In the presence of a reagent, halogen groups W are converted by metal-catalyzed sulfamidation, sulfination, or sulfonylation. 3 Compound (I) can be formed by further operations. A chemist of normal ability will readily understand that coupling reactions, such as those shown in step 3a, can be carried out under a variety of known conditions.

[0173] Scheme B In another embodiment, the general formula (IB) defined herein: [ka] Compounds of formula (I) having can be synthesized according to scheme B.

[0174] Step B-1a: Ring Ar 1 Preparation of compounds: [ka] In step B-1a, compound B-1 (wherein W is used in the formula) 4 (where is a halogen, for example fluoro or chloro) is used in the presence of a suitable base in a suitable organic solvent such as NMP, dioxane, acetonitrile, tetrahydrofuran, DMF, methylene chloride, etc. 2 Compound B-2 can be formed by reacting with a reagent. Examples of compound B-1 include, but are not limited to, (1) 2-fluoroisonicotinic acid, (2) 2-fluoro-6-methylisonicotinic acid, (3) 2-chloropyrimidine-4-carboxylic acid, or (4) 2-chloro-6-methylpyrimidine-4-carboxylic acid. 2 Examples of reagents include, but are not limited to, (1) (R)-2-methylmorpholine, (2) 4,4-difluoropiperidine hydrochloride, or (3) 3,3-difluoroazetidine hydrochloride. Examples of bases include, but are not limited to, diisopropylethylamine and potassium carbonate.

[0175] Step B-2a: Ring Ar 2 Preparation of compounds: [ka] In step B-2a, compound B-3 (wherein W) 5 and W 6Each of these is independently a halogen, e.g., fluoro, chloro, bromo, or iodine), and in a suitable organic solvent such as NMP, acetonitrile, tetrahydrofuran, DMF, methylene chloride, or DMSO, (1) 6-azaspiro[2.5]octane hydrochloride, (2) 4,4-dimethylpiperidine hydrochloride, (3) 3,4,4-trimethylpiperidine hydrochloride, (4) 4-methyl-6-azaspiro[2.5]octane hydrochloride, or (5) 7-azaspiro[3.5]nonane hydrochloride, etc. x Compound B-4 can be formed by reacting it with a reagent. Examples of compound B-3 include, but are not limited to, (1) 4-bromo-2-fluoro-1-nitrobenzene, (2) 4-iodo-2-fluoro-1-nitrobenzene, or (3) 6-bromo-2-fluoro-3-nitropyridine. Subsequently, compound B-5 can be formed by reacting it with a reducing agent, such as, but not limited to, palladium carbon, and a hydrogen source such as hydrogen gas, to convert the nitro group on compound B-4 to an amino group.

[0176] Step B-3a: Ring Ar 1 The compound's ring Ar 2 Coupling into compounds: [ka] In step B-3a, compound B-2 obtained in step B-1a can be reacted with compound B-5 obtained in step B-2a in a suitable organic solvent such as acetonitrile, tetrahydrofuran, DMF, or methylene chloride, in the presence of a coupling agent such as N,N'-diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, carbonyldiimidazole, or polyphosphonic anhydride to form compound B-6. Those skilled in the art will readily understand that other coupling agents may be used. Next, in a suitable organic solvent such as DMSO, acetonitrile, tetrahydrofuran, or DMF, a metal catalyst and (1) oxetane 3-amine, (2) 2-amino-2-methylpropan-1-ol, (3) (3-aminooxetane-3-yl)methanol, (4) ethyl 2-sulfamoylpropanoate, (5) 2-hydroxypropane-1-sulfonamide, (6) 2-hydroxyethane-1-sulfonamide, (7) 2-mercaptopropan-1-ol, (8) 2-mercapto-2-methylpropan-1-ol, (9) 2-aminoethane-1-ol, or (10) cyclopropanethol, etc. 1 In the presence of a reagent, halogen groups W are converted by transformation reactions such as SNAr, metal-catalyzed sulfamidation, sulfination, or sulfonylation. 6 Further operations can be carried out to form compound (IB). Those skilled in the art will readily understand that coupling reactions, such as those shown in step B-3a, can be carried out under a variety of known conditions.

[0177] Those skilled in the art will understand that the above transformation may be carried out at an earlier stage of the synthesis process, depending on the feasibility of the transformation. [Examples]

[0178] Ring Ar 1 Preparation of intermediates Intermediate 1 (R)-6-methyl-2-(2-methylmorpholino)pyrimidine-4-amine [ka] A mixture of 2-chloro-6-methylpyrimidine-4-amine (30.0 g, 209 mmol, Combi-Blocks, San Diego, CA), (R)-2-methylmorpholine (40.3 g, 293 mmol, Wuxi AppTec, China), and DIPEA (109 mL, 627 mmol) was placed in an autoclave (600 mL) and heated at 150°C for 12 hours. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (2 × 1500 mL). The organic layer was washed with brine (500 mL), dried, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as the eluent to obtain the title compound as a yellow solid (25.0 g, yield 57%). 1 H NMR(400MHz,DMSO-d6)δ ppm 6.28(s,2H),5.62(s,1H),4.45-4.31(m,2H),3.83(ddd,J=11.4,3.5,1.3Hz,1H),3.42(ddt,J=14.4,9.7,2.8Hz, 2H),2.78-2.70(m,1H),2.43(dd,J=13.0,10.3Hz,1H),2.05(s,3H),1.11(d,J=6.2Hz,3H).m / z(ESI):209.2(M+H) + .

[0179] Intermediate 2 2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-amine [ka] A mixture of 2-chloro-6-methylpyrimidine-4-amine (46 g, 320 mmol, Combi-Blocks, San Diego, CA), 4,4-difluoropiperidine hydrochloride (76 g, 480 mmol, Combi-Blocks, San Diego, CA), and DIPEA (166 mL, 961 mmol) in NMP (460 mL) was placed in an autoclave and heated at 180 °C for 30 hours. The reaction mixture was cooled to room temperature, quenched with water (500 mL), and extracted with ethyl acetate (2 × 1000 mL). The organic layer was washed with brine (500 mL), dried, filtered, and concentrated under reduced pressure. The crude material was adsorbed onto a silica gel plug and purified by column chromatography on silica gel (60-120 mesh) eluted with 50-100% ethyl acetate in hexane to obtain the target compound. This was redissolved in ethyl acetate (500 mL) and washed with water (2 × 500 mL). The organic layer was taken, dried with (Na₂SO₄), filtered, and concentrated under reduced pressure. The resulting yellow solid was suspended again in hexane (400 mL) and stirred for 30 minutes. The slurry was filtered, washed with hexane (100 mL), and dried under vacuum to obtain the title compound as a pale yellow solid (58 g, yield 79%). 1 H NMR(400MHz,DMSO-d6)δ 6.33(s,2H),5.63(s,1H),3.80-3.78(dd,J=6.8,4.7Hz,4H),2.06(s,3H),1.95-1.85(tt,J=14.2,5.7Hz,4H).m / z(ESI):229.2(M+H) + .

