Compositions and methods for treating cancer

Abstract

Disclosed herein are inhibitors of TACC and methods of treating certain diseases and disorders (eg, diseases and disorders associated with TACC).

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 323,339, filed March 24, 2022, the contents of which are incorporated herein by reference in their entireties. [Background technology]

[0002] Cancer is a complex disease characterized by uncontrolled cell division. Among cancer types, breast, lung, and colorectal cancer account for 50% of all cases in women, while prostate, lung, and colorectal cancer account for 46% of all newly diagnosed cases in men in the United States (Siegel et al., 2021). Furthermore, new treatments for cancer are needed, as available treatments have many drawbacks and limited efficacy. Summary of the Invention

[0003] In one aspect, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof:

[0004] [ka] (In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is amino or heterocyclyl; A is a 6-membered heteroaryl; R 1 is H, alkyl, or benzyl).

[0005] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0006] In yet another aspect, the present disclosure provides a method of treating a disease or disorder mediated by transforming acidic coiled-coil protein (TACC) in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0007] [Figure 1] Exemplary biological activities of exemplary compounds of the present disclosure are shown. Compound 80 exhibits superior tumor growth inhibition in xenograft models compared to standard of care. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Transforming acidic coiled-coil protein (TACC) family members have emerged as important proteins for microtubule and centrosome-associated functions. Vertebrates express three different isoforms of TACC: TACC1, TACC2, and TACC3. TACC plays important roles in gene regulation, cell growth and differentiation, mRNA processing, transcription, migration, etc. by interacting with different molecules involved in microtubule / centrosome dynamics / transcription (Ha et al., 2013). Members share a conserved domain called the TACC domain, which is necessary for TACC proteins to interact with the spindle and centrosome apparatus (Gergely et al., 2000). Although TACC family members were described as centrosomal proteins, they also distribute throughout the cell during interphase. For example, TACC3 and TACC2 form complexes with different histone acetyltransferases, including hGCN5L2 and pCAF, indicating their regulatory function in transcription (Gangisetty et al., 2004). Notably, TACC3 interacts with MBD2 (mCpG-binding domain 2) in interphase nuclei facilitating the association of MBD2 with histone acetyltransferases to reactivate methylated promoters.

[0009] TACC protein levels are elevated in many cancer types, including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, and breast cancer. The first member of the TACC family, TACC1, was independently discovered as a breast cancer amplicon 8p11 (Still et al., 1999), and was subsequently found to be capable of promoting breast tumorigenesis, possibly via activation of the Ras / PI3K signaling pathway (Cully et al., 2005). TACC2 has been found to promote androgen-mediated growth in prostate cancer and is associated with poor prognosis (Takayama et al., 2012). Moreover, overexpression of TACC2 results in proliferation of breast cancer cells (Cheng et al., 2010). TACC3, when disrupted, also results in a series of distinct cellular outcomes, including multipolar spindle formation leading to mitotic arrest (Yao et al., 2012), chromosome misalignment resulting in caspase-dependent apoptosis (Schneider et al., 2007), and, in some cases, senescence (Schmidt et al., 2010). Furthermore, knockdown of TACC3 suppresses renal cell carcinoma (RCC) tumorigenesis and cell growth (Guo & Liu, 2018). The above studies indicate that the TACC family of proteins are key molecules participating in spindle formation in cancer cells, making them important and potential targets for cancer targeted therapy.

[0010] However, to date, there are no available inhibitors for TACC1 and TACC2, and only two inhibitors targeting TACC3. KHS101, a small molecule TACC3 inhibitor, was first identified to promote neural differentiation in rats (Wurdak et al., 2010). Although tumor growth of glioblastoma (GBM) xenografts was suppressed by KHS101 treatment (Polson et al., 2018), KHS101 has many drawbacks, such as poor oral systemic stability and high work volume (Wurdak et al., 2010). Another TACC3 inhibitor, SPL-B, has been shown to inhibit centrosomal microtubule nucleation in ovarian cancer cells and suppress tumor growth of ovarian cancer xenografts (Yao et al., 2014). However, similar to KHS101, SPL-B has not been approved for the treatment of cancer.

[0011] In view of the above, there is a clear unmet need for novel TACC inhibitors for the treatment of cancer and other TACC-mediated diseases.

[0012] In one aspect, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof:

[0013] [ka] (In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is amino or heterocyclyl; A is a 6-membered heteroaryl; R 1 is H, alkyl, or benzyl).

