How to treat cancers associated with transformed acid-coiled-coil proteins

Abstract

Disclosed herein are methods for treating solid tumors in the subject.

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 551,832, filed on 9 February 2024, and U.S. Provisional Application No. 63 / 540,716, filed on 27 September 2023, the contents of these applications being incorporated in their entirety by reference. [Background technology]

[0002] Cancer is a complex disease characterized by uncontrolled cell proliferation. In the United States, solid tumors account for a significant proportion of all cancer cases. Currently available treatments have many shortcomings and limited effectiveness. Therefore, new therapies for treating solid tumors are needed. [Overview of the project]

[0003] In one embodiment, the present disclosure provides a method for treating a solid tumor in a subject, the method comprising administering a compound having a structure represented by formula I, or a pharmaceutically acceptable salt thereof, to the subject: [ka] (In the formula, E and B are, independently, aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, A is a 6-membered heteroaryl, R 1 (The element is H, alkyl, or benzyl). [Brief explanation of the drawing]

[0004] [Figure 1] The biological activity of the exemplary compounds of this disclosure is shown. Compound 80 exhibits superior tumor growth inhibitory effects in xenograft models compared to standard treatment. [Modes for carrying out the invention]

[0005] Members of the transformed acid-coiled-coil (TACC) protein family are gaining attention as important proteins in microtubule and centrosome-related functions. Vertebrates express three different TACC isoforms: TACC1, TACC2, and TACC3. TACCs play crucial roles in gene regulation, cell proliferation and differentiation, mRNA processing, transcription, and cell migration by interacting with various molecules involved in microtubule / centrosome dynamics and transcription (Ha et al., 2013). The members share a conserved domain called the TACC domain, which is required for TACC proteins to interact with spindle and centrosome mechanisms (Gergely et al., 2000). Although members of the TACC family were described as centrosome proteins, they are also distributed throughout the cell during interphase. For example, TACC3 and TACC2 form complexes with various histone acetyltransferases, including hGCN5L2 and pCAF, and exhibit regulatory functions in transcription (Gangisetty et al., 2004). Of particular note is that TACC3 interacts with MBD2 (mCpG-binding domain 2) in the interphase nucleus, promoting the binding of MBD2 to histone acetyltransferase, thereby reactivating the methylated promoter.

[0006] TACC protein levels are elevated in many types of cancer, including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, and breast cancer. TACC1, the first member of the TACC family, was independently identified as an amplicon in the 8p11 region of breast cancer (Still et al., 1999), and it was subsequently revealed that it may promote mammary tumorigenesis through activation of the Ras / PI3K signaling pathway (Cully et al., 2005). TACC2 has been found to promote androgen-mediated proliferation in prostate cancer and is associated with poor prognosis (Takayama et al., 2012). Furthermore, overexpression of TACC2 induces proliferation of breast cancer cells (Cheng et al., 2010). Inhibition of TACC3 function leads to a variety of cytological changes, including the formation of multipolar spindles that cause mitotic arrest (Yao et al., 2012), chromosomal abnormalities that lead to caspase-dependent apoptosis (Schneider et al., 2007), and, in some cases, cellular senescence (Schmidt et al., 2010). Furthermore, knockdown of TACC3 suppresses tumorigenesis and cell proliferation in renal cell carcinoma (RCC) (Guo & Liu, 2018) and pancreatic cancer (Shi et al., 2023). TACC3 has been shown to be an independent prognostic factor and therapeutic target in a variety of cancers, including but not limited to sarcomas (Matsuda et al., 2017), liver cancer (Zhou et al., 2015), and gastric cancer (Akanda et al., 2021). As shown in the aforementioned studies, the TACC family has been shown to be important molecules involved in spindle formation in cancer cells, and therefore they are important and promising targets in cancer targeted therapy.

[0007] However, currently, there are no inhibitors for TACC1 and TACC2, and only two inhibitors target TACC3. The small molecule TACC3 inhibitor KHS101 was the first to be shown to promote neuronal differentiation in rats (Wurdak et al., 2010). Although KHS101 treatment suppressed tumor growth in a glioblastoma (GBM) xenograft model (Polson et al., 2018), KHS101 has many drawbacks, including poor systemic stability when administered orally and a large effective dose (Wurdak et al., 2010). Another TACC3 inhibitor, SPL-B, has been shown to inhibit centrosome microtubule nucleation in ovarian cancer cells and suppress tumor growth in an ovarian cancer xenograft model (Yao et al., 2014). However, like KHS101, SPL-B is not approved as a cancer treatment.

[0008] Based on the above, there are clearly unmet needs in the treatment of solid tumors, such as solid tumors involving TACC (e.g., TACC3).

[0009] In one embodiment, the present disclosure provides a method for treating a solid tumor in a subject, the method comprising administering a compound having a structure represented by formula I, or a pharmaceutically acceptable salt thereof, to the subject: [ka] (In the formula, E and B are, independently, aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, A is a 6-membered heteroaryl, R 1 (The element is H, alkyl, or benzyl).

[0010] In some embodiments, A is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain preferred embodiments, A is pyridyl. In other preferred embodiments, A is pyridazinyl.

[0011] In certain embodiments, the compound is represented by Formula Ia or a pharmaceutically acceptable salt thereof,

Chemical Formula

[0012] In certain embodiments, the compound is represented by Formula IIb or a pharmaceutically acceptable salt thereof:

Chemical Formula

[0013] In certain preferred embodiments, R 3 This is a halo (for example, a fluoro).

[0014] In certain embodiments, the compound is represented by formula IIb or a pharmaceutically acceptable salt thereof: [ka]

[0015] In certain preferred embodiments, R 4 is a halo (e.g., fluorocarbon). In another preferred embodiment, R 4 These are hydroxyl or alkoxy (e.g., methoxy).

[0016] In certain embodiments, the compound is represented by formula IIc or a pharmaceutically acceptable salt thereof: [ka]

[0017] In a particular embodiment, R 2 is H, alkyl (e.g., methyl or ethyl), halo (e.g., chloro), hydroxyl, alkoxy (e.g., methoxy), amino (e.g., aminoalkyl such as methylamino), amide (e.g., N-methylamide), acetyl, carboxy, or ester (e.g., methyl ester). In certain preferred embodiments, R 2 is a halo (e.g., fluorocarbon). In another preferred embodiment, R 2 H is H.

[0018] In a particular embodiment, R 5 is H or alkyl (e.g., methyl). In certain preferred embodiments, R 2 H is H.

[0019] In a particular embodiment, R 1 H is H. In a particular embodiment, R 1This is an alkyl group (for example, methyl or ethyl).

[0020] In certain embodiments, B is a heteroaryl (e.g., pyridinyl, pyrimidinyl, or triazinyl). In certain preferred embodiments, B is pyrimidinyl.

[0021] In certain embodiments, B is at least one R 4 It is replaced by each R 4 B is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide. In certain embodiments, B is at least one R 4 It is replaced by each R 4 These are independently selected from alkyl (e.g., methyl), oxo, and halo (e.g., chloro or fluoro). In certain preferred embodiments, B is one or two R 4 It has been replaced with.

[0022] In certain embodiments, the compound is represented by formula Ib or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, E and B are, independently, aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, X 1 is N or CR 2 And, X 2 is N or CR 3 And, X 3 is N or CR 4 And, X 4 is N or CR 5 And, X 5 is N or CR 8 And, X 6 is N or CR 9 And, R 1 is H, alkyl, or benzyl, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 Each of these is independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

[0023] In certain embodiments, the compound is represented by formula IIIa or a pharmaceutically acceptable salt thereof: [ka]

[0024] In certain embodiments, the compound is represented by formula IIIb or a pharmaceutically acceptable salt thereof: [ka]

[0025] In certain embodiments, the compound is represented by formula IIIc or a pharmaceutically acceptable salt thereof: [ka]

[0026] In a particular embodiment, X 5 CR 8 That is the case.

[0027] In a particular embodiment, R 8 is H or a halo (e.g., fluoro). In certain preferred embodiments, R 8 It is fluoro.

[0028] In a particular embodiment, X 5 It is N.

[0029] In a particular embodiment, X 6 CR 9 In other embodiments, X 6 It is N.

[0030] In a particular embodiment, R 9 is H or a halo (e.g., fluoro). In certain preferred embodiments, R 9 It is fluoro.

[0031] In certain embodiments, the compound is represented by formula IVa or a pharmaceutically acceptable salt thereof: [ka]

[0032] In certain embodiments, the compound is represented by formula IVb or a pharmaceutically acceptable salt thereof: [ka]

[0033] In certain embodiments, the compound is represented by formula IVc or a pharmaceutically acceptable salt thereof: [ka]

[0034] In certain embodiments, the compound is represented by formula IVd or a pharmaceutically acceptable salt thereof: [ka]

[0035] In certain embodiments, the compound is represented by formula IVe or a pharmaceutically acceptable salt thereof: [ka]

[0036] In a particular embodiment, R 6 R is H, hydroxyl, oxo, halo (e.g., fluoro), alkyl (e.g., methyl, hydroxyalkyl such as hydroxymethyl, or alkyloxyalkyl such as methoxyethyl), or alkoxy (e.g., methoxy). In certain preferred embodiments, R 6 is a halo (e.g., fluorocarbon). In another preferred embodiment, R 6 H is H.

[0037] In a particular embodiment, R 7 R is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amide (e.g., methylamide). In certain preferred embodiments, R 7 This is a halo (for example, a fluoro).

[0038] In certain embodiments, D is an amino acid. In certain embodiments, D is an N-linked heterocycline (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxydethiomorpholinyl, azabicyclooctanyl, oxazabicyclooctane, hexahydrophyrrolyl, or azabicyclohexanyl). In certain preferred embodiments, D is an N-linked morpholinyl, which is optionally substituted.

[0039] In a particular embodiment, D is at least one R 10 It is replaced by each R 10D is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide, or D is at least two R 5 It is replaced with R 5 Two of these combine to form a biring heterocycline.

[0040] In a particular embodiment, D is at least one R 10 It is replaced by each R 10 D is independently selected from alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), halo (e.g., fluoro), cycloalkyl (e.g., cyclopropyl or cyclobutyl), or heterocyclyl (e.g., oxetanyl). In certain embodiments, D is one or two R 10 It is replaced by. In a particular preferred embodiment, D is two R 10 It has been replaced with.

[0041] In certain embodiments, the compound is represented by formula V or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 10a and R 10b Each of these is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

[0042] In certain embodiments, D has a structure represented by formula V* or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 10a and R 10b Each of these is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

[0043] In a particular embodiment, R 10a R is an alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), a halo (e.g., fluoro), a cycloalkyl (e.g., cyclopropyl or cyclobutyl), or a heterocyclyl (e.g., oxetanyl). In certain preferred embodiments, R 10a It is methyl.

[0044] In a particular embodiment, R 10b R is an alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), a halo (e.g., fluoro), a cycloalkyl (e.g., cyclopropyl or cyclobutyl), or a heterocyclyl (e.g., oxetanyl). In certain preferred embodiments, R 10b It is methyl.

[0045] In a particular preferred embodiment, D is [ka] That is the case.

[0046] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a more preferred embodiment, D is [ka] In another, more preferred embodiment, D is [ka] In another, more preferred embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] In a particular embodiment, D is [ka] That is the case.

[0047] In certain embodiments, E is an aryl (e.g., phenyl, dihydrobenzofuran, or benzodioxol). In certain preferred embodiments, E is phenyl. In other embodiments, E is a heteroaryl (e.g., pyridinyl, pyrazinyl, benzofuranyl, or benzodioxyl). In certain preferred embodiments, E is pyridinyl. In other preferred embodiments, E is pyrazinyl.

[0048] In certain embodiments, E is at least one R 11 It is replaced by each R 11 E is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide alkyls. In certain embodiments, E is at least one R 6 It is replaced by each R 11 These are independently selected from alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), hydroxyl, halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl.

[0049] In certain preferred embodiments, E is one R 11 It is replaced by. In another preferred embodiment, E is two R 11 It is replaced by. In yet another embodiment, E is three R 11 It has been replaced with.

[0050] In certain embodiments, E has a structure represented by Formula VIa, VIb, or VIc,

Chemical Formula

[0051] In certain embodiments, E has a structure represented by Formula VIa:

Chemical Formula

[0052] In certain embodiments, E has a structure represented by Formula VIb:

Chemical Formula

[0053] In certain embodiments, E has a structure represented by Formula VIc:

Chemical Formula

[0054] In certain embodiments, R 11aThis is selected from alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl. In certain preferred embodiments, R 11a It is difluoromethoxy.

[0055] In a particular embodiment, R 11b The elements are selected from alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl.

[0056] In certain preferred embodiments, E is [ka] That is the case.

[0057] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] In certain embodiments, E is [ka] is. In certain embodiments, E is,

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0058] In certain embodiments, the compound is represented by formula VIIa, VIIb, or a pharmaceutically acceptable salt thereof. [ka] During the ceremony, R 4 and R 7each independently is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamido, R 10a and R 10b each are H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido, R 11a is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamido.

[0059] In certain embodiments, the compound is represented by Formula VIIa*, VIIb*, or a pharmaceutically acceptable salt thereof:

Chemical Formula

[0060] In certain embodiments, the compound is represented by formula VIIa or a pharmaceutically acceptable salt thereof; [ka]

[0061] In a particular embodiment of formula VIIa, R 4 R is alkyl (e.g., methyl), oxo, or halo (e.g., chloro or fluoro). In a particular preferred embodiment of formula VIIa, R 4 This is a halo (for example, chloro or fluoro).

[0062] In certain embodiments, the compound is represented by formula VIIb or a pharmaceutically acceptable salt thereof: [ka]

[0063] In a particular embodiment of formula VIIb, R 7 R is H, hydroxyl, oxo, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amide (e.g., methylamide). In a particular embodiment of formula VIIb, R 7R is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amide (e.g., methylamide). In a particular preferred embodiment of formula VIIb, R 7 This is a halo (for example, a fluoro).

[0064] In certain preferred embodiments of formula VIIa or VIIb, R 10a It is an alkyl group (for example, methyl).

[0065] In certain preferred embodiments of formula VIIa or VIIb, R 10b It is an alkyl group (for example, methyl).

[0066] In certain embodiments of formula VIIa or VIIb, R 11a These are alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), hydroxyl, halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl. In certain preferred embodiments of formula VIIa or VIIb, R 11a It is difluoromethyl.

[0067] In certain embodiments, the compound is selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33]

[0068] In certain preferred embodiments, the compound is compound 80.

[0069] Some of the compounds disclosed herein may exist in tautomeristic forms. Such forms, although not explicitly shown in the formulas described herein, are intended to be included within the scope of this disclosure.

[0070] This disclosure also includes all suitable isotopic variants of the compounds of this disclosure. An isotopic variant of a compound of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but with an atomic mass different from the atomic mass commonly or primarily found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I, and 131 I is one example. Therefore, unless otherwise specified, the description of "hydrogen" or "H" is... 1 H (protium), 2 H (deuterium), and 3 It should be understood that this includes H (tritium). Specific isotopic variants of the compound of the present invention, for example, 3 H or 14 The incorporation of one or more radioactive isotopes, such as 14C, is useful in drug and / or substrate tissue distribution studies. Tritiated and carbon-14, i.e. 1413C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium may result in certain therapeutic advantages arising from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose, and may therefore be preferred in some situations. Such variants may also have advantageous optical properties resulting from changes in vibrational modes, for example, by heavier isotopes. Isotope variants of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art (e.g., by exemplary methods or by preparations described in the following examples using suitable isotope variants of preferred reagents).

[0071] In certain embodiments, the solid tumor is characterized by TACC. In certain embodiments, the solid tumor is characterized by TACC1. In certain embodiments, the solid tumor is characterized by TACC12. In certain embodiments, the solid tumor is characterized by TACC3.