[0180] Intermediate 3 2-(4,4-difluoropiperidine-1-yl)isonicotinic acid [ka] A mixture of 2-fluoro-4-pyridinecarboxylic acid (0.90 g, 6.4 mmol, Matrix Scientific), 4,4-difluoropiperidine hydrochloride (1.106 g, 7.02 mmol, Matrix Scientific), and DIPEA (3.34 mL, 19.14 mmol, Sigma-Aldrich Corporation) in 5 mL of NMP was heated in a microwave at 125°C for 4 hours. The mixture was placed on a silica gel column and eluted with 10% to 100% ethyl acetate in heptane to obtain a material containing both 2-(4,4-difluoropiperidine-1-yl)isonicotinic acid and NMP. The material was stirred in 10 mL of heptane. The insoluble solid was collected and dried to obtain 2-(4,4-difluoropiperidine-1-yl)isonicotinic acid as a brown solid (1.40 g, 5.80 mmol, yield 91%). m / z(ESI):243.1(M+H) + .

[0181] Ring Ar 2 Preparation of intermediates Intermediate 4 6-Fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid [ka] To a solution of 2,6-difluoronicotinic acid (6.0 g, 38 mmol, Combi-Blocks) in ACN (120 mL), DIPEA (7.80 mL, 45.3 mmol) and 6-azaspiro[2.5]octane (4.61 g, 41.5 mmol, Wuxi AppTec, China) were added, and the reaction mixture was stirred at room temperature for 48 hours. Subsequently, the reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography using a gradient of 0-10% MeOH in DCM to obtain 6-fluoro-2-(6-azaspiro[2.5]octane-6-yl)nicotinic acid as a white solid (6 g, 1.26 mmol, yield 76%). 1H NMR(400MHz,DMSO-d6):δ ppm 12.94(s,1H),8.07(t,J=8.4,8.4Hz,1H),6.41(dd,J=8.2,3.3Hz,1H),3.36-3.43(m,4H),1.37-1.44(m,4H),0.34(s,4H).m / z(ESI):251.1(M+H) +

[0182] [Table 6]

[0183] Intermediate 5 4-Bromo-2-(6-Azaspiro[2.5]Octane-6-yl)aniline [ka] Step 1: A mixture of 4-bromo-2-fluoro-1-nitrobenzene (3.17 g, 14.4 mmol, Combi-Blocks), 6-azaspiro[2.5]octane hydrochloride (2.447 g, 16.57 mmol, AstaTech), and potassium carbonate (5.97 g, 43.2 mmol, Sigma-Aldrich Corporation) in DMSO (12 mL) was heated in an oil bath at 60 °C for 10 minutes, followed by heating at 90 °C for 1 hour. The mixture was cooled to RT, treated with 20 mL of water, and extracted with SiO2 (2 × 50 mL). The combined organic extract was washed with water (2 × 5 mL), dried, and the solvent was removed under vacuum. The residue was purified on a silica gel column (15%–45% Â in heptane) to obtain 6-(5-bromo-2-nitrophenyl)-6-azaspiro[2.5]octane as an orange solid (4.26 g, 13.7 mmol, 95% yield). m / z(ESI): 311.0 / 313.0(M+H) + .

[0184] Step 2: Iron powder (3.13 g, 56.1 mmol, Sigma-Aldrich Corporation) was added 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, Sigma-Aldrich Corporation) in EtOH (16 mL) and water (4 mL). The heterogeneous mixture was heated in an oil bath at 85 °C for 2 hours. The dark mixture was diluted with 50 mL of MeOH and filtered through a CELITE® pad. The filtrate cake was rinsed with 2 × 5 mL of MeOH and the filtrate was concentrated under vacuum. The residue was partitioned into 10 mL of water and 75 mL of siRNA. The organic layer was separated, dried over Na2SO4, and concentrated to obtain 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)aniline as a brown oil (2.23 g, 7.95 mmol, yield 85%). 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) + .

[0185] Ar 1 and Ar 2 coupling with Intermediate 6 (R)-6-fluoro-N-(6-methyl-2-(2-methylmorpholino)pyrimidine-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] To a solution of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (0.70 g, 2.8 mmol, intermediate 4) in dichloromethane (10 mL), oxalyl chloride (0.362 mL, 4.20 mmol) and DMF (1 drop) were added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under an N2 atmosphere to obtain 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride, which was immediately transferred to the next step without further purification. To a solution of 6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinoyl chloride in dichloromethane (5 mL), a solution of (R)-6-methyl-2-(2-methylmorpholino)pyrimidine-4-amine (0.583 g, 2.80 mmol, intermediate 1) and DIPEA (0.489 mL, 2.80 mmol) in dichloromethane (5 mL) was added under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 hours, then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The concentrate was purified by flash column chromatography using a 10%-15% ethyl acetate / petroleum ether gradient to obtain the title compound as a yellowish, viscous solid (0.12 g, 0.27 mmol, yield 10%). m / z(ESI): 441.2(M+H) + .

[0186] [Table 7]

[0187] Intermediate 7 6-Chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] Step 1: 4,6-Dichloronicotinic acid (1.48 g, 7.71 mmol, Ochem Incorporation), 2-(4,4-Difluoropiperidine-1-yl)-6-methylpyrimidine-4-amine (2.16 g, 9.46 mmol, Intermediate 2), and 1,3,5,2,4,6-Trioxatriphospholinane, 2,4,6-Tripropyl-,2,4,6-Trioxide (14.72 g, 23.13 mmol, Sigma-Aldrich Corporation) in DCE (20 mL) and DMF (8 mL) were heated at 100 °C for 4.5 hours. After cooling to RT, the mixture was stirred with 80 mL of ethyl acetate and 50 mL of brine. The organic layer was separated, dried (Na2SO4), and the solvent was removed under vacuum. The residue was adsorbed onto a silica gel plug and purified by silica gel chromatography using 0-20% ELISA in heptane to obtain 4,6-dichloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)nicotinamide as a white solid. m / z(ESI):402.0(M+H) + .