[0014] In certain embodiments, A is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In certain preferred embodiments, A is pyridyl. In other preferred embodiments, A is pyridazinyl.

[0015] In certain embodiments, the compound is represented by formula Ia, or a pharma- ceutically acceptable salt thereof:

[0016] [ka] During the ceremony, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is amino or heterocyclyl; 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 R 1 is H, alkyl, or benzyl; R 2 , R 3 , R 4 , and R 5 are each independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamido.

[0017] In certain embodiments, the compound has the formula IIb or a pharma- ceutically acceptable salt thereof:

[0018] [ka]

[0019] In certain preferred embodiments, R 3 is halo (e.g., fluoro).

[0020] In certain embodiments, the compound has the formula IIb or a pharma- ceutically acceptable salt thereof:

[0021] [ka]

[0022] In certain preferred embodiments, R 4 is halo (e.g., fluoro). In other preferred embodiments, R 4 is hydroxyl or alkoxy (e.g., methoxy).

[0023] In certain embodiments, the compound has formula IIc or a pharma- ceutically acceptable salt thereof:

[0024] [ka]

[0025] In certain embodiments, 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), amido (e.g., N-methylamido), acetyl, carboxy, or ester (e.g., methyl ester). In certain preferred embodiments, R 2 is halo (e.g., fluoro). In other preferred embodiments, R 2 is H.

[0026] In certain embodiments, R 5 is H or alkyl (e.g., methyl). In certain preferred embodiments, R 2 is H.

[0027] In certain embodiments, R 1 is H. In certain embodiments, R 1 is alkyl (e.g., methyl or ethyl).

[0028] In certain embodiments, B is heteroaryl (e.g., pyridinyl, pyrimidinyl, or triazinyl). In certain preferred embodiments, B is pyrimidinyl.

[0029] In certain embodiments, B is selected from the group consisting of at least one R 4 Each R 4 is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido. 4 Each R 4 is independently selected from alkyl (e.g., methyl), oxo, and halo (e.g., chloro or fluoro). In certain preferred embodiments, B is selected from one or two R 4 has been replaced with.

[0030] In certain embodiments, the compound is represented by formula Ia, or a pharma- ceutically acceptable salt thereof:

[0031] [ka] During the ceremony, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is amino or heterocyclyl; 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 are each independently 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.

[0032] In certain embodiments, the compound has formula IIIa or a pharma- ceutically acceptable salt thereof:

[0033] [ka]

[0034] In certain embodiments, the compound has the formula IIIb or a pharma- ceutically acceptable salt thereof:

[0035] [ka]

[0036] In certain embodiments, the compound has formula IIIc or a pharma- ceutically acceptable salt thereof:

[0037] [ka]

[0038] In certain embodiments, X 5 CR 8 It is.

[0039] In certain embodiments, R 8 is H or halo (e.g., fluoro). In certain preferred embodiments, R 8 is fluoro.

[0040] In certain embodiments, X 5 is N.

[0041] In certain embodiments, X 6 CR 9 In another embodiment, X 6 is N.

[0042] In certain embodiments, R 9 is H or halo (e.g., fluoro). In certain preferred embodiments, R 9 is fluoro.

[0043] In certain embodiments, the compound has Formula IVa or a pharma- ceutically acceptable salt thereof:

[0044] [ka]

[0045] In certain embodiments, the compound has Formula IVb or a pharma- ceutically acceptable salt thereof:

[0046] [ka]

[0047] In certain embodiments, the compound has formula IVc or a pharma- ceutically acceptable salt thereof:

[0048] [ka]

[0049] In certain embodiments, the compound has formula IVd or a pharma- ceutically acceptable salt thereof:

[0050] [ka]

[0051] In certain embodiments, the compound has formula IVe or a pharma- ceutically acceptable salt thereof:

[0052] [ka]

[0053] In certain embodiments, R 6 is H, hydroxyl, oxo, halo (e.g., fluoro), alkyl (e.g., hydroxyalkyl, such as methyl, hydroxymethyl, or alkyloxyalkyl, such as methoxyethyl), or alkoxy (e.g., methoxy). In certain preferred embodiments, R 6 is halo (e.g., fluoro). In other preferred embodiments, R 6 is H.

[0054] In certain embodiments, R 7 is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amido (e.g., methylamido). In certain preferred embodiments, R 7 is halo (e.g., fluoro).