[0072] In certain embodiments, the solid tumor is a brain tumor. In certain preferred embodiments, the brain tumor is a metastasis of the primary cancer. In certain embodiments, the primary cancer is lung cancer. In certain preferred embodiments, the primary cancer is breast cancer. In certain embodiments, the primary cancer is single-negative breast cancer. In certain embodiments, the primary cancer is double-negative breast cancer. In certain preferred embodiments, the primary cancer is triple-negative breast cancer. In certain embodiments, the primary cancer is ovarian cancer. In certain embodiments, the primary cancer is cervical cancer. In certain embodiments, the primary cancer is bladder cancer. In certain embodiments, the primary cancer is endometrial cancer. In certain embodiments, the primary cancer is liver cancer. In certain embodiments, the primary cancer is kidney cancer. In certain embodiments, the primary cancer is skin cancer. In certain embodiments, the primary cancer is prostate cancer.

[0073] In certain embodiments, the brain tumor is a glioma, astrocytoma, glioblastoma, low-grade astrocytoma, meningioma, mixed oligoastrocytoma, pilocytic astrocytoma, pleomorphic xanthoblastoma, subventricular giant cell astrocytoma, or anaplastic astrocytoma. In certain preferred embodiments, the brain tumor is a glioblastoma. In other preferred embodiments, the brain tumor is a meningioma. In certain preferred embodiments, the brain tumor is recurrent or refractory.

[0074] In certain embodiments, the solid tumor is bladder cancer. In certain embodiments, the bladder cancer is urothelial bladder cancer, squamous cell bladder cancer, adenocarcinoma, sarcoma, or small cell bladder cancer. In certain preferred embodiments, the bladder cancer is urothelial bladder cancer. In certain preferred embodiments, the bladder cancer is recurrent or refractory.

[0075] In certain embodiments, the solid tumor is cervical cancer. In certain preferred embodiments, the cervical cancer is squamous cell carcinoma. In other preferred embodiments, the cervical cancer is cervical adenocarcinoma. In certain preferred embodiments, the cervical cancer is recurrent or refractory.

[0076] In certain embodiments, the solid tumor is uterine cancer. In certain preferred embodiments, the uterine cancer is endometrial cancer. In other preferred embodiments, the uterine cancer is uterine sarcoma. In certain preferred embodiments, the uterine cancer is recurrent or refractory.

[0077] In certain embodiments, solid tumors are gastrointestinal cancers. In certain embodiments, gastrointestinal cancers are anal cancer, intestinal cancer, colorectal adenocarcinoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid cancer, islet cell carcinoma, rectal cancer, small intestine cancer, or bile duct cancer. In certain embodiments, gastrointestinal cancers are gastrointestinal stromal tumors, carcinoid tumors, gastric remnant cancer, or gastric adenocarcinoma. In certain preferred embodiments, gastrointestinal cancers are recurrent or refractory.

[0078] In certain embodiments, the solid tumor is liver cancer. In certain preferred embodiments, the liver cancer is hepatocellular carcinoma. In other preferred embodiments, the liver cancer is cholangiocarcinoma. In certain preferred embodiments, the liver cancer is recurrent or refractory.

[0079] In certain embodiments, the solid tumor is a sarcoma. In certain embodiments, the sarcoma is Ewing's sarcoma, soft tissue sarcoma, leiomyosarcoma, epithelioid sarcoma, fibrosarcoma, chordoma, synovial sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, liposarcoma, angiosarcoma, or cutaneous fibrosarcoma. In certain preferred embodiments, the sarcoma is recurrent or refractory.

[0080] In certain embodiments, the solid tumor is breast cancer. In certain embodiments, the solid tumor is breast cancer. In certain embodiments, the breast cancer is ductal carcinoma, lobular carcinoma, metaplastic carcinoma, inflammatory breast cancer, triple-negative breast cancer, mucinous neoplasm, medullary carcinoma, invasive ductal carcinoma, invasive lobular carcinoma, hormone-positive breast cancer, or HER2-positive breast cancer. In certain preferred embodiments, the breast cancer is recurrent or refractory.

[0081] In certain embodiments, the solid tumor is esophageal cancer. In certain embodiments, the esophageal cancer is squamous cell carcinoma. In certain embodiments, the esophageal cancer is adenocarcinoma. In certain preferred embodiments, the esophageal cancer is recurrent or refractory.

[0082] In certain embodiments, the solid tumor is a head and neck cancer. In certain embodiments, the head and neck cancer is a hypopharyngeal cancer, laryngeal cancer, lip cancer and oral cancer, metastatic squamous cell carcinoma of unknown primary site, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus cancer and nasal cavity cancer, or salivary gland cancer. In certain preferred embodiments, the head and neck cancer is recurrent or refractory.

[0083] In certain embodiments, the solid tumor is lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer, large cell carcinoma, small cell carcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, adenocarcinoma, or mesothelioma. In certain preferred embodiments, the lung cancer is recurrent or refractory.

[0084] In certain embodiments, the solid tumor is ovarian cancer. In certain embodiments, the ovarian cancer is epithelial ovarian cancer, germ cell tumor, or stromal cell carcinoma. In certain preferred embodiments, the ovarian cancer is recurrent or refractory.

[0085] In certain embodiments, the solid tumor is prostate cancer. In certain embodiments, the solid tumor is adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, or small cell prostate cancer. In certain preferred embodiments, the prostate cancer is recurrent or refractory.

[0086] In certain embodiments, the solid tumor is a skin cancer. In certain embodiments, the skin cancer is basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, or malignant melanoma. In certain preferred embodiments, the skin cancer is recurrent or refractory.

[0087] In certain embodiments, the solid tumor is renal cancer. In certain embodiments, the renal cancer is renal cell carcinoma, urothelial carcinoma, Wilms' tumor, renal sarcoma, renal adenoma, oncocytoma, or angiomyolipoma. In certain preferred embodiments, the renal cancer is recurrent or refractory.

[0088] In certain embodiments, the solid tumor is cancer. In certain embodiments, the solid tumor is adenocarcinoma. In certain embodiments, the solid tumor is squamous cell carcinoma.

[0089] In certain embodiments, the solid tumor is a neuroendocrine carcinoma.

[0090] In certain embodiments, the solid tumor is a leiomyosarcoma.

[0091] In a preferred embodiment, the solid tumor is a metastasis of the primary cancer. In a specific embodiment, the primary cancer is lung cancer. In a specific preferred embodiment, the primary cancer is breast cancer. In a specific embodiment, the primary cancer is single-negative breast cancer. In a specific embodiment, the primary cancer is double-negative breast cancer. In a specific preferred embodiment, the primary cancer is triple-negative breast cancer. In a specific embodiment, the primary cancer is ovarian cancer. In a specific embodiment, the primary cancer is cervical cancer. In a specific embodiment, the primary cancer is bladder cancer. In a specific embodiment, the primary cancer is endometrial cancer. In a specific embodiment, the primary cancer is liver cancer. In a specific embodiment, the primary cancer is kidney cancer. In a specific embodiment, the primary cancer is skin cancer. In a specific embodiment, the primary cancer is prostate cancer. In certain preferred embodiments, the solid tumor is recurrent (e.g., cancer that was previously cured or functionally cured but has recurred). In certain preferred embodiments, the solid tumor is refractory (e.g., cancer that previously responded to one or more treatments but has since become unresponsive to those treatments).

[0092] Pharmaceutical composition The compositions and methods of the present invention can be used to treat individuals in need of treatment. In certain embodiments, the individuals are mammals such as humans, or non-human mammals. When administered to animals such as humans, the compositions or compounds are preferably administered as a pharmaceutical composition comprising, for example, the compounds of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents, or vehicles such as glycols or glycerols, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such a pharmaceutical composition is for human administration, particularly for invasive administration routes (i.e., routes such as injection or transplantation that avoid transport or diffusion across the epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to result in delayed release of the drug or to selectively target one or more cells, tissues, or organs. Pharmaceutical compositions may be in the form of administration units such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, reconstituted parental solutions, powders, liquids, syrups, suppositories, and injections. Compositions may also be present in transdermal delivery systems, such as skin patches. Compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0093] A pharmaceutically acceptable carrier may include, for example, a physiologically acceptable agent that acts to stabilize a compound, such as the compound of the present invention, increase its solubility, or increase its absorption. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran; antioxidants such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, for example, in which the compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to manufacture and administer.

[0094] The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio, within the bounds of sound medical judgment.

[0095] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that may function as pharmaceutically acceptable carriers are: (1) sugars, e.g., lactose, glucose, and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil; (10) Glycols, such as propylene glycol, (11) Polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) Esters, such as ethyl oleate and ethyl laurate, (13) Agar, (14) Buffers, such as magnesium hydroxide and aluminum hydroxide, (15) Alginic acid, (16) Water free of pyrogens, (17) Isotonic saline, (18) Ringer's solution, (19) Ethyl alcohol, (20) Phosphate buffer, and (21) Other non-toxic, suitable substances used in pharmaceutical formulations.

[0096] Pharmaceutical compositions (preparations) can be administered to a target by any of a number of routes of administration, including, for example, oral (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, and pastes for application to the tongue), absorption through the oral mucosa (e.g., sublingually), subcutaneously, transdermally (e.g., as a patch applied to the skin), and topically (e.g., as a cream, ointment, or spray applied to the skin). Compounds may also be prepared for inhalation. In certain embodiments, compounds may be simply dissolved or suspended in sterile water. Details of suitable administration routes and compositions therefor can be found, for example, in U.S. Patents 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited herein.

[0097] The formulations can be conveniently presented in unit dosage forms and can be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the specific mode of administration. Generally, the amount of active ingredient that can be combined with a carrier material to produce a single dosage form is the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount is in the range of about 1 percent to about 99 percent of the active ingredient, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent.

[0098] Methods for preparing these formulations or compositions include the step of combining an active compound, such as the compound of the present invention, with a carrier and optionally one or more auxiliary components. Generally, formulations are prepared by uniformly and closely combining the compound of the present invention with a liquid carrier or a finely divided solid carrier, or both, and then optionally shaping the product.

[0099] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules, or liquids or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as licks or syrups, or as lozenges (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. Compositions or compounds may also be administered as boluses, licks or pastes.

[0100] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, sugar-coated tablets, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, e.g., glycerol, 4) Disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) Dissolution retarders, e.g., paraffin; (6) Absorption enhancers, e.g., quaternary ammonium compounds; (7) Wetting agents, e.g., cetyl alcohol and glycerol monostearate; (8) Absorbents, e.g., kaolin and bentonite clay; (9) Lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; (10) Complexing agents, e.g., modified and unmodified cyclodextrins; and (11) Colorants. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions can also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0101] Tablets can be prepared by compression or molding, using one or more optional auxiliary components. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Wet tablets can be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0102] Other solid dosage forms of pharmaceutical compositions, such as tablets, and sugar-coated tablets, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be prepared with score lines or coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation field. They may also be prepared to provide sustained or controlled release of the active ingredient therein, for example, using oxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various ratios to yield a desired release profile. They may be sterilized, for example, by filtration with a bacterial-retaining filter or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injection medium immediately before use. These compositions may also optionally contain opacifiers, which may optionally release the active ingredient only, or preferentially, in a delayed manner in a specific part of the gastrointestinal tract. Examples of usable embedding compositions include polymers and waxes. The active ingredient may also, where appropriate, be in a microencapsulated form together with one or more of the excipients described above.

[0103] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, parental solutions for reconstitution, microemulsifies, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor oil, sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.

[0104] In addition to inert diluents, oral compositions may also contain auxiliary agents such as humectants, emulsifiers and suspending agents, sweeteners, flavorings, colorants, fragrances and preservatives.

[0105] In addition to the active compound, the suspension may include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, metahydroxyaluminum, bentonite, agar and tragacanth, and mixtures thereof.

[0106] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0107] Ointments, pastes, creams, and gels may contain excipients such as animal and plant fats and physical fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof, in addition to the active compound.

[0108] Powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof, in addition to the active compound. Sprays may also contain conventional propellants such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

[0109] Transdermal patches offer the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The velocity of such a flux can be controlled by providing a velocity-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0110] As used herein, the phrases “parenteral administration” and “administered parenterally” typically refer to modes of administration other than enteral and topical administration by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, subarachnoid, intrathecal, intracystic, intraorbital, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. Pharmaceutical compositions suitable for parenteral administration include one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or one or more active compounds in combination with a sterile powder, which may be reconstituted into a sterile injection solution or dispersion immediately before use, and may contain antioxidants, buffers, bacteriostatic agents, the blood or suspension of the recipient of the intended purpose, or a solvent that makes the formulation isotonic with the formulation.

[0111] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the particle size required in the case of dispersions, and using surfactants.

[0112] These compositions may also contain auxiliary agents such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. Furthermore, sustained absorption of injectable dosage forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0113] In some cases, it is desirable to slow down the absorption of a drug from subcutaneous or intramuscular injection in order to maintain the drug's effect. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low water solubility. Then, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0114] Injectable depot formulations are prepared by forming a microencapsulation matrix of the target compound with biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Depot-injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsifies that are compatible with body tissues.

[0115] For use in the method of the present invention, the active compound can be provided by itself or, for example, in combination with a pharmaceutically acceptable carrier as a pharmaceutical composition containing 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient.

[0116] The method of delivery may also be provided by rechargeable or biodegradable devices. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein-based biopharmaceuticals. Various biocompatible polymers (including hydrogels), including both biodegradable and non-biodegradable polymers, can be used to form implants for the sustained release of compounds at specific target sites.

[0117] The actual dosage level of the active ingredient in a pharmaceutical composition can be modified to obtain an effective amount of the active ingredient that achieves the therapeutic response, composition, and mode of administration for a particular patient without causing toxicity to the patient.

[0118] The selected dosage level depends on a variety of factors, including those well known in the medical field, such as the activity of the specific compound or combination of compounds used, or their esters, salts, or amides; the route of administration; the time of administration; the elimination rate of the specific compound used; the duration of treatment; other drugs, compounds, and / or substances used in combination with the specific compound used; and the age, sex, weight, condition, general health status, and prior medical history of the patient being treated.

[0119] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the required therapeutically effective dose of a pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the pharmaceutical composition or compound at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "Therapeutically effective dose" means a concentration of the compound sufficient to produce the desired therapeutic effect. It is generally understood that the effective dose of a compound varies depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective dose include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, other types of therapeutic agents administered with the compound of the present invention. Many total doses can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0120] Generally, the preferred daily dose of the active compound used in the compositions and methods of the present invention is the minimum dose of the compound that is effective in producing a therapeutic effect. Such an effective dose generally depends on the factors mentioned above.

[0121] If necessary, the effective daily dose of the active compound may be administered as one, two, three, four, five, or six or more subdoses, optionally administered separately in unit dosage forms at appropriate intervals throughout the day. In certain embodiments of the present invention, the active compound may be administered twice or three times daily. In preferred embodiments, the active compound is administered once daily.

[0122] Patients receiving this treatment are any animal in need of treatment, including primates, especially humans; as well as other mammals, such as horses, cattle, pigs, sheep, cats, and dogs; poultry; and common pets.

[0123] In certain embodiments, the compounds of the present invention may be used alone or in combination with other types of therapeutic agents.

[0124] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in compositions and methods of the present invention. In certain embodiments, the salts intended for the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts. In certain embodiments, the salts intended for the present invention include, but are not limited to, L-arginine, venentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydravamin, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the salts intended for the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, the salts intended for use in the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, and d-glucoheptoic acid. Examples of undecylenic acid salts include, but are not limited to, nic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hypric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid salts.

[0125] pharmaceutically acceptable acid addition salts can also exist as various solvates with water, methanol, ethanol, dimethylformamide, and others. Mixtures of such solvates can also be prepared. The source of such solvates may be from the crystallization solvent, specific to the preparation or crystallization solvent, or indeterminate to such solvent.

[0126] Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives and antioxidants may also be present in the composition.

[0127] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0128] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings generally understood by those of an ordinary skill in the art. Generally, the nomenclature and techniques used in relation to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry as described herein are well known and commonly used in the art.

[0129] The methods and techniques described herein are generally well known in the art unless otherwise indicated, and are carried out in accordance with the conventional methods described in various general and more specific references cited and discussed throughout this specification. See, for example, “Principles of Neural Science,” McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics,” Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.,” WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.,” WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th ed.,” Sinauer Associates, Inc., Sunderland, MA (2000).