[0188] Step 2: 4,6-dichloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)nicotinamide (1.60 g, 3.98 mmol), 6-azaspiro[2.5]octane (0.54 g, 4.9 mmol, Wuxi AppTec, China), and potassium carbonate (1.0 g, 7.24 mmol, Sigma-Aldrich Corporation) in 20 mL of NMP were heated at 40°C for 2 hours, then cooled to RT and stirred for a further 5 hours. The mixture was partitioned into ethyl acetate (60 mL) and brine / water (20 mL). The organic layer was separated, washed with brine, dried, and the solvent was removed under vacuum. The residue was adsorbed onto a silica gel plug and purified by silica gel chromatography using 0-20% siRNA in heptane to obtain 6-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide. m / z(ESI):477.2(M+H) +.

[0189] [Table 8]

[0190] Intermediate 8 2-Chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)pyrimidine-5-carboxamide [ka] Step 1: To a solution of 2-chloro-4-(6-azaspiro[2,5]octan-6-yl)pyrimidine-5-carboxylic acid (1.5 g, 5.6 mmol, intermediate 4-4) in THF (15 mL), oxalyl chloride (2.45 mL, 28.0 mmol) and DMF (1 drop) were added under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated. The crude material was dissolved in DCM (15 mL), and 2,3,4,5,6-pentafluorophenol (1.55 g, 8.40 mmol) and DIPEA (1.96 mL, 11.21 mmol) were added at 0°C. The resulting mixture was stirred at ambient temperature for 2 hours, then quenched with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain perfluorophenyl 2-chloro-4-(6-azaspiro[2.5]octan-6-yl)pyrimidine-5-carboxylate as a pale yellow solid, which was then carried to the next step without purification. 1 H NMR (400MHz, chloroform-d): δ ppm 8.84(s,1H),3.72(d,J=5.8Hz,4H),1.39(d,J=6.7Hz,4H),0.45(d,J=1.9Hz,4H).m / z(ESI):434.0(M+H) + .

[0191] Step 2: Sodium hydride (0.415 g, 10.4 mmol) was added at 0°C to a solution of 2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-amine (1.89 g, 8.30 mmol, intermediate 2) in DMF (25 mL). After 30 minutes, a solution of perfluorophenyl 2-chloro-4-(6-azaspiro[2.5]octan-6-yl)pyrimidine-5-carboxylate (3.0 g, 6.9 mmol) in DMF (5 mL) was added to the reaction mixture. Subsequently, the reaction mixture was stirred at ambient temperature for 2 hours, then quenched with saturated NH4Cl solution and extracted with ELISA. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 30% to 35% ethyl acetate in petroleum ether to obtain 2-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)pyrimidine-5-carboxamide as a pale yellow solid (0.70 g, 1.46 mmol, yield 21%). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.99(s,1H),8.22(s,1H),7.21(s,1H),3.86(s,4H),3.57(t,J=5.5Hz,4H),2.30(s ,3H),1.97(s,4H),1.40(dd,J=6.6,4.2Hz,4H),0.34(s,4H).m / z(ESI):478.1(M+H) + .

[0192] Intermediate 9 5-Amino-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide [ka] Step 1: To a solution of 3,5-dichloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)pyrazine-2-carboxamide (400 mg, 0.992 mmol, intermediate 7-3) in ethanol (5 mL), DIPEA (347 μL, 1.98 mmol) and (4-methoxyphenyl)methaneamine (136 mg, 0.992 mmol) were added at room temperature. Subsequently, the reaction mixture was heated to 80°C for 2 hours, quenched with ice water, and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0-30% ethyl acetate in petroleum ether to obtain 3-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((4-methoxybenzyl)amino)pyrazine-2-carboxamide as a pale yellow solid (250 mg, 0.496 mmol, yield 50.0%). 1 H NMR(400MHz,DMSO-d6)δ ppm 10.00(s,1H),8.77(t,J=5.7Hz,1H),7.99(d,J=1.1Hz,1H),7.27-7.36(m,3H),6.89-6.97(m,2H),4.48(d,J= 5.7Hz,2H),3.83-3.90(m,4H),3.74(d,J=1.1Hz,3H),2.32(s,3H),1.90-2.03(m,4H).m / z(ESI):504.2(M+H) + .

[0193] Step 2: A solution of 3-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((4-methoxybenzyl)amino)pyrazine-2-carboxamide (230 mg, 0.456 mmol), 6-azaspiro[2.5]octane (76 mg, 0.68 mmol, Wuxi AppTec), and DIPEA (118 mg, 0.913 mmol) in dimethyl sulfoxide (3 mL) was heated at 60°C for 4 hours. Subsequently, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 0-20% ethyl acetate in petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((4-methoxybenzyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a pale yellow solid (190 mg, 0.33 mmol, yield 72%). 1 H NMR(300MHz,DMSO-d6)δ ppm 9.99(s,1H),8.33(br s,1H),7.44(s,1H),δ 7.34(s,1H),δ 7.20-7.32(m,2H),6.86(d,J=8.3Hz,2H),3.95-3.88(m,4H),3.86(s,3H),3.45-3.32(m,4 H),2.28(s,3H),2.01-1.81(m,4H),1.45-1.35(m,4H),0.33(s,4H).m / z(ESI):579.3(M+H) + .

[0194] Step 3: Anisole (0.028 mL, 0.26 mmol) was added to a solution of N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((4-methoxybenzyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (150 mg, 0.259 mmol) in TFA (2.0 mL, 26 mmol), and the reaction mixture was heated at 60°C for 5 hours. The reaction mixture was then concentrated, and the concentrate was diluted with ELISA / H2O. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography using 40% ethyl acetate in petroleum ether to obtain 5-amino-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a pale yellow solid (95 mg, 0.207 mmol, yield 80%). 1 H NMR(400MHz,DMSO-d6):δ ppm 10.10(s,1H),7.39(s,1H),7.35(s,1H),7.06(br s,2H),3.92-3.83(m,4H),3.44-3.36(m,4H),2.29(s,3H),2.04-1.90(m,4H),1.49-1.42(m,4H),0.34(s,4H).m / z(ESI):459.2(M+H) + .

[0195] Example 1 N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] To a solution of N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-fluoro-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (100 mg, 0.217 mmol, intermediate 6-1) in DMSO (5 mL), cesium carbonate (142 mg, 0.434 mmol) and 2-hydroxyethane-1-sulfonamide (40.8 mg, 0.326 mmol, Wuxi AppTec) were added. The reaction mixture was stirred at 120°C for 16 hours, then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 30% to 40% ethyl acetate in petroleum ether. The material thus obtained was further pulverized with a mixture of diethyl ether and petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a grayish-white solid (36.5 mg, 0.065 mmol, yield 30%). 1 H NMR(300MHz,DMSO-d6):δ ppm 11.92(s,1H),10.94(s,1H),8.14(d,J=8.4Hz,1H),7.34(s,1H),6.67(d,J=8.4Hz,1H),4.95(s,1H),3.6 1-4.07(m,8H),3.17(m,4H),2.32(s,3H),1.99(m,4H),1.63(m,4H),0.35(s,4H).m / z(ESI):566.1(M+H) + .