[0055] In certain embodiments, D is amino. In certain embodiments, D is N-linked heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxydethiomorpholinyl, azabicyclooctanyl, oxazabicyclooctane, hexahydrofuropyrrolyl, or azabicyclohexanyl).

[0056] In certain embodiments, D is selected from the group consisting of at least one R 10 Each R 10 is independently selected from 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, or D is selected from at least two R 5 is replaced by R 5 Two of these are combined to complete a bicyclic heterocyclyl.

[0057] In certain embodiments, D is selected from the group consisting of at least one R 10 Each R 10 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 selected from one or two R 10 In certain preferred embodiments, D is substituted with two R 10 has been replaced with.

[0058] In certain embodiments, the compound is represented by formula V, or a pharma- ceutically acceptable salt thereof:

[0059] [ka] During the ceremony, 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, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0060] In certain embodiments, R 10a is 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 preferred embodiments, R 10a is methyl.

[0061] In certain embodiments, R 10b is 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 preferred embodiments, R 10b is methyl.

[0062] In certain preferred embodiments, D is

[0063] [ka] It is.

[0064] In certain embodiments, D is

[0065] [ka] In certain embodiments, D is

[0066] [ka] In a more preferred embodiment, D is

[0067] [ka] In another more preferred embodiment, D is

[0068] [ka] In another more preferred embodiment, D is

[0069] [ka] In certain embodiments, D is

[0070] [ka] In certain embodiments, D is

[0071] [ka] In certain embodiments, D is

[0072] [ka] In certain embodiments, D is

[0073] [ka] In certain embodiments, D is

[0074] [ka] In certain embodiments, D is

[0075] [ka] In certain embodiments, D is

[0076] [ka] In certain embodiments, D is

[0077] [ka] In certain embodiments, D is

[0078] [ka] In certain embodiments, D is

[0079] [ka] In certain embodiments, D is

[0080] [ka] In certain embodiments, D is

[0081] [ka] In certain embodiments, D is

[0082] [ka] In certain embodiments, D is

[0083] [ka] In certain embodiments, D is

[0084] [ka] In certain embodiments, D is

[0085] [ka] In certain embodiments, D is

[0086] [ka] In certain embodiments, D is

[0087] [ka] In certain embodiments, D is

[0088] [ka] In certain embodiments, D is

[0089] [ka] In certain embodiments, D is

[0090] [ka] In certain embodiments, D is

[0091] [ka] In certain embodiments, D is

[0092] [ka] In certain embodiments, D is

[0093] [ka] In certain embodiments, D is

[0094] [ka] In certain embodiments, D is

[0095] [ka] In certain embodiments, D is

[0096] [ka] In certain embodiments, D is

[0097] [ka] In certain embodiments, D is

[0098] [ka] In certain embodiments, D is

[0099] [ka] It is.

[0100] In certain embodiments, E is aryl (e.g., phenyl, dihydrobenzofuran, or benzodioxole). In certain preferred embodiments, E is phenyl. In other embodiments, E is heteroaryl (e.g., pyridinyl, pyrazinyl, benzofuranyl, or benzodioxyl). In certain preferred embodiments, E is pyridinyl. In other preferred embodiments, E is pyrazinyl.

[0101] In certain embodiments, E is selected from the group consisting of at least one R 11 Each R 11 is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido alkyl. In certain embodiments, E is selected from at least one R6 Each R 11 is 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.

[0102] In certain preferred embodiments, E is one R 11 In another preferred embodiment, E is substituted with two R 11 In yet another embodiment, E is substituted with three R 11 has been replaced with.

[0103] In certain embodiments, E has a structure represented by formula VIa, VIb, or VIc:

[0104] [ka] During the ceremony, R 11a and R 11b are each independently selected from hydrogen, 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.

[0105] In certain embodiments, E has a structure represented by formula VIa:

[0106] [ka]

[0107] In certain embodiments, E has the structure of formula VIb:

[0108] [ka]

[0109] In certain embodiments, E has a structure represented by formula VIc:

[0110] [ka]

[0111] In certain embodiments, R 11a 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 is difluoromethoxy.

[0112] In certain embodiments, R 11b 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.

[0113] In certain preferred embodiments, E is

[0114] [ka] It is.

[0115] In certain embodiments, E is

[0116] [ka] In certain embodiments, E is

[0117] [ka] It is.