[0130] Chemical terms used herein, unless otherwise defined herein, are used in accordance with their prior art usage, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0131] All of the foregoing, and any other publications, patents, and published patent applications referenced herein, are incorporated herein by reference. In case of any conflict, this specification, including specific definitions, shall prevail.

[0132] The term "pharmaceuticals" is used herein to refer to compounds (such as organic or inorganic compounds, mixtures of compounds), biological macromolecules (such as nucleic acids, antibodies, parts thereof, and humanized, chimeric, and human antibodies and monoclonal antibodies, proteins or parts thereof, e.g., peptides, lipids, carbohydrates), or extracts made from biological materials such as cells or tissues of bacteria, plants, fungi, or animals (especially mammals). Pharmaceuticals include, for example, pharmaceuticals with known structures and pharmaceuticals with unknown structures.

[0133] The terms "patient," "subject," or "individual" are used interchangeably and refer to either human or non-human animals. These terms include mammals such as humans, primates, livestock (including cattle and pigs), companion animals (e.g., dogs and cats), and rodents (e.g., mice and rats).

[0134] "Treating" a condition or patient means taking measures to obtain a beneficial or desirable outcome, including clinical outcomes. Beneficial or desirable clinical outcomes may include, but are not limited to, relief or improvement of one or more symptoms or conditions, whether detectable or undetectable; a reduction in the severity of the disease; a stable (i.e., non-worsening) state of the disease; prevention of disease progression; delay or slowing of disease progression; improvement or temporary relief of the condition; and remission (partial or complete remission). "Treatment" may also mean extending survival compared to the survival expected without treatment.

[0135] The term “prevent” is recognized in the art and is well understood in the art when used in relation to conditions such as local recurrence (e.g., pain), diseases such as cancer, complex syndromes such as heart failure, or any other medical condition, and includes the administration of a composition that reduces the frequency of symptoms of a medical condition in a subject or delays the onset of the condition compared to a subject who does not receive the composition. Thus, cancer prevention includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in the treated population by a statistically and / or clinically significant amount compared to an untreated control population.

[0136] The "administration" or "delivery" of a substance, compound, or drug to a target can be carried out using one of the various methods known in the art. For example, a compound or drug can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, orally, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through the skin canal). The compound or drug can also be appropriately introduced by rechargeable or biodegradable polymer devices or other devices, e.g., patches and pumps, or formulations that provide sustained, sustained-release, or controlled release of the compound or drug. Deliveries can also be carried out, for example, once, multiple times, and / or over a period of time longer than one.

[0137] The appropriate method for administering a substance, compound, or drug to a subject also depends, for example, on the subject's age and / or physical condition, as well as the chemical and biological properties of the compound or drug (e.g., solubility, digestibility, bioavailability, stability, and toxicity). In some embodiments, the compound or drug is administered orally, for example, by ingestion. In some embodiments, the orally administered compound or drug is in a sustained-release or sustained-release formulation, or is administered using a device for such sustained-release or sustained-release.

[0138] As used herein, the phrase “co-administration” refers to any form of administration of two or more different therapeutic agents such that a second agent is administered while a previously administered therapeutic agent is still effective in the body (for example, the two agents may be effective for the patient simultaneously and may involve a synergistic effect between the two agents). For example, different therapeutic compounds may be administered simultaneously or sequentially, in the same formulation or in separate formulations. Thus, an individual receiving such treatment may benefit from the combined effects of different therapeutic agents.

[0139] The "therapeutic effective dose" or "therapeutic effective dose" of a drug or medication is the amount of the drug or medication administered to a subject that produces the intended therapeutic effect. Complete therapeutic effect does not necessarily occur with a single dose, but may only occur after a series of doses. Therefore, a therapeutic effective dose may be administered in one or more doses. The exact effective dose required by the subject depends, for example, on the subject's size, health, and age, as well as the nature and severity of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective dose for a given situation through routine experimentation.

[0140] Where used herein, the terms “optional” or “optionally” mean that the events or circumstances described below may or may not occur, and the descriptions include both cases in which the events or circumstances occur and cases in which they do not. For example, “optionally substituted alkyl” means both cases in which the alkyl can be substituted and cases in which the alkyl is not substituted.

[0141] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to yield chemically stable compounds that can be readily synthesized from readily available starting materials using known techniques in the art and by the methods described below. If the substituent itself is substituted with multiple groups, it is understood that these multiple groups may be on the same carbon or different carbons, as long as a stable structure is obtained.

[0142] As used herein, the term “optionally substituted” means substituting 1 to 6 hydrogen radicals in a given structure with radicals of specific substituents, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” means substituting 1 to 4 hydrogen radicals in a given structure with the above substituents. More preferably, 1 to 3 hydrogen radicals are replaced by the above substituents. It is understood that further substitutions of substituents may be possible.

[0143] As used herein, the term "alkyl" refers to C1-C 10 Linear alkyl groups or C1-C 10 This refers to saturated aliphatic groups, including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 linear alkyl group or a C1-C6 branched alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 linear alkyl group or a C1-C4 branched alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group can be optionally substituted.

[0144] The term "acyl" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0145] The term "acylamino" is recognized in the art and refers to an amino group substituted with an acyl group, which can be represented, for example, by the formula hydrocarbyl C(O)NH-.

[0146] The term "acyloxy" is recognized in the art and refers to a group represented by the general formula hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0147] The term "alkoxy" refers to an alkyl group to which oxygen is bonded. Typical alkoxyl groups include methoxy, ethoxy, propoxy, and tert-butoxy.

[0148] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, and can be represented by the general formula alkyl-O-alkyl.

[0149] The term "alkyl" refers to saturated aliphatic groups, including linear alkyl groups, branched alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, linear or branched alkyl groups have 30 or fewer (for example, C for linear groups) in their skeleton. 1~30 Regarding branched chains, C 3~30 ), more preferably having 20 or fewer carbon atoms.

[0150] Furthermore, as used herein, in the examples and throughout the claims, the term “alkyl” is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to an alkyl moiety having substituents that substitute hydrogens on one or more carbons of a hydrocarbon skeleton, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0151] "C x~y " or "C x ~C yThe term "alkyl" means a group containing x to y carbon atoms in a chain, when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy. C0 alkyl indicates a hydrogen atom at a terminal position, while internal hydrogen atoms indicate a bond. For example, C 1~6 Alkyl groups contain 1 to 6 carbon atoms in their chain.

[0152] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0153] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and can be represented by the general formula alkylS-.

[0154] As used herein, the term "amide" means base [ka] It refers to, and in the formula, R 9 and R 10 Each of these independently represents either a hydrogen atom or a hydrocarbyl group, or R 9 and R 10 These atoms, together with the N atoms to which they are bonded, complete a heterocycle with 4 to 8 atoms in the ring structure.

[0155] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, and their salts, for example, [ka] This refers to the part that can be expressed by, in the formula, R 9 , R 10 , and R 10‘ Each of these independently represents either a hydrogen atom or a hydrocarbyl group, or R 9 and R 10 These atoms, together with the N atoms to which they are bonded, complete a heterocycle with 4 to 8 atoms in the ring structure.

[0156] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0157] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0158] As used herein, the term “aryl” includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings, in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline.

[0159] The term "carbamate" is recognized in the art, and is based on [ka] It refers to, and in the formula, R 9 and R 10 This independently represents a hydrogen atom or a hydrocarbyl group.

[0160] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0161] The term "carbocyclic ring" includes monocyclic rings with 5 to 7 members and bicyclic rings with 8 to 12 members. Each ring in a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. Carbocyclic rings include bicyclic molecules in which one, two, or three or more atoms are shared between the two rings. The term "condensed carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring in a condensed carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, e.g., phenyl, may be condensed to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, as long as the valence allows. Exemplary “carbocyclic” compounds include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octa-3-ene, naphthalene, and adamantane. Exemplary condensed carbocyclic compounds include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A “carbocyclic” compound can be substituted at any one or more positions that can retain a hydrogen atom.

[0162] As used herein, the term "carbocykrylalkyl" refers to an alkyl group substituted with a carbocyclic group.

[0163] The term "carbonate" is recognized in this technical field and refers to the group -OCO2-.

[0164] As used herein, the term "carboxyl" refers to the group represented by the formula -CO2H.

[0165] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is cycloalkyl, and substituents (e.g., R) 100 The ) is bonded to a cycloalkyl ring, and for example, the other cyclic ring may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, and tetrahydroquinoline.

[0166] As used herein, the term "ester" refers to the group -C(O)OR 9 It refers to, and in the formula, R 9 This represents a hydrocarbyl group.

[0167] As used herein, the term “ether” refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Therefore, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic groups. Ethers also include “alkoxyalkyl” groups, which can be represented by the general formula alkyl-O-alkyl.

[0168] As used herein, the terms "halo" and "halogen" mean halogens, including chloro, fluoro, bromo, and iodine.

[0169] As used herein, the terms “hetallalkyl” and “hetallalkyl” refer to alkyl groups substituted with hetalil groups.

[0170] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, wherein the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is a heteroaromatic ring, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0171] As used herein, the term “heteroatom” means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0172] As used herein, the term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group.

[0173] The terms “heterocyclyl,” “heterocyclic,” and “heterocyclic formula” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, the ring structure containing at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heterocyclyl groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, and the like.

[0174] As used herein, the term "hydrocarbyl" refers to a group that is bonded via a carbon atom without an =O or =S substituent, and typically has at least one carbon-hydrogen bond and is primarily a carbon skeleton, but can optionally include a heteroatom. Therefore, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, but not substituents such as acetyl (which has an =O substituent on the bonded carbon) and ethoxy (which is bonded via oxygen rather than carbon). Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0175] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

[0176] When used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term “lower” means that the substituent includes groups having 10 or fewer atoms, preferably 6 or fewer. For example, “lower alkyl” refers to an alkyl group having 10 or fewer carbon atoms, preferably 6 or fewer. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are, for example, hydroxyalkyl and aralkyl in the reference (in this case, for example, atoms in the aryl group are not counted when counting the carbon atoms of the alkyl substituent), lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents.

[0177] The terms “polycyclyl,” “polycycle,” and “polycyclic” refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings (e.g., the rings are “fused rings”). Each ring in the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring in the polycyclic ring contains 3 to 10 atoms, preferably 5 to 7 atoms.

[0178] The term "sulfate" is recognized in the art and refers to the group -OSO3H or its pharmaceutically acceptable salts.

[0179] The term "sulfonamide" is recognized in the art and has a general formula. [ka] This refers to the group represented by , where R 9 and R 10 This independently represents hydrogen or hydrocarbyl.

[0180] The term "sulfoxide" is recognized in this technical field and refers to the group -S(O)-.

[0181] The term "sulfonate" is recognized in the art and refers to the SO3H group or its pharmaceutically acceptable salts.

[0182] The term "sulfone" is recognized in this technical field and refers to the group -S(O)2-.

[0183] The term “substituted” refers to a portion of a skeleton having substituents that substitute for hydrogens on one or more carbon atoms. “Substituted” or “substituted with ~” will be understood to imply the implicit condition that such substitutions conform to the allowable valencies of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. As used herein, the term “substituted” is intended to include all allowable substituents of an organic compound. In broad embodiments, allowable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more allowable substituents, which may be the same or different for a given organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any allowable substituents of the organic compounds described herein that satisfy the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls, formyls, or acyls, etc.), thiocarbonyls (thioesters, thioacetates, or thioformates, etc.), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that a substituted moiety on a hydrocarbon chain may, where appropriate, be substituted by itself.

[0184] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0185] As used herein, the term "thioester" refers to the group -C(O)SR 9 Or SC(O)R 9 It refers to, and in the formula, R 9 This represents hydrocarbyl.

[0186] As used herein, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0187] The term "urea" is recognized in the art, and the general formula [ka] It can be expressed as, in the formula, R 9 and R 10 These are independently hydrogen or hydrocarbyl.

[0188] As used herein, the term “modulate” includes inhibiting or suppressing a function or activity (such as cell proliferation), as well as enhancing a function or activity.

[0189] The phrase "pharmaceutically acceptable" is recognized in the art. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0190] "Pharmacologically acceptable salt" or "salt" is used herein to mean an acid addition salt or basic addition salt that is suitable or appropriate for the treatment of a patient.

[0191] As used herein, the term “pharmaceutically acceptable acid addition salt” means any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochlorides, hydrobroms, sulfates, and phosphates, as well as metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. They can form either mono or dicarboxylic acids, and such salts may exist in hydrate, solvated, or substantially anhydrous forms. Generally, acid addition salts of compounds of formula I are soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The selection of appropriate salts is known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula I for laboratory use or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0192] As used herein, the term “pharmaceutically acceptable basic addition salt” means any non-toxic organic or inorganic base addition salt of any acidic compound represented by formula I or any of its intermediates. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of a suitable salt is known to those skilled in the art.

[0193] Many of the compounds useful for the methods and compositions of this disclosure have at least one stereocenter in their structure. This stereocenter may be in an R or S configuration, and the R and S notations are used in accordance with the rules set out in Pure Appl. Chem. (1976), 45, 11-30. This disclosure intends all stereoisomeric forms, such as enantiomers and diastereoisomers, of compounds, salts, prodrugs, or mixtures thereof (including all possible mixtures of stereoisomers). See, for example, International Publication No. 01 / 062726.

[0194] Furthermore, certain compounds containing alkenyl groups may exist as Z (tuzamen) or E (entgegen) isomers. In each case, this disclosure includes both mixtures and distinct individual isomers.

[0195] A “prodrug” or “pharmaceutically acceptable prodrug” refers to a compound that, after administration, is metabolized in the host, for example, by hydrolysis or oxidation, to form the compounds of the Disclosure (e.g., compounds of formula I). ​​Typical examples of prodrugs include compounds having a biologically unstable or cleavable (protecting) group on the functional portion of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using esters or phosphoramic acids as biologically unstable or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, which are incorporated herein by reference. The prodrugs of the Disclosure are metabolized to produce compounds of formula I. The Disclosure, to its extent, includes prodrugs of the compounds described herein. Conventional procedures for selecting and preparing suitable prodrugs are described, for example, in "Design of Prodrugs" by Ed. H. Bundgaard, Elsevier, 1985.

[0196] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filter, diluent, excipient, solvent, or encapsulating material, that is useful for preparing a drug for medicinal or therapeutic use.

[0197] As used herein, the terms “logarithm of solubility,” “LogS,” or “logS” are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Low solubility often results in insufficient absorption. The LogS value is the unit strip logarithm (decimal) of solubility measured in mol / liter. [Examples]

[0198] The following representative examples are intended to illustrate the present invention and are not intended to limit the scope of the invention, nor should they be construed as such. In fact, various modifications of the invention and many further embodiments thereof will be apparent to those skilled in the art from the following examples and the entirety of this document, including references to scientific and patent documents cited herein, in addition to those shown and described herein. Furthermore, it should be understood that the contents of these cited references are incorporated herein by reference to help illustrate the latest art. The following examples contain important further information, examples, and guidance that may be adapted to the implementation of the invention in various embodiments and equivalents thereof.

[0199] Example 1: Synthesis of Exemplary Compounds in this Disclosure General Procedure A. [ka] General Procedure B. [ka] General Procedure C. [ka]

[0200] A typical example of D: [ka]

[0201] Typical example of E: [ka]

[0202] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine [ka] A mixture of compound 2-chloropyrimidine-4-amine (2.0 g, 15.4 mmol, 1.0 equivalent), compound (2R,6S)-2,6-dimethylmorpholine (5.33 g, 46.3 mmol, 3.0 equivalents), and DIEA (10.0 g, 77.0 mmol, 5.0 equivalents) in IPA (40 mL) was stirred at 80°C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by column chromatography (PE:EA=5:1~DCM:MeOH=40:1) to obtain 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (3.1 g, 97%) as a white solid. LCMS:209.03[M+1]+;1H NMR(400MHz,CD3OD)δ7.76(d,J=5.9Hz,1H),5.86(d,J=5.9Hz,1H),4.49-4.36(m,2H),3.61(dd d,J=10.5,6.3,2.5Hz,2H),3.38(s,1H),2.48(dd,J=13.2,10.7Hz,2H),1.22(d,J=6.2Hz,6H).