[0196] [Table 9]

[0197] Example 2 (R)-N-(6-methyl-2-(2-methylmorpholino)pyrimidine-4-yl)-6-(oxetane-3-ylamino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] To a solution of (R)-6-fluoro-N-(6-methyl-2-(2-methylmorpholino)pyrimidine-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.150 g, 0.341 mmol, intermediate 6) in DMSO (3 mL), oxetane-3-amine (0.037 g, 0.51 mmol) and DIPEA (0.178 mL, 1.02 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours, then quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 30% to 45% siRNA in petroleum ether to obtain (R)-N-(6-methyl-2-(2-methylmorpholino)pyrimidine-4-yl)-6-(oxetane-3-ylamino)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a grayish-white solid (0.100 g, 0.203 mmol, yield 59.5%). 1 H NMR(400MHz,DMSO-d6):δ ppm 12.51(s,1H),7.97-8.10(m,2H),7.34(d,J=3.0Hz,1H),6.39(dd,J=8.9,2.9Hz,1H),4.95(br s,1H),4.82(td,J=6.8,2.9Hz,2H),4.39-4.54(m,4H),3.88(d,J=11.4Hz,1 H),3.49(ddt,J=12.0,9.1,4.2Hz,2H),3.05(d,J=6.6Hz,4H),2.91(t,J=12 .5Hz,1H),2.60(td,J=10.4,5.2Hz,1H),2.28(d,J=3.0Hz,3H),1.67(s,4H) ,1.16(dd,J=6.2,2.9Hz,3H),0.35(d,J=3.0Hz,4H).m / z(ESI):494.2(M+H) + .

[0198] [Table 10]

[0199] Example 3 6-(cyclopropylsulfonyl)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] 6-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (138 mg, 0.29 mmol, intermediate 7) and sodium cyclopropanesulfinate (50 mg, 0.39 mmol, Accela ChemBio Inc.) in 2 mL of NMP were heated at 140°C for 35 minutes. An additional 0.095 g of sodium cyclopropanesulfinate was added, and the mixture was heated in a microwave at 140°C for 30 minutes. The mixture was adsorbed onto a silica gel plug and purified by silica gel chromatography using 0-50% siRNA in heptane to obtain 6-(cyclopropylsulfonyl)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.14-10.87(m,1H),8.99-9.36(m,1H),7.60-7.98(m,1H),7.32-7.53(m ,1H),3.91-4.04(m,4H),3.39-3.55(m,1H),3.19-3.32(m,3H),2.83-2.9 5(m,1H),2.33-2.46(m,3H),1.91-2.10(m,4H),1.66-1.81(m,4H),1.22- 1.33(m,2H),1.07-1.17(m,2H),0.35-0.49(m,4H).m / z(ESI):546.2(M+H) + .

[0200] Examples 4-1 and 4-2: 4-(6-azaspiro[2.5]octan-6-yl)-6-(S-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)-3-pyridinecarboxamide (Example 4-1) and 4-(6-azaspiro[2.5]octan-6-yl)-6-(R-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)-3-pyridinecarboxamide (Example 4-2) [ka] Step 1: 6 mL of dioxane was flushed with 6-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.66 g, 1.38 mmol, intermediate 7), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.080 g, 0.14 mmol, Sigma-Aldrich Corporation), and tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (0.14 g, 0.14 mmol, Strem Chemicals, Inc.) with N2 for 5 minutes. Diisopropylethylamine (0.36 g, 2.77 mmol, Sigma-Aldrich Corporation) and cyclopropanechiol (0.13 g, 1.75 mmol, Enamine) were added, and the mixture was heated in a sealed vial at 90°C for 3.5 hours. The mixture was adsorbed onto a silica gel plug and purified by silica gel chromatography (0-20% ethyl phosphate in heptane) to obtain 6-(cyclopropylthio)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide. 1H NMR(400MHz,chloroform-d)δ ppm 10.95-11.58(m,1H),8.97-9.19(m,1H),7.45-7.49(m,1H),7.14-7.17(m,1H),3.95-4.03(m,4H),3.10-3.18(m,4H),2.37-2.41(m,3H), 2.30-2.36(m,1H),1.93-2.08(m,4H),1.69-1.80(m,4H),1.16-1.23(m,2H),0.74-0.80(m,2H),0.39-0.45(m,4H).m / z(ESI):514.4(M+H) + .

[0201] Step 2: Ammonium carbonate (0.17 g, 1.75 mmol, Sigma-Aldrich Corporation) and 6-(cyclopropylthio)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (0.6 g, 1.17 mmol) were added to 7 mL of DCM and 3.5 mL of MeOH, to which (acetyloxy)(phenyl)-iodanyl acetate (0.86 g, 2.68 mmol, Sigma-Aldrich Corporation) was added. This mixture was stirred at RT for 7 hours. The mixture was stirred with 40 mL of ethyl acetate and 25 mL of brine for 5 minutes. The organic layer was separated, dried, and evaporated. The mixture was adsorbed onto a silica gel plug and purified by silica gel chromatography (0-80% ethyl acetate in heptane) to obtain 6-(cyclopropanesulfonimidoyl)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide. The racemic mixture was chiral separated by preparative SFC using a Chiral tech AD (250 × 21 mm, 5 mm) with a mobile phase of 70 mL / min consisting of 75% liquid CO2, 25% EtOH, and 0.2% TEA to obtain:

[0202] Example 4-1: 4-(6-azaspiro[2.5]octan-6-yl)-6-(S-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)-3-pyridinecarboxamide. First elution peak (107 mg, ee>99%); 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.66-10.84(m,1H),9.12-9.23(m,1H),7.77-7.90(m,1H),7.34-7.50(m ,1H),3.92-4.05(m,4H),3.19-3.28(m,4H),2.81-3.00(m,2H),2.36-2.4 4(m,3H),1.92-2.08(m,4H),1.68-1.79(m,4H),1.41-1.48(m,1H),1.18- 1.22(m,2H),0.96-1.07(m,1H),0.39-0.47(m,4H).m / z(ESI):546.2(M+H) + .