[0118] In certain embodiments, E is

[0119] [ka] In certain embodiments, E is

[0120] [ka] In certain embodiments, E is

[0121] [ka] In certain embodiments, E is

[0122] [ka] In certain embodiments, E is

[0123] [ka] In certain embodiments, E is

[0124] [ka] In certain embodiments, E is

[0125] [ka] In certain embodiments, E is

[0126] [ka] In certain embodiments, E is

[0127] [ka] In certain embodiments, E is

[0128] [ka] In certain embodiments, E is

[0129] [ka] In certain embodiments, E is

[0130] [ka] In certain embodiments, E is

[0131] [ka] In certain embodiments, E is

[0132] [ka] In certain embodiments, E is

[0133] [ka] In certain preferred embodiments, E is

[0134] [ka] In an even more preferred embodiment, E is

[0135] [ka] In certain embodiments,

[0136] [ka] In certain embodiments, E is

[0137] [ka] In certain embodiments, E is

[0138] [ka] In certain embodiments, E is

[0139] [ka] In certain embodiments, E is

[0140] [ka] In certain embodiments, E is

[0141] [ka] In certain embodiments, E is

[0142] [ka] In certain embodiments, E is

[0143] [ka] In certain embodiments, E is

[0144] [ka] In certain embodiments, E is

[0145] [ka] In certain embodiments, E is

[0146] [ka] In certain embodiments, E is

[0147] [ka] In certain embodiments, E is

[0148] [ka] In certain embodiments, E is

[0149] [ka] In certain embodiments, E is

[0150] [ka] In certain embodiments, E is

[0151] [ka] It is.

[0152] In certain embodiments, the compound is represented by formula VIIa, VIIb, or a pharma- ceutically acceptable salt thereof:

[0153] [ka] During the ceremony, R 4 and R 7 are each independently 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 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, respectively; 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.

[0154] In certain embodiments, the compound has formula VIIa or a pharma- ceutically acceptable salt thereof:

[0155] [ka]

[0156] In certain embodiments of Formula VIIa, R 4 is alkyl (e.g., methyl), oxo, or halo (e.g., chloro or fluoro). In certain preferred embodiments of Formula VIIa, R 4 is halo (e.g., chloro or fluoro).

[0157] In certain embodiments, the compound has formula VIIb or a pharma- ceutically acceptable salt thereof:

[0158] [ka]

[0159] In certain embodiments of Formula VIIb, R 7 is H, hydroxyl, oxo, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amido (e.g., methylamido). In certain embodiments of Formula VIIb, R 7 is H, alkyl (e.g., methyl), halo (e.g., fluoro), acyl (e.g., acetyl), or amido (e.g., methylamido). In certain preferred embodiments of Formula VIIb, R 7 is halo (e.g., fluoro).

[0160] In certain preferred embodiments of formula VIIa or VIIb, R 10a is alkyl (e.g., methyl).

[0161] In certain preferred embodiments of formula VIIa or VIIb, R 10b is alkyl (e.g., methyl).

[0162] In certain embodiments of formula VIIa or VIIb, R 11ais 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 is difluoromethyl.

[0163] In certain embodiments, the compound is selected from the compounds listed in Table 1, or a pharma- ceutically acceptable salt thereof.

[0164] Table 1: Exemplary compounds of the present disclosure [Table 1-1]

[0165] [Table 1-2]

[0166] [Table 1-3]

[0167] [Table 1-4]

[0168] [Table 1-5]

[0169] [Table 1-6]

[0170]

Table 1-7

[0171]

Table 1-8

[0172]

Table 1-9

[0173]

Table 1-10

[0174]

Table 1-11

[0175]

Table 1-12

[0176]

Table 1-13

[0177]

Table 1-14

[0178]

Table 1-15

[0179]

Table 1-16

[0180]

Table 1-17

[0181]

Table 1-18

[0182]

Table 1-19

[0183]

Table 1-20

[0184]

Table 1-21

[0185]

Table 1-22

[0186]

Table 1-23

[0187]

Table 1-24

[0188]

Table 1-25

[0189]

Table 1-26

[0190] [Table 1-27]

[0191] Some of the compounds disclosed herein may also exist in tautomeric forms. Such forms, although not explicitly shown in the formulas set forth herein, are intended to be included within the scope of the present disclosure.