[0203] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine [ka] To a solution of compound 2-chloro-5-fluoropyrimidine-4-amine (50 g, 338.9 mmol, 1.0 equivalent) and compound (2R,6S)-2,6-dimethylmorpholine (78 g, 667.8 mmol, 2.0 equivalents) in IPA (500 mL), DIEA (87.6 g, 667.8 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred at 80°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:SiO=20:1 to obtain 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (47 g, 61%) as a white solid. LCMS: 227.12[M+H] + ; 1 H NMR(400MHz,DMSO-d6):δ7.76(d,J=3.5Hz,1H),6.83(s,2H),4.28(d,J=12.0Hz,2H) ,3.46(dd,J=7.9,6.3Hz,2H),2.32(dd,J=12.7,10.9Hz,2H),1.07(d,J=6.2Hz,6H).

[0204] Synthesis of 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine [ka] To a solution of compound 2-chloro-5-fluoropyrimidine-4-amine (325 mg, 2.2 mmol, 1.5 equivalents) and compound (2S,6S)-2,6-dimethylmorpholine (170 mg, 1.47 mmol, 1.0 equivalent) in IPA (3 mL), DIEA (569 mg, 4.4 mmol, 2.0 equivalents) was added. The reaction mixture was stirred at 80°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH=40 / 1 to obtain 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (92 mg, 18%) as a white solid. LCMS: 227.10[M+1]+; 1H NMR(400MHz,DMSO-d6)δ7.76(d,J=3.5Hz,1H),6.82(s,2H),3.96-3.83(m,2H),3 .61(dd,J=12.9,3.2Hz,2H),3.24(dd,J=12.9,6.2Hz,2H),1.07(d,J=6.4Hz,6H).

[0205] Synthesis of 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine [ka] To a solution of compound 2-chloro-5-fluoropyrimidine-4-amine (200 mg, 1.36 mmol, 1.0 equivalent) in IPA (4 mL), compounds (2R,6R)-2,6-dimethylmorpholine (391 mg, 3.40 mmol, 2.5 equivalents) and DIEA (526 mg, 4.08 mmol, 3.0 equivalents) were added. The reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (DCM / MeOH / NH3·H2O=50 / 1 / 0.5) to obtain 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (70 mg, white solid). LC-MS: 227.12[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ7.77(d,J=3.6Hz,1H),6.84(s,2H),3.92(td,J=6.3,3.5Hz,2 H),3.63(dd,J=12.9,3.3Hz,2H),3.26(dd,J=12.9,6.2Hz,2H),1.08(d,J=6.4Hz,6H).

[0206] Synthesis of 5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-amine [ka] To a solution of 2-chloro-5-fluoropyrimidine-4-amine (200 mg, 1.36 mmol, 1.0 equivalent) in IPA (4 mL), pyrrolidine (290 mg, 4.08 mmol, 3.0 equivalents) and DIEA (526 mg, 4.08 mmol, 3.0 equivalents) were added. The reaction mixture was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (PE / EA = 1 / 1) to obtain 5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-amine (230 mg, white solid). LC-MS: 183.1 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.75 (d, J = 3.8 Hz, 1H), 6.72 (s, 2H), 3.35 (t, J = 6.6 Hz, 4H), 1.84 (t, J = 6.6 Hz, 4H).

[0207] Synthesis of 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-amine [ka] Step a: To a solution of 2-chloro-5-fluoropyrimidine-4-amine (300 mg, 2.03 mmol, 1.0 equivalent), Boc2O (1.77 g, 8.13 mmol, 4.0 equivalents), and TEA (821 mg, 8.13 mmol, 4.0 equivalents) in DCM (3 mL), DMAP (12 mg, 0.10 mmol, 0.05 equivalents) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:siRNA = 100:1 to obtain a bis-N-Boc protected compound (600 mg, 85%) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.49 (s, 1H), 1.44 (s, 18H). Step b: To a solution of bis-N-Boc protecting compound (512 mg, 1.47 mmol, 1.0 equivalent), 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (3 mL) of DIEA was added. The reaction mixture was stirred at 100°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC using PE / EA = 3 / 1 to obtain the product (110 mg, crude) as a white solid. LCMS: 411.35 [M+1] + Step c: To a solution of the bis-N-Boc product from step b (110 mg crude, 0.268 mmol, 1.0 equivalent) in dioxane (1 mL), HCl / dioxane (4 M, 1 mL) was added. The reaction mixture was stirred at 40 °C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated Na2CO3 solution (50 mL). The separated organic layer was dried (over Na2SO4 or MgSO4) and evaporated to dryness. The residue was purified by preparative TLC using DCM / MeOH=40 / 1 to obtain 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-amine (12 mg, 21%) as a white solid. 1 H NMR(400MHz,CDCl3)δ7.90(d,J=3.0Hz,1H),4.85(s,2H),3.85-3.65(m,3H),3.40(dt,J=7.4,4. 4Hz,2H), 2.92(td,J=6.9,5.0Hz,1H),0.92(q,J=6.8Hz,1H),0.57(ddd,J=6.9,4.8,3.6Hz,1H).

[0208] Synthesis of (2R,6S)-4-(4,6-difluoropyrimidine-2-yl)-2,6-dimethylmorpholine [ka] (2R,6S)-2,6-dimethylmorpholine (258 mg, 2.24 mmol, 1.0 equivalent) was added to a solution of 2,4,6-trifluoropyrimidine (300 mg, 2.24 mmol, 1.0 equivalent) and K2CO3 (619 mg, 4.48 mmol, 2.0 equivalent) in ACN (30 mL). The reaction mixture was stirred under ice for 10 minutes and then stirred at room temperature for a further 1 hour. The mixture was concentrated under vacuum to obtain the residue, which was purified by column chromatography using silica gel eluted with (PE / EA = 100 / 1 to 50 / 1) to obtain (2R,6S)-4-(4,6-difluoropyrimidine-2-yl)-2,6-dimethylmorpholine (250 mg, 49%) as a white solid. 1 H NMR(400MHz,CDCl3)δ5.68(t,J=1.6Hz,1H),4.43(dd,J=13.2,1.3Hz,2H),3.58( m,J=12.5,6.2,2.4Hz,2H),2.61(dd,J=13.4,10.8Hz,2H),1.23(d,J=6.2Hz,6H).

[0209] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazine-3-amine [ka] Dioxane (10 mL) contains 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (700 mg, 3.36 mmol, 1.0 equivalent), 3,5-dichloropyridazine (500 mg, 3.36 mmol, 1.0 equivalent), xanthophos (197 mg, 0.34 mmol, 0.1 equivalent), and C S2To a solution of CO3 (2.2 g, 6.72 mmol, 2.0 equivalents), Pd2(dba)3 (97 mg, 0.17 mmol, 0.05 equivalents) was added under N2 conditions at room temperature. The reaction mixture was then stirred under N2 conditions at 110°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by column chromatography (PE:EA=5:1~DCM:MeOH=40:1) to obtain 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazin-3-amine (200 mg, 18.5%) as a yellow solid. LCMS: 321.00[M+1] +

[0210] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3-amine [ka] To a solution of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (35.5 g, 157.08 mmol, 1.0 equivalent), 3,5-dichloropyridazine (35 g, 234.90 mmol, 1.5 equivalent), xanthophos (4.54 g, 7.85 mmol, 0.05 equivalent), and Cs2CO3 (153.5 g, 471.15 mmol, 3.0 equivalent) in Tol (500 mL), Pd(dppf)Cl2 (5.75 g, 7.86 mmol, 0.05 equivalent) was added at room temperature under N2. The reaction mixture was stirred at 80°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using PE:siRNA=5:1 elution to obtain 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (29 g, 55%) as a yellow solid. LCMS:339.11[M+H] + ; 1H NMR (400MHz, DMSO-d6): δ10.69(s,1H),9.05(s,1H),8.47(d,J=2.0Hz,1H),8.17(d,J=3.2 Hz,1H),4.20(d,J=12.5Hz,2H),3.52(d,J=7.3Hz,2H),2.51(s,2H),1.10(d,J=6.1Hz,6H).

[0211] Synthesis of 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine [ka] To a solution of 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (92 mg, 0.41 mmol, 1.0 equivalent), 3,5-dichloropyridazine (91 mg, 0.61 mmol, 1.5 equivalents), xanthophos (12 mg, 0.02 mmol, 0.05 equivalents), and Cs2CO3 (398 mg, 1.22 mmol, 3.0 equivalents) in Tol (3 mL), Pd(dppf)Cl2 (15 mg, 0.02 mmol, 0.05 equivalents) was added at room temperature under N2. The reaction mixture was then stirred under N2 at 80°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (50 mL). The separated organic layer was washed with water, dried (on Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=2 / 1 to obtain 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (75 mg, 54%) as a yellow solid. LCMS: 339.10[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),9.06(d,7=2.1Hz,1H),8.44(d,J=2.2Hz,1H),8.17(d,J=3.3Hz, 1H),4.01-3.91(m,2H),3.67(dd,J=13.0,3.3Hz,2H),3.33(m,1H),3.29(m,1H),1.10(d,J=6.4Hz,6H).

[0212] Synthesis of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3-amine [ka] To a solution of 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (70 mg, 0.31 mmol, 1.0 equivalent) in toluene (4 mL), 3,5-dichloropyridazine (46 mg, 0.31 mmol, 1.0 equivalent), Cs2CO3 (202 mg, 0.62 mmol, 2.0 equivalents), xanthophos (18 mg, 0.031 mmol, 0.1 equivalent), and Pd(dppf)Cl2 (23 mg, 0.031 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 80°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA=2 / 1) to obtain 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (50 mg). LC-MS: 339.05 [M+1] +

[0213] Synthesis of 5-chloro-N-(5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-yl)pyridazine-3-amine [ka] To a solution of 5-fluoro-2-(pyrrolinidine-1-yl)pyrimidine-4-amine (230 mg, 1.26 mmol, 1.0 equivalent) in toluene (5 mL), 3,5-dichloropyridazine (188 mg, 1.26 mmol, 1.0 equivalent), Cs2CO3 (819 mg, 2.52 mmol, 2.0 equivalent), xanthophos (73 mg, 0.126 mmol, 0.1 equivalent), and Pd(dppf)Cl2 (92 mg, 0.126 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 80°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting with (PE / EA=2 / 1) to obtain 5-chloro-N-(5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-yl)pyridazin-3-amine (50 mg, crude). LC-MS: 295.00 [M+1] +

[0214] Synthesis of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-yl)-5-chloropyridazine-3amine [ka] Pd(dppf)Cl2 (2 mg, 0.003 mmol, 0.05 equivalent) was added at room temperature to a solution of 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-amine (12 mg, 0.06 mmol, 1.0 equivalent), 3,5-dichloropyridazine (13 mg, 0.09 mmol, 1.5 equivalent), xanthophos (2 mg, 0.003 mmol, 0.05 equivalent), and Cs2CO3 (59 mg, 0.18 mmol, 3.0 equivalent) in Tol (3 mL). The reaction mixture was then stirred at 80°C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water. The separated organic layer was washed with water, dried (over Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=1 / 1 to obtain N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-yl)-5-chloropyridazine-3-amine (10 mg, 54%) as a white solid. LCMS: 323.07[M+1] + ; 1 H NMR (400MHz, CDCl3) δ9.12(s,1H),8.85(s,1H),8.10(s,2H),3.88(m,3H),3.46(m,J=25.7Hz,2H),2.88(s,1H),1.08(d,J=6.2Hz,1H),0.66(s,1H).

[0215] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methylpyridazine-3-amine [ka] A reaction mixture of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (100 mg, 0.44 mmol, 1.0 equivalent), 4,6-dichloro-3-methylpyridazine (71 mg, 0.44 mmol, 1.0 equivalent), xanthophos (35 mg, 0.044 mmol, 0.1 equivalent), Pd2(dba)3 (56 mg, 0.044 mmol, 0.1 equivalent), and Cs2CO3 (380 mg, 0.88 mmol, 2.0 equivalent) in toluene (5 mL) was stirred at 110 °C for 16 hours under N2. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting (PE / EA = 7 / 1 to 4 / 1) to obtain 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methylpyridazine-3-amine (70 mg, 45%) as a white solid. 1 H NMR(400MHz, CDCl3):5 8.70(s,1H),8.04(s,1H),7.92(s,1H),4.35(d,J=12.9Hz,2H),3.67(s,2H),2.74(s,3H),2.65(t,J=11.5Hz,2H),1.28(d,J=6.1Hz,6H).

[0216] Synthesis of N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)-5-(2-fluoro-4-methoxyphenyl)pyridazine-3-amine compound 3 [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazin-3-amine (100 mg, 0.31 mmol, 1.0 equivalent), (2-fluoro-4-methoxyphenyl)boronic acid (80 mg, 0.47 mmol, 1.5 equivalents), and K2CO3 (86 mg, 0.62 mmol, 2.0 equivalents) in dioxane / H2O (5 mL / 0.5 mL), Pd(PPh3)4 (36 mg, 0.031 mmol, 0.1 equivalent) was added at room temperature under N2. The reaction mixture was then stirred under N2 at 110°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The separated organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by column chromatography (PE:EA = 5:1 to 1:1) to obtain N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)-5-(2-fluoro-4-methoxyphenyl)pyridazin-3-amine (70 mg, 74.7%) as a brown solid. LCMS: 411.05[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.03(d,J=2.3Hz,1H),8.68(s,1H),8.04(d,J=5.6Hz,1H),7.83(t,J=8.9Hz,1H),6.91(d,J=8.6Hz,1H),6.81(dd,J= 13.0,2.3Hz,1H),6.17(d,J=5.7Hz,1H),4.40(d,J=13.1Hz,2H),3.85(s,3H),3.65-3.57(m,2H),2.59-2.49(m,2H),1.17(d,J=6.2Hz,6H).

[0217] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazine-3-amine compound 20 [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazin-3-amine (75 mg, 0.23 mmol, 1.0 equivalent) in dioxane / H2O (2 mL / 0.2 mL), (4-(difluoromethoxy)phenyl)boronic acid (80 mg, 0.46 mmol, 2.0 equivalents), K3PO4 (149 mg, 0.7 mmol, 3.0 equivalents), and Pd(dppf)Cl2 (17 mg, 0.023 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=0 / 1) to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)pyridazin-3-amine as a white solid (68 mg, 68%). LCMS:[M+1]:429.10; 1 H NMR(400MHz,CD3OD)δ9.12(s,1H),8.72(s,1H),8.10(d,J=5.5Hz,1H),8.02(d,J=8.6Hz,2H),7.31(d,J=8.4Hz,2H),6.94 (t,J=73.6Hz,1H),6.21(d,J=5.6Hz,1H),4.45(d,J=12.5Hz,2H),3.65(m,2H),2.67-2.57(m,2H),1.19(d,J=6.2Hz,6H).

[0218] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3-amine compound 80 [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (9 g, 26.57 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (9 g, 53.13 mmol, 2.0 equivalent), and K3PO4 (16.9 g, 79.7 mmol, 3.0 equivalent) in dioxane / H2O (10:1, 90 mL / 10 mL), Pd(dppf)Cl2 (1.94 g, 2.66 mmol, 0.05 equivalent) was added at room temperature under N2. The reaction mixture was then stirred at 110 °C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using PE:HCl = 2:1 elution to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (5.2 g, 44%) as a yellow solid. LCMS: 447.35[M+H] + ; 1 H NMR(400MHz,DMSO-d6):δ10.42(s,1H),9.31(s,1H),8.61(s,1H),8.16(d,J=3.0Hz,1H),7.95(d,J=8.6Hz, 2H),7.55-7.12(m,3H),4.20(d,J=12.5Hz,2H),3.49(t,2H),2.42(d,J=12.6Hz,2H),0.96(d,J=5.0Hz,6H).

[0219] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3-amine compound 91 [ka] To a solution of 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (75 mg, 0.22 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (76 mg, 0.44 mmol, 2.0 equivalents), and K3PO4 (141 mg, 0.66 mmol, 3.0 equivalents) in dioxane / H2O (2 mL / 0.2 mL), Pd(dppf)Cl2 (16 mg, 0.02 mmol, 0.1 equivalent) was added at room temperature under N2. The reaction mixture was then stirred under N2 at 110°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The separated organic layer was washed with water, dried (on Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=1 / 1 to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (63 mg, 64%) as a yellow solid. LCMS: 447.35[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.17(s,1H),8.83(s,1H),8.03(s,1H),7.86(d,J=8.6Hz,2H),7.33(d,J=8.3Hz,2H),6.9 5(t,J=73.3Hz,1H),4.02(s,2H),3.75(d,J=13.0Hz,2H),3.40(dd,J=12.8,6.3Hz,2H),1.11(d,J=6.3Hz,6H).