[0203] Example 4-2: 4-(6-azaspiro[2.5]octan-6-yl)-6-(R-cyclopropylsulfonimidoyl)-N-(2-(4,4-difluoro-1-piperidinyl)-6-methyl-4-pyrimidinyl)-3-pyridinecarboxamide. Second elution peak (106 mg, ee 99.3%); 1 ¹H NMR (400 MHz, chloroform-d) δ ppm 10.63-10.92(m,1H),9.01-9.31(m,1H),7.76-7.98(m,1H),7.38-7.47(m ,1H),3.90-4.03(m,4H),3.15-3.31(m,4H),2.82-2.97(m,2H),2.33-2.4 4(m,3H),1.92-2.08(m,4H),1.69-1.77(m,4H),1.38-1.47(m,1H),1.11- 1.18(m,2H),0.97-1.05(m,1H),0.36-0.50(m,4H).m / z(ESI):546.2(M+H) + .

[0204] Stereochemistry was assigned arbitrarily.

[0205] [Table 11]

[0206] Example 6 N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2-hydroxyethyl)sulfonamide)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide [ka] Step 1: A solution of 5-bromo-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2,5]octan-6-yl)picolinamide (0.4 g, 0.77 mmol, intermediate 7-2) in DMF (4 mL) was successively treated with (2,4-dimethoxyphenyl)methaneamine (0.128 g, 0.77 mmol, Chempure), cesium carbonate (0.50 g, 1.53 mmol), followed by xanthophos (0.044 g, 0.077 mmol, Arbor) and purged with nitrogen gas. Subsequently, Pd2(dba)3 (0.070 g, 0.077 mmol, Hindustan Platinum) was added, and the mixture was stirred in a microwave initiator at 120°C for 1 hour. Next, the reaction mixture was filtered through a Celite plug, and the filtrate was diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 40% to 60% ethyl acetate in petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2,4-dimethoxybenzyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide (0.225 g, 0.370 mmol, yield 48%) as a yellow solid. 1H NMR(300MHz,DMSO-d6):δ ppm 12.11(s,1H),7.85(d,J=2.2Hz,1H),7.38(s,1H),7.20(d,J=8.3Hz,1H),7.07(t,J=5. 7Hz,1H),6.80(d,J=2.4Hz,1H),6.60(d,J=2.4Hz,1H),6.50(dd,J=8.3,2.4Hz,1H),4. 25(d,J=5.7Hz,2H),3.88(d,J=6.2Hz,3H),3.84(s,3H),3.75(s,3H),2.97(t,J=5.2Hz ,4H),2.30(s,4H),1.86-2.09(m,4H),1.63(s,4H),0.36(s,4H).m / z(ESI):608.3(M+H) + .

[0207] Step 2: A solution of N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2,4-dimethoxybenzyl)amino)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide (0.220 g, 0.362 mmol) in chloroform (5 mL) was treated with DIPEA (0.252 mL, 1.81 mmol), followed by a solution of methyl 2-(chlorosulfonyl) acetate (0.219 g, 1.27 mmol, Combi-Blocks) in chloroform (0.5 mL). The reaction mixture was stirred at ambient temperature for 16 hours, then quenched with water (15 mL) and extracted with CHCl2 (2 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 30% to 40% siRNA in petroleum ether to obtain methyl 2-(N-(6-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-5-(6-azaspiro[2.5]octan-6-yl)pyridine-3-yl)-N-(2,4-dimethoxybenzyl)sulfamoyl) acetate as a pale yellow solid (0.140 g, 0.188 mmol, yield 52%). 1H NMR(300MHz,DMSO-d6):δ ppm 11.49(s,1H),8.17(d,J=1.9Hz,1H),7.65(s,1H),7.32(s,1H),7.16(d,J=8 .2Hz,1H),6.46(d,J=8.3Hz,2H),4.88(s,2H),4.58(s,2H),3.87(s,3H),3. 71(d,J=2.9Hz,6H),3.67(s,3H),3.03(d,J=5.8Hz,4H),2.32(s,4H),1.98( d,J=7.4Hz,4H),1.53(d,J=6.5Hz,4H),0.35(s,4H).m / z(ESI):744.3(M+H) + .

[0208] Step 3: A mixture of methyl 2-(N-(6-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-5-(6-azaspiro[2.5]octan-6-yl)pyridine-3-yl)-N-(2,4-dimethoxybenzyl)sulfamoyl) acetate (0.130 g, 0.175 mmol) and trifluoroacetic acid (2 mL, 26.0 mmol) was stirred at 60°C for 4 hours. The reaction mixture was concentrated and the concentrate was dissolved in ELISA (20 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was ground with diethyl ether and pentane to obtain methyl 2-(N-(6-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-5-(6-azaspiro[2.5]octan-6-yl)pyridine-3-yl)sulfamoyl) acetate as a pale yellow solid (0.1 g, 0.168 mmol, yield 96%), which was used in the next step without purification. m / z(ESI): 594.2(M+H) + .

[0209] Step 4: To a solution of methyl 2-(N-(6-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-5-(6-azaspiro[2.5]octan-6-yl)pyridine-3-yl)sulfamoyl) acetate (0.1 g, 0.168 mmol) in tetrahydrofuran (3 mL), lithium borohydride (0.084 mL, 0.168 mmol, 1.0 M solution in tetrahydrofuran, Aldrich) was added dropwise over 2 hours at -78°C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with ELISA (2 × 15 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 50% to 70% siRNA in petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2-hydroxyethyl)sulfonamide)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide (0.035 g, 0.062 mmol, yield 37%) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 11.53(s,1H),10.40(s,1H),8.19(d,J=2.1Hz,1H),7.50(d,J=2.2Hz,1H ),7.36(s,1H),4.97(t,J=5.5Hz,1H),3.89(s,4H),3.78(m,2H),3.42(d ,J=12.4Hz,2H),3.05(t,J=5.4Hz,4H),2.32(d,J=1.3Hz,3H),1.96(d,J=15.0Hz,4H),1.59(t,J=5.4Hz,4H),0.36(s,4H).m / z(ESI):566.2(M+H) + .

[0210] Example 7 N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-((2-hydroxyethyl)sulfonamide)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide [ka] A mixture of 6-chloro-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-4-(6-azaspiro[2,5]octan-6-yl)nicotinamide (0.150 g, 0.314 mmol, intermediate 7), 2-hydroxyethane-1-sulfonamide (0.059 g, 0.472 mmol, Wuxi AppTec), copper(I) iodide (0.060 g, 0.314 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.022 g, 0.157 mmol) in DMF (1.5 mL) was heated at 105 °C for 16 hours. The reaction was then filtered through a Celite plug, the filtrate was diluted with ELISA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 1% to 40% siRNA in petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-((2-hydroxyethyl)sulfonamide)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide 2,2,2-trifluoroacetate as a white solid. This was further purified by preparative HPLC to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-6-((2-hydroxyethyl)sulfonamide)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide 2,2,2-trifluoroacetate as a grayish-white solid (0.060 g, 0.088 mmol, yield 28%). 1 H NMR(400MHz,DMSO-d6)δ 11.18(s,1H),8.31(s,1H),7.32(s,1H),6.72(s,1H),3.90(t,J=5.6Hz,4H),3.78(t,J=6.7Hz,2H),3.56(s,2H)3.09 (t,J=5.2Hz,4H),2.32(s,3H),1.99(dp,J=19.1,5.8Hz,4H),1.72-1.42(m,4H),0.35(s,4H).m / z(ESI):566.1(M+H) + .

[0211] [Table 12]

[0212] Example 8 5-(cyclopropylsulfonyl)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide [ka] 3 mL of NMP contained 5-bromo-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide (0.28 g, 0.54 mmol, intermediate 7-2), copper(I) iodide (20 mg, 0.10 mmol, Acros Organics), sodium cyclopropanesulfinate (0.12 g, 0.84 mmol, Aurum Pharmatech), and quinoline (60 mg, 0.46 mmol, Oakwood Products, Inc.), which were heated in a microwave at 140°C for 3 hours. The mixture was adsorbed onto a silica gel plug and purified by silica gel chromatography (0-50% ethyl acetate in heptane) to obtain 5-(cyclopropylsulfonyl)-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)picolinamide as a grayish-white solid. 1 H NMR(400MHz,chloroform-d)δ ppm 10.68-10.95(m,1H),8.65-8.81(m,1H),7.88-8.05(m,1H),7.45-7.51(m,1H),3.92-4.00(m,4H),3.19-3.29(m,4H),2.47-2.56(m,1H), 2.34-2.43(m,3H),1.93-2.05(m,4H),1.66-1.72(m,4H),1.39-1.45(m,2H),1.08-1.17(m,2H),0.37-0.46(m,4H).m / z(ESI):547.3(M+H) + .

[0213] Example 9 N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-2-((2-hydroxyethyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)isonicotinamide [ka] Tribasic potassium phosphate (396 mg, 1.86 mmol, Sigma-Aldrich Corporation), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (54 mg, 0.093 mmol, Sigma-Aldrich Corporation), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (32 mg, 0.031 mmol, Strem Chemicals, Inc.), and 2-bromo-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-(6-azaspiro[2.5]octan-6-yl)isonicotinamide (324 mg, 0.62 mmol, intermediate 7-1) were added to a two-necked flask. The flask was flushed with N2 for 10 minutes, and dioxane (6 mL) and ethanolamine (202 mg, 3.31 mmol, Sigma-Aldrich Corporation) were added. The mixture was heated at 100°C for 5 hours. The reaction mixture was cooled to RT, adsorbed onto a silica gel plug, and purified by silica gel chromatography (0-80% ethyl phosphate in heptane) to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-2-((2-hydroxyethyl)amino)-5-(6-azaspiro[2.5]octan-6-yl)isonicotinamide as a yellow solid. 1¹H NMR (400 MHz, chloroform-d) δ ppm 13.61-14.04(m,1H),8.07-8.22(m,1H),7.44-7.48(m,1H),7.30-7.36(m ,1H),5.02-5.10(m,1H),3.95-4.04(m,4H),3.79-3.88(m,2H),3.53-3.6 1(m,2H),2.98-3.13(m,4H),2.33-2.43(m,3H),2.04-2.09(m,1H),1.94- 2.04(m,4H),1.44-1.86(m,4H),0.37-0.45(m,4H).m / z(ESI):502.3(M+H) + .

[0214] Example 10 N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2-hydroxyethyl)sulfonamide)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide [ka] Step 1: To a solution of 5-amino-N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide (95 mg, 0.207 mmol, intermediate 9) in chloroform (1 mL), triethylamine (87 μL, 0.622 mmol) and methyl 2-(chlorosulfonyl) acetate (35.8 mg, 0.207 mmol, Combi-Blocks) in chloroform (1 mL) were added at 0°C. Subsequently, the reaction mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with dichloromethane. The organic layer was taken, washed with brine, dried over Na2SO4, filtered, and concentrated to obtain methyl 2-(N-(5-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-yl)sulfamoyl)acetate as a pale yellow, rubbery solid (150 mg, 0.139 mmol), which was then transferred to the next step without further purification. m / z(ESI): 595.2(M+H) + .

[0215] Step 2: To a solution of methyl 2-(N-(5-((2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)carbamoyl)-6-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-yl)sulfamoyl) acetate (150 mg, 0.139 mmol) in ethanol (2 mL), NaBH4 (10.50 mg, 0.277 mmol) was added at 0°C. The reaction mixture was then stirred at room temperature for 4 hours, quenched with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The concentrate was purified by flash column chromatography using a gradient of 40% ethyl acetate in petroleum ether to obtain N-(2-(4,4-difluoropiperidine-1-yl)-6-methylpyrimidine-4-yl)-5-((2-hydroxyethyl)sulfonamide)-3-(6-azaspiro[2.5]octan-6-yl)pyrazine-2-carboxamide as a grayish-white solid (22 mg, 0.039 mmol, yield 28%). 1 H NMR(400MHz,DMSO-d6)δ ppm 11.18(br s,1H),10.19(s,1H),7.55(s,1H),7.29(s,1H),4.95(br s,1H),3.92-3.82(m,4H),3.79(t,J=6.0Hz,2H),3.68(t,J=6.5Hz,2H),3.50-3.40(m,4H ),2.30(s,3H),2.00-1.90(m,4H),1.61-1.30(m,4H),0.36(s,4H).m / z(ESI):567.2(M+H) + .