[0220] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3-amine compound 90 [ka] To a solution of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine (50 mg, 0.15 mmol, 1.0 equivalent) in toluene / H2O (3 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (43 mg, 0.23 mmol, 1.5 equivalents), K3PO4 (64 mg, 0.30 mmol, 2.0 equivalents), and Pd(dppf)Cl2 (11 mg, 0.015 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with RINKAN (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA=1 / 1) to obtain compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazin-3-amine as a yellow oily substance (21 mg). LC-MS: 447.20[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.16(d,J=2.0Hz,1H),8.81(d,J=2.0Hz,1H),8.02(d,J=3.3Hz,1H),7.89-7.81(m,2H),7.33(d,J=8.6Hz,2 H),6.97(t,7=73.5Hz,1H),4.08-3.98(m,2H),3.75(dd,J=12.9,3.3Hz,2H),3.40(dd,J=12.9,6.5Hz,2H),1.13(d,J=6.4Hz,6H).

[0221] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-yl)pyridazine-3-amine compound 104 [ka] To a solution of 5-chloro-N-(5-fluoro-2-(pyrroridine-1-yl)pyrimidine-4-yl)pyridazin-3-amine (50 mg, 0.17 mmol, 1.0 equivalent) in toluene / H2O (3 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (48 mg, 0.26 mmol, 1.5 equivalents), K3PO4 (72 mg, 0.034 mmol, 2.0 equivalents), and Pd(dppf)Cl2 (13 mg, 0.017 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with RINKAN (15 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 5-(4-(difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidine-1-yl)pyrimidine-4-yl)pyridazine-3-amine as a yellow solid (5 mg). LC-MS: 403.10[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.12(dd,J=17.1,2.0Hz,2H),8.13(s,1H),7.96(d,J=3.8Hz,1H),7.84(d,J=8 .8Hz,2H),7.32(d,J=8.7Hz,2H),6.99(t,J=73.5Hz,1H),3.50(s,4H),2.00(dd,J=7.8,5.6Hz,4H).

[0222] Synthesis of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine-compound 103 [ka] Pd(dppf)Cl2 (2 mg, 0.003 mmol, 0.1 equivalent) was added at room temperature to a solution of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-yl)-5-chloropyridazine-3-amine (10 mg, 0.03 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (10 mg, 0.06 mmol, 2.0 equivalents), and K3PO4 (19 mg, 0.09 mmol, 3.0 equivalents) in dioxane / H2OC (1 mL / 0.1 mL). The reaction mixture was then stirred under N2 at 110 °C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water. The separated organic layer was dried (on Na2SO4 or MgSO4) and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=1 / 1 to obtain N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (63 mg, 64%) as a yellow solid. LCMS: 431.30[M+1] + ; 1 H NMR(400MHz,CDCl3)δ9.09(s,2H),8.12(s,2H),7.62(d,J=7.4Hz,2H),7.26(s,1H),6.59(t,J=72 .9Hz,1H),3.81(d,J=13.6Hz,3H),3.51(d,J=27.5Hz,2H),2.92(s,1H),0.87(s,1H),0.62(s,1H).

[0223] Synthesis of Compound 508: 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methylpyridazine-3-amine [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methylpyridazine-3-amine (70 mg, 0.20 mmol, 1.0 equivalent) in toluene (4 mL), (4-(difluoromethoxy)phenyl)boronic acid (38 mg, 0.20 mmol, 1.0 equivalent), K3PO4 (85 mg, 0.40 mmol, 2.0 equivalents), and Pd(dppf)Cl2 (15 mg, 0.020 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. The mixture was extracted with ELISA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA=2 / 1) to obtain compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methylpyridazine-3-amine (25 mg, 27%) as a white solid. LC-MS: 461.15[M+1] +;1 H NMR(400MHz,CD3OD)δ8.56(s,1H),8.03(d,J=3.3Hz,1H),7.57(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),6.95(t,J=73.6 Hz,1H),4.21(d,J=12.9Hz,2H),3.60-3.47(m,2H),2.60(s,3H),2.44(dd,J=12.8,10.8Hz,2H),1.02(d,J=6.2Hz,6H).

[0224] Synthesis of 5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine [ka] To a solution of 5-chloropyridazine-3-amine (500 mg, 3.86 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (1.45 g, 7.7 mmol, 2.0 equivalents), and K3PO4 (2.46 g, 11.58 mmol, 3.0 equivalents) in dioxane / H2O (20 mL / 2 mL), Pd(dppf)Cl2 (283 mg, 0.39 mmol, 0.1 equivalents) was added at room temperature under N2. The reaction mixture was then stirred under N2 at 110°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The separated organic layer was washed with water, dried (over Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by silica gel chromatography using DCM / MeOH = 80:1 elution to obtain 5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (780 mg, 85%) as a yellow solid. LCMS: 237.07[M+1] + ; 1 H NMR (400MHz, DMSO) δ8.76 (s, 1H), 7.78 (d, J = 8.6Hz, 2H), 7.53-7.10 (m, 3H), 6.92 (s, 1H), 6.40 (s, 2H).

[0225] Synthesis of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-amine [ka] Pd(dppf)Cl2 (220 mg, 0.3 mmol, 0.1 equivalent) was added under N2 conditions to a solution of (4-(difluoromethoxy)phenyl)boronic acid (564 mg, 3.0 mmol, 1.0 equivalent), 5-bromo-2-methoxypyridine-3-amine (609 mg, 3.0 mmol, 1.0 equivalent), and K3PO4 (1.27 g, 6.0 mmol, 2.0 equivalent) in dioxane / H2O (8 mL / 2 mL). The reaction mixture was then stirred under N2 conditions at 110°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted at (PE / EA = 6 / 1 to 4 / 1) to obtain 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-amine (800 mg, white solid). 1H NMR(400MHz,CDCl3)δ7.74(d,J=2.1Hz,1H),7.52-7.45(m,2H),7.17(d,J=8.6H z,2H),7.05(d,J=2.1Hz,1H),6.53(t,J=73.9Hz,1H),4.02(s,3H),3.87(s,2H).

[0226] Synthesis of N-(2-bromopyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (100 mg, 0.42 mmol, 1.0 equivalent) in toluene (4 mL), 2-bromo-4-iodopyridine (180 mg, 0.063 mmol, 1.5 equivalents), Cs2CO3 (273 mg, 0.82 mmol, 2.0 equivalents), xanthophos (24 mg, 0.042 mmol, 0.1 equivalent), and Pd2(dba)3 (39 mg, 0.042 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 100°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (DCM / MeOH=30 / 1) to obtain N-(2-bromopyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (80 mg, yellow solid). LC-MS: 393.00 [M+1] +

[0227] Synthesis of N-(2-chloro-5-fluoropyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine [ka] To a solution of the compounds 5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (100 mg, 0.42 mmol, 1.0 equivalent), 4-bromo-2-chloro-5-fluoropyridine (134 mg, 0.64 mmol, 1.5 equivalents), xanthophos (25 mg, 0.04 mmol, 0.1 equivalent), and Cs2CO3 (414 mg, 1.27 mmol, 3.0 equivalents) in dioxane (2 mL), Pd2(dba)3 (39 mg, 0.04 mmol, 0.1 equivalent) was added at room temperature under N2. The reaction mixture was then stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water. The separated organic layer was washed with water, dried (over Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by preparative TLC using DCM / MeOH=20 / 1 to obtain N-(2-chloro-5-fluoropyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (135 mg, 87%) as a yellow solid. LCMS: 366.05[M+1] + ; 1 H NMR (400MHz, DMSO) δ9.84(s,1H),9.30(s,1H),8.78(d,J=6.1Hz,1H),8.33(d,J=1.9Hz,1H),7.94-7.81(m,3H),7.56-7.15(m,3H).

[0228] Synthesis of N-(6-chloro-3-fluoropyridine-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (100 mg, 0.42 mmol, 1.0 equivalent) in toluene (4 mL), 2,6-dichloro-3-fluoropyridine (105 mg, 0.42 mmol, 1.0 equivalent), Cs2CO3 (273 mg, 0.82 mmol, 2.0 equivalents), xanthophos (24 mg, 0.042 mmol, 0.1 equivalent), and Pd2(dba)3 (39 mg, 0.042 mmol, 0.1 equivalent) were added. The reaction mixture was stirred at 100°C for 16 hours under N2. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (DCM / MeOH=30 / 1) to obtain N-(6-chloro-3-fluoropyridine-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, white solid). LC-MS: 367.00 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ10.28 (s, 1H), 9.26 (s, 1H), 8.24 (s, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.56-7.10 (m, 4H).

[0229] Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)pyrimidine-4-amine [ka] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-amine (300 mg, 1.12 mmol, 1.0 equivalent), 2,4-dichloropyrimidine (184 mg, 1.24 mmol, 1.1 equivalent), and DIEA (434 mg, 3.36 mmol, 3.0 equivalent) in DMSO (5 mL) was stirred at 80°C for 16 hours. The mixture was poured into 60 mL of H2O, extracted with ELISA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (PE / EA = 3 / 1) to obtain 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)pyrimidine-4-amine (150 mg). LC-MS: 379.00 [M+1] + .

[0230] Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-5-fluoropyrimidine-4-amine [ka] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-amine (300 mg, 1.12 mmol, 1.0 equivalent), 2,4-dichloro-5-fluoropyrimidine (207 mg, 1.24 mmol, 1.1 equivalent), and DIEA (434 mg, 3.36 mmol, 3.0 equivalent) in DMSO (5 mL) was stirred at 80°C for 16 hours. The mixture was poured into 60 mL of H2O, extracted with ELISA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (PE / EA = 3 / 1) to obtain 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-5-fluoropyrimidine-4-amine (300 mg, crude). LC-MS:397.00[M+1] + .

[0231] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyridin-4-yl)pyridazine-3-amine compound 428 [ka] To a solution of N-(2-bromopyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)-pyridazine-3-amine (80 mg, 0.20 mmol, 1.0 equivalent) in toluene (4 mL), (2R,6S)-2,6-dimethylmorpholine (47 mg, 0.40 mmol, 2.0 equivalents), Cs2CO3 (130 mg, 0.4 mmol, 2.0 equivalents), xanthophos (12 mg, 0.020 mmol, 0.1 equivalent), and Pd2(dba)3 (18 mg, 0.020 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 100°C for 16 hours. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyridin-4-yl)pyridazine-3-amine (2.1 mg). LC-MS: 428.30 [M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.15(s,1H),7.97(s,1H),7.87(d,J=7.4Hz,3H),7.45(s,1H),7.35(d,J=8.8Hz,2H ),6.96(m,J=81.4,65.7Hz,2H),3.99(d,J=12.4Hz,2H),3.77(s,2H),2.66(s,2H),1.28(d,J=6.0Hz,6H).

[0232] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyridine-4-yl)pyridazine-3-amine compound 469 [ka] To a solution of N-(2-chloro-5-fluoropyridine-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (135 mg, 0.37 mmol, 1.0 equivalent) and (2R,6S)-2,6-dimethylmorpholine (85 mg, 0.74 mmol, 1.0 equivalent) in NMP (5 mL), DIEA (143 mg, 1.11 mmol, 3.0 equivalents) was added, and the reaction mixture was stirred under microwave at 200 °C for 2 hours. The reaction mixture was partitioned between ethyl acetate (500 mL) and water. The separated organic layer was washed with saturated brine, dried (over Na2SO4 or MgSO4), and evaporated to dryness. The residue was purified by preparative TLC and preparative HPLC using DCM / MeOH=40 / 1 to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyridine-4-yl)pyridazine-3-amine (6 mg, 3.7%) as a white solid. LCMS: 445.17[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.10(s,1H),8.29(d,J=5.9Hz,1H),7.87(dd,J=23.4,5.9Hz,3H),7.64(d,1H),7.32(d,J=8.6Hz ,2H),6.94(t,J=73.5Hz,1H),3.97(d,J=12.0Hz,2H),3.70(d,J=6.4Hz,2H),2.49-2.37(m,2H),1.23(d,J=6.2Hz,6H).

[0233] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridine-2-yl)pyridazine-3-amine compound 223 [ka] To a solution of N-(6-chloro-3-fluoropyridine-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.27 mmol, 1.0 equivalent), (2R,6S)-2,6-dimethylmorpholine (95 mg, 0.82 mmol, 3.0 equivalents) in NMP (4 mL) was added, followed by the addition of DIEA (109 mg, 0.82 mmol, 3.0 equivalents). The reaction mixture was stirred at 200°C under microwave for 1 hour. 50 mL of H2O was poured over the mixture, extracted with siRNA (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain compound 5-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridine-2-yl)pyridazine-3-amine (15 mg). LC-MS: 446.20[M+1] + ; 1 H NMR(400MHz,CD3OD)δ9.03(s,1H),8.75(s,1H),7.81(d,J=8.2Hz,2H),7.34(dd,J=21.2,9.2Hz,3H),6.94(t,J=73. 6Hz,1H), 6.30(d,J=8.8Hz,1H),3.86(d,J=12.2Hz,2H),3.64(s,2H),2.38(t,J=11.4Hz,2H),1.08(d,J=6.1Hz,6H).

[0234] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine compound 305 [ka] To a solution of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)pyrimidine-4-amine (150 mg, 0.40 mmol, 1.0 equivalent) in IPA (4 mL), (2R,6S)-2,6-dimethylmorpholine (137 mg, 1.20 mmol, 3.0 equivalents) and DIEA (154 mg, 1.20 mmol, 3.0 equivalents) were added. The reaction mixture was then stirred overnight at 90°C under N2. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA = 5 / 1 to 2 / 1) to obtain N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (50 mg, white solid). LC-MS: 458.15[M+1] + ; 1 H NMR(400MHz,CD3OD)δ8.95(d,J=2.2Hz,1H),7.94(dd,J=16.0,4.0Hz,2H),7.60(d,J=8.6Hz,2H),7.22(d,J=8.6Hz,2H),6.85(t,J=74. 0Hz,1H),6.27(d,J=5.8Hz,1H),4.36(d,J=13.0Hz,2H),4.06(s,3H),3.56(d,J=6.2Hz,2H),2.57-2.46(m,2H),1.07(d,J=6.2Hz,6H).

[0235] Synthesis of 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)pyridine-2(1H)-one compound 264 [ka] To a solution of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (50 mg, 0.109 mmol, 1.0 equivalent) in DMF (1.5 mL), LiBr (95 mg, 1.090 mmol, 10.0 equivalent) was added, and the reaction mixture was stirred overnight at 120 °C under N2. H2O (7 mL) was added, and the mixture was extracted with EA (10 mL x 3) and dried over Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to obtain 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)pyridine-2(1H)-one (5 mg, white solid). LC-MS:444.20[M+1] + ; 1 H NMR(400MHz,CD3OD)δ8.92(d,J=2.4Hz,1H),7.95(d,J=5.8Hz,1H),7.54(d,J=8.7Hz,2H),7.22(dd,J=16.5,5.5Hz,3H),6.84(t,J=70 .2Hz,2H),6.27(d,J=5.8Hz,2H),4.38(d,J=11.3Hz,2H),3.58(d,J=6.3Hz,2H),2.55(dd,J=13.0,10.7Hz,2H),1.11(d,J=6.2Hz,6H); 19 F NMR (400MHz, DMSO-d6) δ-83.55, δ-83.74.

[0236] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine-compound 387 [ka] To a solution of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-5-fluoropyrimidine-4-amine (300 mg, 0.76 mmol, 1.0 equivalent) in IPA (4 mL), (2R,6S)-2,6-dimethylmorpholine (261 mg, 2.27 mmol, 3.0 equivalents) and DIEA (293 mg, 2.27 mmol, 3.0 equivalents) were added. The reaction mixture was then stirred overnight at 90°C under N2. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA = 5 / 1 to 2 / 1) to obtain N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (200 mg, white solid). LC-MS: 476.35[M+1] + ; 1 H NMR(400MHz,CDCl3)δ9.01(s,1H),7.98(d,J=17.6Hz,2H),7.55(d,J=8.2Hz,2H),7.40(s,1H),7.20(d,J=8.3Hz,2H),6 .53(t,J=73.6Hz,1H),4.37(d,J=13.0Hz,2H),4.11(s,3H),3.64(s,2H),2.60(t,J=11.7Hz,2H),1.19(d,J=6.1Hz,6H).

[0237] Synthesis of Compound 346: 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridine-2(1H)-one [ka] To a solution of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (50 mg, 0.105 mmol, 1.0 equivalent) in DMF (1.5 mL), LiBr (92 mg, 1.050 mmol, 10.0 equivalent) was added, and the reaction mixture was stirred overnight at 120 °C under N2. H2O (7 mL) was added, and the mixture was extracted with EA (10 mL x 3) and dried over Na2SO4. The residue was concentrated under reduced pressure. The residue was purified by TLC (DCM / MeOH=20 / 1) to obtain 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridine-2(1H)-one (7 mg, white solid). LC-MS: 462.10[M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.73(s,1H),8.19-8.10(m,2H),7.62(d,J=8.6Hz,2H),7.44(s,1H), 7.19(dd,J=41.4,32.7Hz,3H),4.39-4.22(m,2H),3.64-3.51(m,2H),2.60-2.52(m,2H),1.14-1.03(m,6H); 19 F NMR (400MHz, DMSO-d6) δ-82.26, δ-82.46, δ-169.61.

[0238] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-6-fluoropyrimidine-4-yl)pyridazine-3-amine compound 131 [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (52 mg, 0.22 mmol, 1.0 equivalent) in DMF (1 mL), NaH (13 mg, 0.33 mmol, 1.5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and then (2R,6S)-4-(4,6-difluoropyrimidine-2-yl)-2,6-dimethylmorpholine (50 mg, 0.26 mmol, 1.2 equivalents) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. 30 mL of H2O was poured over the mixture and extracted with ELISA (20 mL x 3). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (PE / EA=1 / 1) to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-6-fluoropyrimidine-4-yl)pyridazin-3-amine (20 mg, yield: 20%) as a white solid. LCMS:[M+1]:447.30; 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.25(s,1H),8.49(s,1H),7.92(d,J=8.6Hz,2H),7.5 4-7.15(m,3H),6.30(s,1H),4.29(d,J=12.4Hz,2H),3.53(s,2H),2.55(s,2H),1.05(s,6H).

[0239] Synthesis of 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine [ka] To a solution of 6-chloro-4-iodo-3-methoxypyridazine (200 mg, 0.74 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (139 mg, 0.74 mmol, 1.0 equivalent), and K3PO4 (471 mg, 2.22 mmol, 3.0 equivalents) in dioxane / H2O (6 mL / 0.6 mL), Pd(dppf)Cl2 (16 mg, 0.07 mmol, 0.1 equivalent) was added at room temperature under N2. The reaction mixture was then stirred at 80°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water, dried over anhydrous Na2SO4, and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=5 / 1 to obtain 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (120 mg, 57%) as a yellow solid. LCMS: 287.03[M+1] + ; 1 H NMR (400MHz, DMSO) δ7.88 (s, 1H), 7.78 (d, J = 8.3Hz, 2H), 7.54-7.09 (m, 3H), 4.04 (s, 3H).

[0240] Synthesis of Compound 526: 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methoxypyridazine-3-amine [ka] To a solution of 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (120 mg, 0.42 mmol, 1.0 equivalent), 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (142 mg, 0.63 mmol, 1.5 equivalents), xanthophos (25 mg, 0.04 mmol, 0.1 equivalent), and Cs2CO3 (409 mg, 1.26 mmol, 3.0 equivalents) in dioxane (2 mL), Pd2(dba)3 (39 mg, 0.04 mmol, 0.1 equivalent) was added at room temperature under N2. The reaction mixture was then stirred at 80°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The separated organic layer was washed with water, dried on anhydrous Na2SO4, and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=2 / 1 to obtain 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-6-methoxypyridazine-3-amine (63 mg, 32%) as a yellow solid. LC-MS: 477.35[M+1] + ; 1 H NMR(400MHz,DMSO)δ10.25(s,1H),8.31(s,1H),8.09(s,1H),7.75(d,J=8.6Hz,2H),7.50- 7.11(m,3H),4.09(s,2H),4.02(s,3H),3.41(s,2H),2.34(t,J=11.5Hz,2H),0.88(s,6H).

[0241] Synthesis of Compound 598: 5-(4-(difluoromethoxy)phenyl)-N3-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3,6-diamine [ka] Step a: To a solution of 4-bromo-6-chloropyridazine-3-amine (1.2 g, 5.77 mmol, 1.0 equivalent) in THF (10 mL), Boc2O (2.5 g, 11.54 mmol, 2.0 equivalents) and TEA (1.75 g, 17.31 mmol, 3.0 equivalents) were added. The reaction mixture was stirred at 60°C for 3 hours. 100 mL of H2O was poured over the mixture, extracted with siRNA (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (PE / EA = 10 / 1 to 5 / 1) to obtain the bis-N-Boc product (1.2 g, white solid). LC-MS: 408.02 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 1.41 (s, 18H). Step b: To a solution of bis-N-Boc compound (408 mg, 1.0 mmol, 1.0 equivalent) in toluene / H2O (5 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 equivalent), K3PO4 (636 mg, 3.0 mmol, 3.0 equivalents), and Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to obtain bis-N-Boc protected 6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (255 mg, crude). LCMS:[M+1]:472.15 Step c: To a solution of bis-N-Boc protected 6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazine-3-amine (150 mg, 0.32 mmol, 1.0 equivalent) in toluene (5 mL), 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (72 mg, 0.32 mmol, 1.0 equivalent), Cs2CO3 (208 mg, 0.64 mmol, 2.0 equivalents), xanthophos (19 mg, 0.032 mmol, 0.1 equivalent), and Pd(dppf)Cl2 (24 mg, 0.032 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 100°C for 16 hours. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to obtain the coupling product (90 mg). LCMS:[M+1]:662.2; 1 H NMR(400MHz,CDCl3)δ8.77(s,1H),8.17(s,1H),8.06(s,1H),7.50(d,J=7.4Hz,2H),7.26-7.23(m,2H),6.55(t,J =72.0Hz,1H),4.26(d,J=12.0Hz,2H),3.59(s,2H),2.56(t,J=12.2Hz,2H),1.32(s,18H),1.12(d,J=6.0Hz,6H). Step d: Boc-protecting compound (90 mg, 0.136 mmol, 1.0 equivalent) was added to HCl / EA (4 M, 5 mL). The reaction mixture was stirred at 40°C for 1 hour. It was then concentrated under reduced pressure. 50 mL of NaHCO3 (aq) was poured over the residue, extracted with ELISA (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1 / 1) to obtain the final product 5-(4-(difluoromethoxy)phenyl)-N 3 -(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)pyridazine-3,6-diamine (19 mg) was obtained. LCMS:[M+1]:462.15; 1H NMR(400MHz,CD3OD)δ8.46(s,1H),8.18(d,J=4.0Hz,1H),7.68(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),6. 99(t,J=73.2Hz,1H),4.06(d,J=13.0Hz,2H),3.58(s,2H),2.64(t,J=11.8Hz,2H),1.05(d,J=5.2Hz,6H).

[0242] Synthesis of 4-(4-(difluoromethoxy)phenyl)-N6-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-N3-methylpyridazine-3,6-diamine-compound 544 [ka] Step a: To a solution of 6-chloro-N-methylpyridazine-3-amine (1.0 g, 7.0 mmol, 1.0 equivalent) in AcOH / H2O (5 mL / 5 mL), Br2 (3.36 g, 21 mmol, 3.0 equivalent), KBr (2.5 g, 21 mmol, 3.0 equivalent), and KOAc (1.03 g, 10.5 mmol, 1.5 equivalent) were added. The reaction mixture was stirred at 80°C for 16 hours. 100 mL of H2O was poured over the mixture, extracted with siRNA (35 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluted with (PE / EA = 5 / 1 to 2 / 1) to obtain 4-bromo-6-chloro-N-methylpyridazine-3-amine (400 mg, crude). LC-MS:221.94[M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 1H), 6.98 (s, 1H), 2.90 (d, J = 3.9Hz, 3H). Step b: To a solution of 4-bromo-6-chloro-N-methylpyridazine-3-amine (400 mg, 1.79 mmol, 1.0 equivalent) in THF (7 mL), Boc2O (782 mg, 3.59 mmol, 2.0 equivalent), TEA (542 mg, 5.37 mmol, 3.0 equivalent), and DMAP (22 mg, 0.179 mg, 0.1 equivalent) were added. The reaction mixture was stirred at 60°C for 3 hours. 100 mL of H2O was poured over the mixture, extracted with siRNA (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting at (PE / EA=10 / 1) to obtain tert-butyl(4-bromo-6-chloropyridazine-3-yl)(methyl)carbamate (640 mg, colorless oily substance). LC-MS: 321.99 [M+1] + Step c: To a solution of tert-butyl(4-bromo-6-chloropyridazin-3-yl)(methyl)carbamate (320 mg, 1.0 mmol, 1.0 equivalent) in toluene / H2O (5 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 equivalent), K3PO4 (636 mg, 3.0 mmol, 3.0 equivalent), and Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 110°C for 16 hours. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to obtain tert-butyl(6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazin-3-yl)(methyl)carbamate (70 mg). LCMS:[M+1]:386.1; 1 H NMR (400MHz, CDCl3) δ7.52-7.40(m,3H),7.27(d,J=7.1Hz,2H),6.56(t,J=73.0Hz,1H),3.48(s,3H),1.08(s,3H). Step d: To a solution of tert-butyl(6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazin-3-yl)(methyl)carbamate (70 mg, 0.18 mmol, 1.0 equivalent) in toluene (5 mL), 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (41 mg, 0.18 mmol, 1.0 equivalent), Cs2CO3 (117 mg, 0.36 mmol, 2.0 equivalent), xanthophos (11 mg, 0.018 mmol, 0.1 equivalent), and Pd(dppf)Cl2 (14 mg, 0.018 mmol, 0.1 equivalent) were added. The reaction mixture was stirred under N2 at 100°C for 16 hours. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=2 / 1) to obtain tert-butyl(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazin-3-yl)(methyl)carbamate (50 mg, yellow oily substance). LCMS:[M+1]:576.2; 1 H NMR(400MHz,CDCl3)δ8.71(s,0H),8.06(d,J=14.0Hz,1H),7.47(s,2H),6.53(t,J=73.0Hz, 1H),4.27(s,2H),3.59(s,2H),3.43(s,3H),2.56(t,J=11.7Hz,2H),1.10(d,J=37.3Hz,5H). Step e: tert-butyl(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazin-3-yl)(methyl)carbamate (50 mg, 0.087 mmol, 1.0 equivalent) was added to HCl / EA (4 M, 5 mL). The reaction mixture was stirred at 40 °C for 1 hour. Then it was concentrated under reduced pressure. 50 mL of NaHCO3 (aq) was poured over the residue, extracted with ELISA (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 1 / 1) to obtain 4-(4-(difluoromethoxy)phenyl)-N 6-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)-N 3 -Methylpyridazine-3,6-diamine (18.5 mg) was obtained. LCMS:[M+1]:476.20; 1 H NMR(400MHz,CD3OD)δ8.33(s,1H),8.02(s,1H),7.61(d,J=8.3Hz,2H),7.36(d,J=8.6Hz,2H),6.96(t,J=73 .3Hz,1H),4.20(d,J=13.0Hz,2H),3.52(s,2H),3.02(s,3H),2.42(t,J=11.5Hz,2H),1.03(d,J=6.1Hz,6H).

[0243] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylate methyl compound 616 [ka] Step a: Pd2(dba)3 (810 mg, 0.88 mmol, 0.1 equivalent) was added at room temperature to a solution of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-amine (2 g, 8.85 mmol, 1.0 equivalent), 4,6-dichloropyridazine-3-carboxylate methyl (2.7 g, 13.27 mmol, 1.5 equivalent), xanthophos (512 g, 0.88 mmol, 0.1 equivalent), and Cs2CO3 (8.6 g, 26.55 mmol, 3.0 equivalent) in toluene (20 mL). The reaction mixture was then stirred at 80°C for 16 hours under N2. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using PE:EA=2:1 elution to obtain methyl 4-chloro-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylate (2.05 g, 58%) as a white solid. 1H NMR(400MHz,DMSO)δ11.15(s,1H),8.63(s,1H),8.23(d,J=2.8Hz,1H),4.21(d,J=1 2.1Hz,2H),3.93(s,3H),3.53(d,J=6.3Hz,2H),2.52(m,2H),1.11(d,J=6.1Hz,6H). Step b: To a solution of methyl 4-chloro-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylate (2 g, 5.05 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (1.3 g, 7.58 mmol, 1.5 equivalent), and K3PO4 (3.2 g, 15.15 mmol, 3.0 equivalent) in dioxane / H2O (40 mL / 4 mL), Pd(dppf)Cl2 (370 mg, 0.51 mmol, 0.1 equivalent) was added at room temperature. The reaction mixture was then stirred under N2 at 110°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel chromatography using DCM / MeOH = 200:1 to obtain methyl 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylate (1.4 g, 55%) as a yellow solid. LCMS: 505.35[M+1] + ; 1 H NMR(400MHz,DMSO)δ10.93(s,1H),8.55(s,1H),8.21(d,J=3.1Hz,1H),7.54-7.1 5(m,5H),4.11(s,2H),3.76(s,3H),3.44(s,2H),2.43-2.34(t,2H),0.93(s,6H).

[0244] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylic acid - Compound 562 [ka] To a solution of methyl 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylate (1.3 g, 2.58 mmol, 1.0 equivalent) in THF / H2O (5 mL / 5 mL), LiOH·H2O (433 mg, 10.32 mmol, 4.0 equivalent) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and 1N HCl (100 mL) aqueous solution. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was added to MeOH (10 mL) and stirred at room temperature for 1 hour. Next, the mixture was filtered, the cake was diluted with MeOH (10 mL x 2), and dried under reduced pressure to obtain 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylic acid (700 mg, 55%) as a white solid. LCMS: 491.30[M+1] + ; 1 H NMR(400MHz,DMSO)δ13.74(s,1H),10.82(s,1H),8.51(s,1H),8.20(d,J=3.1Hz,1H),7 .56-7.14(m,J=8.6Hz,5H),4.12(s,2H),3.44(s,2H),2.42-2.35(t,2H),0.93(s,6H).

[0245] Synthesis of compound 580: 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazin-3-yl)ethane-1-one [ka] Step a: To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylic acid (100 mg, 0.2 mmol, 1.0 equivalent) and HATU (93 mg, 0.24 mmol, 1.2 equivalents) in DMF (2 mL), N,O-dimethylhydroxylamine hydrochloride (24 mg, 0.24 mmol, 1.2 equivalents) and DIEA (79 mg, 0.60 mmol, 3.0 equivalents) were added. The mixture was then stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative TLC using DCM / MeOH=20 / 1 to obtain 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)-N-methoxy-N-methylpyridazine-3-carboxamide (80 mg, 74%) as a white solid. 1 H NMR(400MHz,DMSO)δ10.70(s,1H),8.56(s,1H),8.19(d,J=3.1Hz,1H),7.55(d,J=8.6Hz,2H),7.32(d,J=8.8Hz, 3H), 4.14(d,J=11.5Hz,2H),3.53(s,3H),3.48-3.41(m,2H),3.20(s,3H),2.41(t,J=12.7Hz,2H),0.92(s,6H). Step b: To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)-N-methoxy-N-methylpyridazine-3-carboxamide (80 mg, 0.15 mmol, 1.0 equivalent) in THF (1 mL), MeMgBr (0.18 mL, 0.18 mmol, 1.2 equivalents) was added at 0°C under N2. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to an aqueous solution of NH4Cl (50 mL). The aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by preparative TLC using DCM / MeOH=20 / 1 to obtain 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazin-3-yl)ethane-1-one (40 mg, 55%) as a white solid. LCMS: 489.20[M+1] + ; 1 H NMR(400MHz,DMSO)δ10.92(s,1H),8.42(s,1H),8.22(d,J=3.2Hz,1H),7.49(d,J=8.8Hz,2H),7.2 2(m,J=41.2,32.6Hz,3H),4.10(s,2H),3.43(s,2H),2.73(s,3H),2.41-2.33(t,2H),0.93(s,6H).