[0216] Example 11 2-(4,4-difluoropiperidine-1-yl)-N-(4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)isonicotinamide [ka] A mixture of 2-hydroxyethane-1-sulfonamide (17 mg, 0.135 mmol, Enamine), potassium phosphate (71 mg, 0.336 mmol, Aldrich), dimethylglycine (7 mg, 0.067 mmol, Oakwood), and copper(I) iodide (7 mg, 0.034 mmol, Strem) in 3 mL of DMF was degassed for 3 minutes. The tube was sealed and heated at 50°C for 5 minutes, followed by treatment with N-(4-bromo-2-(6-azaspiro[2.5]octan-6-yl)phenyl)-2-(4,4-difluoropiperidine-1-yl)isonicotinamide (34 mg, 0.067 mmol, intermediate 7-5). The mixture was heated at 100°C for 18 hours, then cooled to RT and partitioned into 5 mL of water and 50 mL of ethyl acetate. The organic layer was washed with 3 mL of brine and concentrated. The residue was purified by reverse-phase HPLC to obtain 10% to 90% (0.1% TFA in acetonitrile) in (0.1% TFA in water) as a brown solid, yielding 2-(4,4-difluoropiperidine-1-yl)-N-(4-((2-hydroxyethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)phenyl)isonicotinamide bis(2,2,2-trifluoroacetate) (25 mg, 0.032 mmol, yield 48%). 1 H NMR(400MHz, methanol-d4)δ 8.24(d,J=6.01Hz,1H),7.99(d,J=8.71Hz,1H),7.67(s,1H),7.23-7.33(m,2H),7.11(dd,J=2.07,8.71H z,1H),3.85-3.97(m,6H),3.26(m,2H),2.98-3.14(m,4H),2.11-2.22(m,4H),1.61(s,4H),0.41(s,4H). 19 F NMR (376 MHz, methanol-d4) δ -77.58 (s, 6F), -98.87 (s, 2F). m / z (ESI): 550.2 (M+H) + .

[0217] Biological examples The assays described below were used to test exemplary compounds of the present invention. The data from these examples, tested according to the procedures described below, are shown in Table A.

[0218] KIF18A Enzyme Assay: The microtubule-stimulated ATPase activity assay is used to measure the KIF18A enzyme activity after treatment with the compound. The compound was serially diluted 2-fold in DMSO (Sigma Inc.) over 22 concentration ranges. Recombinant human KIF18A (1-467 His-tagged) protein was expressed using a baculovirus system and purified by affinity chromatography using Amgen Inc. The concentrations of KIF18A protein, microtubules (MTs), and ATP during the reaction were optimized for 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. Prepare the reaction buffer [(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)]. Add the compound and KIF18A protein (30 nM) to the prepared reaction buffer and incubate at room temperature for 15 minutes, then add ATP (K m Then, add 75 μM of ADP-Glo® reagent to the reaction mixture and incubate at room temperature for another 15 minutes. Mix 5 μl of ADP-Glo® reagent with 2.5 μl of the reaction mixture and incubate at room temperature for 40 minutes. Add 10 μl of ADP-Glo® detection reagent and incubate at room temperature for 40 minutes. Read the luminescence using an EnVision microplate reader (Perkin Elmer Inc) equipped with an ultra-luminescence module. Fit the concentration-response curve and IC using Genedata Screener Software (Standard 15.0.1, Genedata Inc) equipped with a 4-parameter logistic regression fitted model. 50 The determination was made.

[0219] Table A provides the following data on representative compounds of the present invention as exemplified in this application and their priority documents: compound name and biological data. (IC, where available) 50 The unit is μM. (Ex. # refers to the example number.)

[0220] [Table 13]

[0221] [Table 14]

[0222] The above invention has been described in some detail by examples and embodiments for the purpose of clarity and understanding. Those skilled in the art will understand that changes and modifications can be made within the scope of the appended claims. Therefore, it will be understood that the above description is intended to be illustrative and not limiting. Accordingly, the scope of the invention should not be determined by reference to the above description, but rather by reference to the appended claims, together with the entire scope of the equivalent for which such claims are granted.

[0223] All patents, patent applications, and publications cited herein are incorporated herein by reference to the same extent as if each individual patent, patent application, or publication were shown individually.

Claims

1. Compound of formula I: 【Chemistry 1】 or any pharmaceutically acceptable salt thereof The above equation I is, The following equation (Ia) (wherein L is -NR ３ - (C = O), X １ N is X ２ CR ７ X ３ N is X ４ CR ９ It is. 【Chemistry 2】 or The following formula (Ib) (where 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 .): 【Transformation 3】 or The following equation (Ic) (where L is -(C=O)-NR ３ - and X １ N is X ２ CR ７ X ３ CR ８ X ４ CR ９ It is. 【Chemistry 4】 or The following formula (Id) (where L is -(C=O)-NR ３ - and X １ N is X ２ CR ７ X ３ N is X ４ CR ９ It is. 【Transformation 5】 Selected from, R １ is -CN, or base-Z-R １２ And in the formula, Z is -C ０－４ alk-,-NR １１ -, -NR １１ SO ２ -, -SO ２ NR １１ -, -NR １１ -S(=O)(=NH), -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, C ０－４ alk-O-, -(C=O)-, -(C=O)NR １１ -, -C=N(OH)-, or -NR １１ (C=O) or Group-Z-R １２ is -N=S(=O)-(R １２ ) ２ And in the formula, two R １２ The pairs can alternately combine with the sulfur atoms bonded to each to form saturated or partially saturated 3, 4, 5, or 6-membered monocyclic rings containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. R ２ F, Cl, Br, methyl, CF ３ , -OH, -OCHF ２ Morpholinyl or piperidinyl, substituted with zero, one, two, or three substituents selected from CN, or oxo; R ３ H, C １－４ alk, or C １－４ It is a hallucination. R ４ H, Haro, R ４ａ , or R ４ｂ And, R ５ H, Halo, C １－８ alk, or C １－４ It is a hallucination. R ６ H, Halo, C １－８ alk, C １－４ Haloalk, -O-C １－８ alk, or -OR ６ａ And in the formula, R ６ａ This is a saturated or partially saturated 3, 4, 5, or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S. R ７ H, Haro, R ７ａ , or R ７ｂ And, R ８ H, Halo, C １－８ alk, C １－４ Haloalk, -OH, -O-R ８ａ , or -OR ８ｂ And, R ９ H, Haro, R ９ａ , or R ９ｂ And, R １０ｃ , R １０ｄ R 10i and R 10j are each H, methyl, or ethyl, and R １０ａ and R １０ｂ Each pair combines with the carbon atom bonded to it to form a cyclopropyl, cyclobutyl, or cyclopentyl ring that is spiro to the ring containing the carbon atoms to which R10a and R10b are bonded. R １１ is H or C １－８ It is alk, R １２ H, R １２ａ , or R １２ｂ And, R ４ａ 、R ７ａ 、R ８ａ 、R ９ａ 、and R １２ａ are, independently, in each case, 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 [[ID=??]]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 It should be noted that there seems to be an unclear "??" in the original text at line 24 which is maintained as is in the translation for the purpose of following the rules. If this is an error in the original, it may need to be corrected for a more accurate translation. ２－６ alkOR ａ , -C １－６ alkNR ａ R ａ , -C １－６ alkOR ａ , -C １－６ rulekN(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 Selected from the group consisting of saturated, partially saturated, or unsaturated 3, 4, 5, 6, or 7-membered monocyclic rings or 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered bicyclic rings, containing 0, 1, 2, or 3 N atoms substituted by 0, 1, 2, or 3 groups selected from oxo, and 0, 1, or 2 atoms selected from O and S, R ４ｂ , R ７ｂ , R ８ｂ , R ９ｂ , and R １２ｂ Independently, in each case, F, Cl, Br, -OR ａ , -OC １－４ C is substituted with 0, 1, 2, 3, 4, or 5 groups selected from haloalk or CN. １－６ Selected from the group consisting of alk, R １４ Independently, in each case, 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) 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 rulekN(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 Selected from the group consisting of saturated, partially saturated, or unsaturated 3, 4, 5, 6, or 7-membered monocyclic rings or 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered bicyclic rings, containing 0, 1, 2, or 3 N atoms substituted by 0, 1, 2, or 3 groups selected from oxo, and 0 or 1 atom selected from O and S, R ａ Independently, in each case, H or R ｂ And, R ｂ Independently, in each case, C １－６ Alk, phenyl, or benzyl, and the C １－６ alk is a halo, -OH, -OC １－４ alk, -NH ２ , - NHC １－４ alk, -OC(=O)C １－４ alk, or -N(C) １－４ (alk) C １－４ Substituted with 0, 1, 2, or 3 substituents selected from alk, wherein the phenyl or benzyl is a 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 A compound of formula I, or any pharmaceutically acceptable salt thereof, substituted with 0, 1, 2, or 3 substituents selected from alk.