[0246] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)-N-methylpyridazine-3-carboxamide-compound 634 [ka] To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)pyridazine-3-carboxylic acid (100 mg, 0.2 mmol, 1.0 equivalent) and HATU (93 mg, 0.24 mmol, 1.2 equivalents) in DMF (2 mL), methylamine hydrochloride (17 mg, 0.24 mmol, 1.2 equivalents) and DIEA (79 mg, 0.60 mmol, 3.0 equivalents) were added. The mixture was then stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water. The separated organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative TLC using DCM / MeOH=20 / 1 to obtain 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidine-4-yl)amino)-N-methylpyridazine-3-carboxamide (70 mg, 68%) as a white solid. LC-MS: 504.40[M+1] + ; 1 H NMR(400MHz,DMSO)δ10.73(s,1H),8.79(d,J=4.5Hz,1H),8.45(s,1H),8.19(d,J=3.2Hz,1H),7.52(t,J=6.6Hz,2H ),7.24(m,J=41.1,32.6Hz,3H),4.11(s,2H),3.43(s,2H),2.72(d,J=4.6Hz,3H),2.42-2.35(t,2H),0.92(s,6H).

[0247] Synthesis of N-(5-bromo-2-fluoropyridine-3-yl)-2-chloropyrimidine-4-amine [ka] A mixture of 5-bromo-2-fluoropyridine-3-amine (500 mg, 2.6 mmol, 1.0 equivalent) and 2,4-dichloropyrimidine (770 mg, 5.2 mmol, 2.0 equivalent) in DIEA (0.5 mL) was stirred at 119°C for 16 hours. DCM (5 mL) was added, and the residue was purified by column chromatography using silica gel eluted with (DCM / MeOH = 200 / 1 to 50 / 1) to obtain the crude product. The crude product was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain N-(5-bromo-2-fluoropyridine-3-yl)-2-chloropyrimidine-4-amine (50 mg crude product) as a white solid. LC-MS:[M+1] + :303.05.

[0248] Synthesis of N-(5-bromo-2-fluoropyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine [ka] A mixture of N-(5-bromo-2-fluoropyridine-3-yl)-2-chloropyrimidine-4-amine (50 mg, 0.17 mmol, 1.0 equivalent), (2R,6S)-2,6-dimethylmorpholine (38 mg, 0.33 mmol, 2.0 equivalents), and DIEA (64 mg, 0.50 mmol, 3.0 equivalents) in IPA (1 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain N-(5-bromo-2-fluoropyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (27 mg, crude). LC-MS: [M+1] + :382.15.

[0249] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine compound 182 [ka] To a solution of N-(5-bromo-2-fluoropyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (27 mg, 0.07 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (26 mg, 0.14 mmol, 2.0 equivalents), and K3PO4 (45 mg, 0.21 mmol, 3.0 equivalents) in dioxane / H2O (1 mL / 0.1 mL), Pd(dppf)Cl2 (5 mg, 0.007 mmol, 0.1 equivalent) was added under N2 conditions. The reaction mixture was stirred under N2 conditions at 110°C for 16 hours. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridine-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidine-4-amine (2.5 mg). LCMS:[M+1] + :446.30; 1 H NMR (400MHz, DMSO-d6): δ=9.40(s,1H),9.06(d,J=9.3,1H),8.09(s,1H),8.04(d,J=5.6,1H),7.75(d,J=8. 6,2H),7.50-7.10(m,3H),6.37(d,J=5.5,1H),4.31(s,2H),3.49(s,2H),2.44(d,J=11.1,2H),0.98(s,6H).

[0250] Methods for preparing and using the related compounds are disclosed in PCT / TR 2019 / 050164, PCT / TR 2019 / 050951, and U.S. Patent No. 63 / 173796, the contents of which are incorporated herein in full by reference.

[0251] Example 2: Exemplary biological activity of the disclosed compounds Cell culture and reagents The human breast cancer cell line MDA-MB-231 and the human endometrial cancer cell line HEC-59 were purchased from ATCC (American Type Culture Collection; USA). MDA-MB-231 cells were grown in Dulbecco's modified Eagle medium (Lonza, NJ, USA), and HEC-59 cells were grown in Iskoff's modified Dulbecco's medium (Lonza, NJ, USA) supplemented with 10% fetal bovine serum (FBS, Lonza), 1% non-essential amino acid (NEAA), 2 mM L-glutamine (Sigma Aldrich, MO, USA), and 50 U / mL penicillin / streptomycin (P / S). All cell lines were regularly tested using the MycoAlert Mycoplasma Detection Kit (Lonza). The cumulative length of cells from thawing to experimental use was less than 20 passages.

[0252] Cell viability assay protocol MDA-MB-231 and HEC-59 cells at a density of 4000 cells / well were seeded in 96-well plates with 80 μL of medium / well. After approximately 18 hours, 3× drug solutions were prepared by serial dilution (100, 10, 5, 1, 0.5, 0.3, 0.1, 0.05, 0.01 μM), and 40 μL of the drug-containing medium was added to each well. For MDA-MB-231, SRB or CTG assays were performed 3 days after drug treatment. For HEC59, the drug-containing medium was replaced on day 4. After a total of 7 days, SRB or CTG assays were performed. [Table 2]

[0253] Example 3: Further Exemplary Biological Activities of the Disclosed Compounds Female athymoid Balb / c nude mice aged 6-8 weeks were housed in a temperature-controlled 12-hour light / 12-hour dark cycle environment. In vivo colon cancer tumor growth was assessed using 5 × 10⁻⁶ mice. 6RKO cells were prepared in 100 μl of DMEM and injected into the right flank of female nude mice. The body weight and tumor volume of the mice were measured twice a week. Tumor volume was measured as length × width 2 The calculation was performed using a multiplier of 0.5. The tumor volume was approximately 150-175 mm². 3 Once the tumor reached 2500 mm, the xenografts were randomly divided into groups (8 mice per group). As shown in the table, the animals were treated with the vehicle, compound 80, or oxaliplatin. The vehicle and compound 80 formulations were 50% PEG400 and 20% Cremophor RH40 (50% of 40% Cremophor) in acetate buffer (pH=4). Oxaliplatin was prepared in glucose solution. After approximately 3 weeks, or when the tumor reached 2500 mm 3 Mice were sacrificed when the predetermined tumor volume cutoff was reached. Compound 80 showed dose-dependent, strong inhibition of tumor growth in RKO xenografts, with a TGI of 85% at the highest dose (Figure 1). [Table 3]

[0254] Compound 80 was tested in other xenograft models using the following cell lines: triple-negative breast cancer cell line MDA-MB-231, ovarian cancer cell line SKOV-3, and endometrial cell line HEC-59. For SKOV-3 xenografts, 1.5 × 10¹⁶ compounds were tested in 200 μl of 1:1 DMEM:Matrigel (Thermo Fisher, NJ, USA). 7 For the MDA-MB-231 xenograft, SKOV-3 cells were administered in 100 μl of 1:1 DMEM:Matrigel (Thermo Fisher, NJ, USA) in a 1.1 × 10⁶ solution. 7 MDA-MB-231 cells were injected into the right flank of 6-8 week old female athymia Balb / c nude mice. The tumor volume averaged approximately 200 mm² for SKOV-3 xenografts. 3 When it reached the mouse, the MDA-MB-231 xenograft was 150-175 mm. 3When this was reached, mice were randomized into groups of 8 and treated with compound 80 containing vehicle, 20mpk BID, 25mpk BID, and 30mpk BID. For HEC-59 xenografts, 1 × 10¹⁶ units were used in 100 μl of DMEM (Lonza, NJ, USA). 7 HEC-59 cells were injected into the right flank of 6-8 week old female athymia Balb / c nude mice. The average tumor volume was approximately 150 mm². 3 Upon reaching mice, they were randomized into groups of eight and treated with compound 80 of vehicle, 20mpk BID, 40mpk QD, and 30 / 40mpk BID. Statistically significant tumor growth inhibition or regression was observed.

[0255] Example 4: Further Exemplary Bioactivities of the Compounds in this Disclosure The activity of compound 80 against specific cell lines was measured according to the following method.

[0256] In 384-well plates, 1000 cells from each cell line were seeded with 40 μL of culture medium per well. Approximately 18 hours later, 40 μL of culture medium containing the drug (5, 1, 0.2, 0.04, 0.008, 0.0016 μM) or the reference compound (1, 0.2, 0.04, 0.008, 0.0016, 0.00032 μM) was added to each well at the following concentrations. Three days after drug treatment, a CTG assay was performed. Additional cell lines such as ACHN, Caki-2, 786-O, rhabdomyosarcoma (RD), VA-ES-BJ, Aska-SS, HS-SY-II, MDA-MB-435S, SK-MEL-2, IPC-298, HepG2, Hep3B, and SUN387 can also be investigated using the above protocol. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0257] Example 5: Exemplary activity of the compounds disclosed herein in a translocation model Cell culture and xenotransplantation protocols The MDA-MD-231-luc tumor cell line was maintained in vitro as a monolayer culture at 37°C under 100% air conditions in L-15 medium supplemented with 10% fetal bovine serum and 1500 ng / mL puromycin. The medium was changed every 2-3 days, and when the tumor cell density reached 80-90%, it was regularly subcultured using trypsin-EDTA, ensuring that the number of subculturing cycles did not exceed 4-5. Cells in the exponential growth phase were harvested and counted for inoculation into tumors.

[0258] Female athymia-BALB / c nude mice aged 6-8 weeks were anesthetized by intramuscular injection of Zoletil™ 50 (Virbac SA). The skin above the coronal and sagittal sutures of the anesthetized mice was disinfected with iodine and then with alcohol. A 0.5 cm incision was made along the midline to expose the junction of the coronal and sagittal sutures. 3 × 10⁶ luciferase-expressing MDA-MB-231-luc tumor cells were suspended in 2 μL of L-15 medium. 5 The individual cells were injected into the right forebrain, with the needle positioned 2.0 mm lateral to the sagittal suture and 0.5-1.0 mm anterior to the coronal suture, and the injection depth was strictly controlled to 3.0 mm. After the injection was completed and the needle was withdrawn, the puncture site was sealed with bone wax and the incision was sutured. Tumor growth was monitored by image analysis. Once steady tumor growth was confirmed based on luciferase levels, the treatment regimen described in Table 4 was initiated. [Table 5]

[0259] To measure tumor growth, mice were intraperitoneally injected with 15 mg / mL (5 μL per g of body weight) of D-luciferin (Perkin Elmer) and anesthetized by inhaling 1-2% isoflurane. Ten minutes after luciferin injection, images of the mice were taken weekly using IVIS Lumina III (Perkin Elmer). Using Living Image software (Perkin Elmer), regions of interest (ROIs) were calculated from the brain images, and the total bioluminescence signals in each ROI were integrated. The bioluminescence signals (photons / second) from the ROIs were quantified and used as indicators of tumor growth and antitumor activity. BLI reduction rate (%) = (1 - BLI (treatment group) / BLI (control group)) × 100%. Here, BLI (treatment group) and BLI (control group) are the mean values ​​of BLI in the treatment group and control group, respectively, on a specific day after tumor inoculation. As shown in Table 5, a significant suppression of tumor growth was observed due to a decrease in luciferase luminescence intensity. [Table 6]

[0260] Embedding by reference All publications and patents referenced herein are incorporated herein by reference in whole, as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of any conflict, including the definitions herein, this application shall prevail.

[0261] Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not limiting. Many variations of the invention will become apparent to those skilled in the art upon consideration of this specification and the following claims. The full scope of the invention should be determined by referring to the claims, together with the full scope of equivalents, and the specification, together with such variations.

Claims

1. A method for treating solid tumors in a subject, comprising administering to the subject a compound having a structure represented by formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, E and B are, independently, aryl, heteroaryl, or heterocyclyl; D is an amino or heterocycline; A is a six-membered ring heteroaryl; R １ The method wherein is H, alkyl, or benzyl.

2. The method according to claim 1, wherein A is pyridyl, pyridazinil, pyrimidinil, or pyrazinil.

3. The method according to claim 1 or 2, wherein A is pyridyl.

4. The method according to claim 1 or 2, wherein A is pyridazinyl.

5. The compound is represented by formula Ia or a pharmaceutically acceptable salt thereof, 【Chemistry 2】 During the ceremony, E and B are, independently, aryl, heteroaryl, or heterocyclyl; D is an amino or heterocycline; X １ is N or CR ２ And; X ２ is N or CR ３ And; X ３ is N or CR ４ And; X ４ is N or CR ５ and is R １ is H, alkyl, or benzyl; R ２ , R ３ , R ４ , and R ５ The method according to any one of claims 1 to 4, wherein each is independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

6. The method according to any one of claims 1 to 5, wherein the compound is represented by formula IIa or a pharmaceutically acceptable salt thereof: 【Transformation 3】

7. R ３ The method according to claim 5 or 6, wherein the substance is a halo (for example, a fluoro).

8. The method according to any one of claims 1 to 5, wherein the compound is represented by formula IIb or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

9. R ４ The method according to claim 8, wherein the substance is a halo (for example, a fluorocarbon).

10. R ４ The method according to claim 8, wherein the compound is hydroxyl or alkoxy (e.g., methoxy).

11. The method according to any one of claims 1 to 5, wherein the compound is represented by formula IIc or a pharmaceutically acceptable salt thereof: 【Transformation 5】

12. R ２ The method according to any one of claims 5 to 11, wherein is H, alkyl (e.g., methyl or ethyl), halo (e.g., chloro), hydroxyl, alkoxy (e.g., methoxy), amino (e.g., aminoalkyl such as methylamino), amide (e.g., N-methylamide), acetyl, carboxy, or ester (e.g., methyl ester).

13. R ２ The method according to any one of claims 5 to 11, wherein the present agent is a halo (for example, a fluoro).

14. R ２ The method according to any one of claims 5 to 11, wherein H is present.

15. R ５ The method according to any one of claims 5 to 11, wherein the element is H or alkyl (for example, methyl).

16. R ５ The method according to any one of claims 5 to 11, wherein H is present.

17. R １ The method according to any one of claims 1 to 16, wherein H is the case.

18. R １ The method according to any one of claims 1 to 16, wherein the alkyl (for example, methyl or ethyl) is used.

19. The method according to any one of claims 1 to 18, wherein B is a heteroaryl (e.g., pyridinyl, pyrimidinyl, or triazinyl).

20. The method according to any one of claims 1 to 19, wherein B is pyrimidinil.

21. B has at least one R ４ It is replaced by each R ４ The method according to any one of claims 1 to 20, wherein the following are independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

22. B has at least one R ４ It is replaced by each R ４ The method according to any one of claims 1 to 21, wherein the alkyl (e.g., methyl), oxo, and halo (e.g., chloro or fluoro) are independently selected.

23. B is one or two R ４ The method of claim 21 or 22, wherein the substitution is made by the following.

24. The compound is represented by formula Ib or a pharmaceutically acceptable salt thereof. 【Transformation 6】 During the ceremony, E and B are, independently, an aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline; X １ is N or CR ２ And; X ２ is N or CR ３ And; X ３ is N or CR ４ And; X ４ is N or CR ５ And; X ５ is N or CR ８ And; X ６ is N or CR ９ And; R １ is H, alkyl, or benzyl; R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ The method according to any one of claims 1 to 23, wherein each is independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

25. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IIIa or a pharmaceutically acceptable salt thereof: 【Transformation 7】

26. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IIIb or a pharmaceutically acceptable salt thereof: 【Transformation 8】

27. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IIIc or a pharmaceutically acceptable salt thereof: 【Chemistry 9】

28. X ５ However, CR ８ The method according to any one of claims 24 to 27.

29. R ８ The method according to claim 28, wherein is H or halo (e.g., fluoro).

30. X ５ The method according to any one of claims 24 to 27, wherein N is the case.

31. X ６ However, CR ９ The method according to any one of claims 24 to 30.

32. R ９ The method according to claim 31, wherein the element is H or a halo (for example, fluoro).

33. X ６ The method according to any one of claims 24 to 30, wherein N is the case.

34. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IVa or a pharmaceutically acceptable salt thereof: 【Chemistry 10】

35. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IVb or a pharmaceutically acceptable salt thereof: 【Chemistry 11】

36. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IVc or a pharmaceutically acceptable salt thereof: 【Chemistry 12】

37. The method according to any one of claims 1 to 24, wherein the compound is represented by formula IVd or a pharmaceutically acceptable salt thereof: 【Chemistry 13】

38. The compound according to any one of claims 1 to 24, wherein the compound is represented by formula IVe or a pharmaceutically acceptable salt thereof: 【Chemistry 14】

39. R ６ The method according to any one of claims 24 to 38, wherein is H, hydroxyl, oxo, halo (e.g., fluoro), alkyl (e.g., methyl, hydroxymethyl or other hydroxyalkyl, or methoxyethyl or other alkyloxyalkyl), or alkoxy (e.g., methoxy).

40. R ６ The method according to any one of claims 24 to 38, wherein H is the case.

41. R ６ The method according to any one of claims 24 to 38, wherein the present agent is a halo (for example, a fluorocarbon).

42. R ７ The method according to any one of claims 24 to 41, wherein is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amide (e.g., methylamide).

43. R ７ The method according to any one of claims 24 to 41, wherein the present agent is a halo (for example, a fluorocarbon).

44. The method according to any one of claims 1 to 43, wherein D is an N-linked heterocyclyl (e.g., azetidinil, pyrrolidinil, piperidinil, piperazinil, morpholinil, thiomorpholinil, dioxydethiomorpholinil, azabicyclooctanil, oxazabicyclooctane, hexahydroflopyrrolyl, or azabicyclohexanil).

45. The method according to any one of claims 1 to 43, wherein D is optionally substituted morpholinyl.

46. The method according to any one of claims 1 to 43, wherein D is a 4-amino acid (for example, NH2 or alkylamino acid, for example, dimethylamino acid, diethylamino acid, or methylethylamino acid).

47. D is at least one R １０ It is replaced by each R １０ Independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide, or D is at least two R ５ It is replaced by the R ５ The method according to any one of claims 1 to 46, wherein two of the elements are combined to complete a bicyclic heterocycline.

48. D is at least one R １０ It is replaced by each R １０ The method according to any one of claims 1 to 46, wherein the alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), halo (e.g., fluoro), cycloalkyl (e.g., cyclopropyl or cyclobutyl), or heterocyclyl (e.g., oxetanyl) is independently selected.

49. D is replaced with R10 of 1 or 2. The method according to claim 47.

50. D has a structure represented by formula V, 【Chemistry 15】 During the ceremony, R １０ａ and R １０ｂ The method according to any one of claims 1 to 49, wherein each is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

51. R １０ａ The method according to claim 49, wherein the element is an alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), a halo (e.g., fluoro), a cycloalkyl (e.g., cyclopropyl or cyclobutyl), or a heterocyclyl (e.g., oxetanyl).

52. R １０ａ The method according to claim 49, wherein the substance is methyl.

53. R １０ｂ The method according to any one of claims 49 to 51, wherein is an alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), a halo (e.g., fluoro), a cycloalkyl (e.g., cyclopropyl or cyclobutyl), or a heterocyclyl (e.g., oxetanyl).

54. R １０ｂ The method according to any one of claims 49 to 52, wherein the substance is methyl.

55. D is 【Chemistry 16】 The method according to any one of claims 1 to 44.

56. The method according to any one of claims 1 to 54, wherein E is an aryl (for example, phenyl, dihydrobenzofuran, or benzodioxol).

57. The method according to any one of claims 1 to 55, wherein E is phenyl.

58. The method according to any one of claims 1 to 55, wherein E is a heteroaryl (e.g., pyridinyl, pyrazinyl, benzofuranil, or benzodioxyl).

59. E is at least one R １１ It is replaced by each R １１ The method according to any one of claims 1 to 58, wherein is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

60. E is at least one R １１ It is replaced by each R １１ The method according to any one of claims 1 to 58, wherein the following are independently selected from alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethioxy, or trifluoromethioxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), hydroxyl, halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl.

61. E is one R １１ The compound according to claim 59 or 60, which is substituted with

62. E is two R １１ The compound according to claim 59 or 60, which is substituted with

63. E has three R １１ The compound according to claim 59 or 60, which is substituted with

64. E has a structure represented by formula VIa, VIb, or VIc: 【Chemistry 17】 During the ceremony, R １１ａ and R １１ｂ The method according to any one of claims 1 to 54, wherein each is independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide.

65. The method according to claim 64, wherein E has a structure represented by formula VIa: [Chemistry 18]

66. The method according to claim 64, wherein E has a structure represented by formula VIb: 【Chemistry 19】

67. The method according to claim 64, wherein E has a structure represented by formula VIb: 【Chemistry 20】

68. R １１ａ The method according to any one of claims 63 to 66, wherein the alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, difluoromethioxy, or trifluoromethioxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl are selected from alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyl, methoxy, ethoxy, difluoromethioxy, or trifluoromethioxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl.

69. R １１ａ The method according to any one of claims 64 to 67, wherein the difluoromethioxy is used.

70. R １１ｂ The method according to any one of claims 64 to 69, wherein the alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, difluoromethioxy, or trifluoromethioxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl are selected from.

71. E is, 【Chemistry 21】 The method according to any one of claims 1 to 55.

72. The compound is represented as VIIa, VIIb, or a pharmaceutically acceptable salt thereof. 【Chemistry 22】 During the ceremony, R ４ and R ７ Each of these is independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide. R １０ａ and R １０ｂ are each independently H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide, R １１ａ The method according to claim 1, wherein is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

73. The compound according to claim 70, wherein the compound has a structure represented by formula VIIa or a pharmaceutically acceptable salt thereof: 【Chemistry 23】

74. R ４ The method according to claim 71, wherein the element is alkyl (e.g., methyl), oxo, or halo (e.g., chloro or fluoro).

75. R ４ The method according to claim 71, wherein the element is a halo (for example, chloro or fluoro).

76. The method according to claim 70, wherein the compound has a structure represented by formula VIIb or a pharmaceutically acceptable salt thereof: 【Chemistry 24】

77. R ７ The method according to claim 74, wherein is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amide (e.g., methylamide).

78. R ７ The method according to claim 74, wherein the substance is a halo (for example, a fluorocarbon).

79. R １０ａ The method according to any one of claims 71 to 76, wherein is alkyl (e.g., methyl).

80. R １０ｂ The method according to any one of claims 71 to 77, wherein the alkyl (for example, methyl) is used.

81. R １１ａ The method according to any one of claims 71 to 78, wherein the is alkyl (e.g., deuteroalkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkyloxy (e.g., deuteroalkyloxy, methoxy, ethoxy, fluoromethoxy, difluoromethioxy, or trifluoromethioxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), hydroxyl, halo (e.g., fluoro or chloro), cyano, heterocyclyl (e.g., azetidinyl), and hydroxyl.

82. R １１ａ The method according to any one of claims 71 to 79, wherein is difluoromethyl.

83. The aforementioned compound, 【Chemistry 25-1】 【Chemistry 25-2】 【Chemistry 25-3】 【Chemistry 25-4】 【Chemistry 25-5】 【Chemistry 25-6】 【Chemistry 25-7】 【Chemistry 25-8】 【Chemistry 25-9】 【Chemistry 25-10】 【Chemistry 25-11】 【Chemistry 25-12】 【Chemistry 25-13】 [Chemistry 25-14] 【Chemistry 25-15】 [Chemistry 25-16] 【Chemistry 25-17】 [Chemistry 25-18] 【Chemistry 25-19】 【Chemistry 25-20】 【Chemistry 25-21】 [Chemistry 25-22] [Chemistry 25-23] [Chemistry 25-24] The method according to any one of the prior claims, or selected from a pharmaceutically acceptable salt thereof.

84. The method according to any one of claims 1 to 83, wherein the solid tumor is characterized by TACC.

85. The method according to any one of claims 1 to 83, wherein the solid tumor is characterized by TACC1.

86. The method according to any one of claims 1 to 83, wherein the solid tumor is characterized by TACC2.

87. The method according to any one of claims 1 to 83, wherein the solid tumor is characterized by TACC3.

88. The method according to any one of claims 1 to 87, wherein the solid tumor is a brain tumor.

89. The method according to claim 88, wherein the brain tumor is a glioma, astrocytoma, glioblastoma, low-grade astrocytoma, meningioma, mixed oligoastrocytoma, pilocytic astrocytoma, pleomorphic xanthoblastoma, subventricular giant cell astrocytoma, or anaplastic astrocytoma.

90. The method according to claim 88, wherein the brain tumor is a glioblastoma.

91. The method according to claim 88, wherein the brain tumor is a meningioma.

92. The method according to claim 88, wherein the brain tumor is a metastasis of a primary cancer.

93. The method according to claim 92, wherein the primary cancer is lung cancer.

94. The method according to claim 92, wherein the primary cancer is breast cancer.

95. The method according to claim 92, wherein the primary cancer is single-negative breast cancer.

96. The method according to claim 92, wherein the primary cancer is double-negative breast cancer.

97. The method according to claim 92, wherein the primary cancer is triple-negative breast cancer.

98. The method according to claim 92, wherein the primary cancer is ovarian cancer.

99. The method according to claim 92, wherein the primary cancer is cervical cancer.

100. The method according to claim 92, wherein the primary cancer is bladder cancer.

101. The method according to claim 92, wherein the primary cancer is endometrial cancer.

102. The method according to claim 92, wherein the primary cancer is liver cancer.

103. The method according to claim 92, wherein the primary cancer is kidney cancer.

104. The method according to claim 92, wherein the primary cancer is skin cancer.

105. The method according to claim 92, wherein the primary cancer is prostate cancer.

106. The method according to any one of claims 1 to 87, wherein the solid tumor is bladder cancer.

107. The method according to claim 106, wherein the bladder cancer is urothelial bladder cancer, squamous cell bladder cancer, adenocarcinoma, sarcoma, or small cell bladder cancer.

108. The method according to claim 107, wherein the bladder cancer is urothelial bladder cancer.

109. The method according to any one of claims 1 to 87, wherein the solid tumor is cervical cancer.

110. The method according to claim 109, wherein the cervical cancer is squamous cell carcinoma.

111. The method according to claim 109, wherein the cervical cancer is cervical adenocarcinoma.

112. The method according to any one of claims 1 to 87, wherein the solid tumor is uterine cancer.

113. The method according to claim 112, wherein the uterine cancer is endometrial cancer.

114. The method according to claim 112, wherein the uterine cancer is a uterine sarcoma.

115. The method according to any one of claims 1 to 87, wherein the solid tumor is a gastrointestinal cancer.

116. The method according to claim 115, wherein the digestive cancer is anal cancer, intestinal cancer, colorectal adenocarcinoma, gallbladder cancer, gastric cancer, digestive carcinoid cancer, islet cell carcinoma, rectal cancer, small intestine cancer, or bile duct cancer.

117. The method according to claim 115, wherein the gastrointestinal cancer is a gastrointestinal stromal tumor (or multiple tumors), a carcinoid tumor, neoplastic carcinoma of the remnant stomach, or gastric adenocarcinoma.

118. The method according to any one of claims 1 to 87, wherein the solid tumor is liver cancer.

119. The method according to claim 118, wherein the liver cancer is hepatocellular carcinoma.

120. The method according to claim 118, wherein the liver cancer is bile duct cancer.

121. The method according to any one of claims 1 to 87, wherein the solid tumor is a sarcoma.

122. The method according to claim 121, wherein the sarcoma is Ewing's sarcoma, soft tissue sarcoma, leiomyosarcoma, epithelioid sarcoma, fibrosarcoma, chordoma, synovial sarcoma, Kaposi's sarcoma, osteosarcoma, rhabdomyosarcoma, liposarcoma, angiosarcoma, or dermatofibrosarcoma.

123. The method according to any one of claims 1 to 87, wherein the solid tumor is breast cancer.

124. The method according to claim 123, wherein the breast cancer is ductal carcinoma, lobular carcinoma, metaplastic carcinoma, inflammatory breast cancer, triple-negative breast cancer, mucinous neoplasm, medullary carcinoma, invasive ductal carcinoma, invasive lobular carcinoma, hormone-positive breast cancer, or HER2-positive breast cancer.

125. The method according to any one of claims 1 to 87, wherein the solid tumor is esophageal cancer.

126. The method according to claim 125, wherein the esophageal cancer is squamous cell carcinoma.

127. The method according to claim 125, wherein the esophageal cancer is an adenocarcinoma.

128. The method according to any one of claims 1 to 87, wherein the solid tumor is a head and neck cancer.

129. The method according to claim 128, wherein the head and neck cancer is hypopharyngeal cancer, laryngeal cancer, lip cancer and oral cancer, metastatic squamous cell carcinoma of unknown primary site, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus cancer and nasal cavity cancer, or salivary gland cancer.

130. The method according to any one of claims 1 to 87, wherein the solid tumor is lung cancer.

131. The method according to claim 130, wherein the lung cancer is non-small cell lung cancer, large cell carcinoma, small cell carcinoma, squamous cell carcinoma, adenosquamous cell carcinoma, adenocarcinoma, or mesothelioma.

132. The method according to any one of claims 1 to 87, wherein the solid tumor is ovarian cancer.

133. The method according to claim 132, wherein the ovarian cancer is epithelial ovarian cancer, germ cell tumor, or stromal cell carcinoma.

134. The method according to any one of claims 1 to 87, wherein the solid tumor is prostate cancer.

135. The method according to any one of claims 1 to 87, wherein the solid tumor is adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, or small cell prostate cancer.

136. The method according to any one of claims 1 to 87, wherein the solid tumor is a carcinoma.

137. The method according to any one of claims 1 to 87, wherein the solid tumor is an adenocarcinoma.

138. The method according to any one of claims 1 to 87, wherein the solid tumor is squamous cell carcinoma.

139. The method according to any one of claims 1 to 87, wherein the solid tumor is a skin cancer.

140. The method according to claim 139, wherein the skin cancer is basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, or malignant melanoma.

141. The method according to claim 139, wherein the skin cancer is malignant melanoma.

142. The method according to any one of claims 1 to 87, wherein the solid tumor is renal cancer.

143. The method according to claim 142, wherein the kidney cancer is renal cell carcinoma, urothelial carcinoma, Wilms' tumor, nephrosarcoma, renal adenoma, oncocytoma, or angiomyolipoma.

144. The method according to any one of claims 1 to 87, wherein the solid tumor is a neuroendocrine carcinoma.

145. The method according to any one of claims 1 to 87, wherein the solid tumor is a leiomyosarcoma.

146. The method according to any one of claims 1 to 87, wherein the solid tumor is a metastasis of a primary cancer.

147. The method according to claim 146, wherein the primary cancer is lung cancer.

148. The method according to claim 146, wherein the primary cancer is breast cancer.

149. The method according to claim 146, wherein the primary cancer is single-negative breast cancer.

150. The method according to claim 146, wherein the primary cancer is double-negative breast cancer.

151. The method according to claim 146, wherein the primary cancer is triple-negative breast cancer.

152. The method according to claim 146, wherein the primary cancer is ovarian cancer.

153. The method according to claim 146, wherein the primary cancer is cervical cancer.

154. The method according to claim 146, wherein the primary cancer is bladder cancer.

155. The method according to claim 146, wherein the primary cancer is endometrial cancer.

156. The method according to claim 146, wherein the primary cancer is liver cancer.

157. The method according to claim 146, wherein the primary cancer is kidney cancer.

158. The method according to claim 146, wherein the primary cancer is skin cancer.

159. The method according to claim 146, wherein the primary cancer is prostate cancer.

160. The method according to any one of claims 1 to 159, wherein the cancer recurs.

161. The method according to any one of claims 1 to 160, wherein the cancer is intractable.

Images