2. The above equation I is, The following equation (Ia) (wherein L is -NR ３ - (C = O), X １ N is X ２ CR ７ X ３ N is X ４ CR ９ It is. 【Transformation 6】 The compound according to claim 1.

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

4. Z is absent, -NH-, -NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -(C=O)-, or -(C=O)NH-, R １２ (a) H; (b) F, Cl, Br, -OH, -OCH ３ , or substituted with 0, 1, 2, or 3 groups selected from cyclopropyl, C 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 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, or, R １２ The compound according to any one of claims 1 to 3, which is selected from cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, azetidinyl, tetrahydrofuranyl, or 1,3,4-oxathiadinyl.

5. R １ is -CN, or base-Z-R １２ And Z is absent, -NH-, -NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -(C=O)-, -(C=O)NH-, or -NH(C=O)-, R １２ teeth, (a) H; (b) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyranil, oxetanil, tetrahydrofuranil, azetidinil, imidazolyl, morpholinil, pyrrolidinil, piperazinil, 【Transformation 7】 (Each ring contains 0, 1, 2, or 3 OH, F, methyl, -CH ２ OH, -C(=O)OCH ３ , -C(=O)OC(CH ３ ) ３ NH ２ (substituted with CN and oxo); or (c) 0, 1, 2, or 3 OH, F, -C(=O)OCH ３ , -NH ２ ,-NH(CH ３ ), or -N (CH ３ ) ２ C is replaced by １－６ A compound according to any one of claims 1 to 4, selected from alk.

6. R １ is -CN or base-Z-R １２ And Z is absent, -NH-, -NHSO ２ -, -SO ２ NH-, -S(=O)(=NH)-, -S-, -S(=O)-, -SO ２ -, -(C=O)-, or -(C=O)NH-, R １２ teeth, (a) H; (b) Oxetanyl, cyclopropyl; or (c) C substituted with 0, 1, 2, or 3 OH groups １－６ is it alk or The aforementioned base-Z-R １２ is -N=S(=O)-(R １２ ) ２ And in the formula, two R １２ The pairs of these combine with the sulfur atoms bonded to each of them alternately, 【Transformation 8】 A saturated or partially saturated 3, 4, 5, or 6-membered monocyclic ring can be formed containing 0, 1, 2, or 3 N atoms selected from, and 0, 1, or 2 atoms selected from O and S, or, R １ is, base-Z-R １２ And in the formula, Z is -NHSO ２ - or - SO ２ NH- and R １２ is either oxetanyl, cyclopropyl, or R １２ C is substituted with 0, 1, 2, or 3 OH groups. １－６ is it an alk, or, R １ is, base-Z-R １２ And in the formula, Z is -NHSO ２ - and R １２ ha-CH ２ -CH ２ A compound according to any one of claims 1 to 5, wherein it is -OH.

7. R ２ is morpholinyl substituted with 1, 2, or 3 methyl groups, or R ２ is either a piperidinyl substituted with one, two, or three fluoro groups, or R ２ teeth, 【Chemistry 9】 The compound according to any one of claims 1 to 6.

8. R ４ The compound according to any one of claims 1 to 7, wherein is methyl.

9. R ５ The compound according to any one of claims 1 to 8, wherein is H.

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

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

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. 【Request Item 14】 【Table 1】 Table 2 Table 3 Table 4 A compound according to claim 1, or any pharmaceutically acceptable salt thereof, selected from the above.

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

16. A drug for use in a method of treating a condition that can be treated with a KIF18a inhibitor, wherein the drug comprises a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to claim 15, the method comprising administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the composition to a patient in need thereof, wherein the condition is (a) a solid tumor or blood-derived tumor selected from cancers of bladder cancer, endometrial cancer, squamous cell carcinoma of the lung, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer. The drug is a tumor, (b) a lymphoid hematopoietic malignancy selected from leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, pilocytic cell lymphoma, and Burkitt lymphoma, (c) a myeloid hematopoietic malignancy selected from acute and chronic myeloid leukemia, myelodysplastic syndrome, and promyelocytic leukemia, (d) a mesenchymal tumor selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma, and schwannoma, or (f) a cancer selected from the group consisting of melanoma, seminomas, teratomas, osteosarcoma, xeroderma pigmentosum, keratosacral cell tumor, follicular carcinoma of the thyroid, or Kaposi's sarcoma.

17. A drug for use in a method for reducing the size of a solid tumor in a subject, wherein the drug comprises a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to claim 15, and the method comprises administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the composition according to claim 15 to the subject in need thereof, or A drug for use in a method for treating cell proliferation disorders in a subject, wherein the drug comprises a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to claim 15, and the method comprises administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the composition according to claim 15 to the subject in need thereof, or A drug for use in a method for inhibiting KIF18A in cells, wherein the drug comprises a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a composition according to claim 15, the method comprising contacting the cells with the compound, or a pharmaceutically acceptable salt thereof, or the composition.

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