[0192] The present disclosure also includes all suitable isotopic variants of the compounds of the present 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 an atomic mass different from the atomic mass that is usually or predominantly found in nature.Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 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. Thus, unless otherwise specified, the reference to "hydrogen" or "H" is 1 H (protium), 2 H (deuterium), and 3 H (tritium). Specific isotopic variations of the compounds of the invention, such as 3 H or 14 Those incorporating one or more radioactive isotopes, such as C, are useful in drug and / or substrate tissue distribution studies. Tritiated and carbon-14, i.e.14 C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced required dosage, and may therefore be preferred in some circumstances. Such variants may also have advantageous optical properties, for example resulting from changes to vibrational modes by the heavier isotope. Isotopic variants of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art (for example, by the exemplary method or by the preparation described in the following examples using appropriate isotopic variants of suitable reagents).

[0193] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0194] In yet another aspect, the disclosure provides a method of treating a TACC-mediated disease or disorder in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0195] In yet another aspect, the disclosure provides a method of treating a disease or disorder characterized by dysregulation of TACC in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0196] In certain embodiments, TACC is TACC1. In other embodiments, TACC is TACC2. In other preferred embodiments, TACC is TACC3.

[0197] In certain embodiments, the TACC-mediated disease or disorder is cancer. In certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia, renal cancer, or prostate cancer. In certain embodiments, the cancer is breast cancer, ovarian cancer, esophageal cancer, endometrial cancer, prostate cancer, colon cancer, pancreatic cancer, head and neck cancer, or lung cancer.

[0198] In yet another aspect, the present disclosure provides a method of treating cancer in a subject, the method comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof. In certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia, renal cancer, or prostate cancer. In certain embodiments, the cancer is breast cancer, ovarian cancer, esophageal cancer, endometrial cancer, prostate cancer, colon cancer, pancreatic cancer, head and neck cancer, or lung cancer.

[0199] Pharmaceutical Compositions The compositions and methods of the present invention can be utilized to treat individuals in need of treatment. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition, for example, comprising the compound 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, glycerol, oils, such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized tablets for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0200] Pharmaceutically acceptable carriers can include, for example, physiologically acceptable agents that act to stabilize, increase the solubility, or increase the absorption of a compound, such as the compound of the present invention. 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 choice of a pharma-ceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, in which, for example, 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, and are relatively easy to manufacture and administer.

[0201] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0202] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically 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 of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil; and soybean 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) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffers, and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0203] Pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, as aqueous or non-aqueous solutions or suspensions), 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). The compounds can also be prepared for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 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 therein.

[0204] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art 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, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0205] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, optionally shaping the product.

[0206] 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 (with a flavored base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as electuaries or syrups, or as pastilles (with an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0207] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) sorbitol, ... Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retarders, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, (7) wetting agents, such as cetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents, such as modified and unmodified cyclodextrins, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules, using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, and the like.

[0208] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0209] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, can be prepared with coatings and shells, such as optionally scored or enteric coatings and other coatings known in the pharmaceutical formulation art. They can 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 provide the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents, and can be compositions that release the active ingredient only, or preferentially, in a certain part of the digestive tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, where appropriate, with one or more of the above-mentioned excipients.

[0210] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilisates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its 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 fatty acid esters of sorbitan, and mixtures thereof.

[0211] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0212] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxylate, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0213] 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 pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0214] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal, vegetable and physical fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0215] Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0216] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be made by dissolving or dispersing active compound in suitable medium.Absorption enhancers can also be used to increase the flux of compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0217] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately prior to use and may contain antioxidants, buffers, bacteriostats, solvents that render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0218] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0219] These compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents in the compositions, such as sugars, sodium chloride, and the like. Furthermore, prolonged absorption of the injectable pharmaceutical form can be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0220] In some cases, it is desirable to delay the absorption of drugs from subcutaneous or intramuscular injections in order to maintain the effect of the drug.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0221] Injectable depot forms are prepared by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0222] For use in the methods of the invention, the active compound may be provided per se or, for example, as a pharmaceutical composition containing 0.1-99.5% (more preferably 0.5-90%) active ingredient in combination with a pharma- ceutically acceptable carrier.

[0223] The method of introduction can also be provided by rechargeable or biodegradable devices. For the controlled delivery of drugs, including proteinaceous biopharmaceuticals, various sustained release polymeric devices have been developed and tested in vivo in recent years. Various biocompatible polymers, including hydrogels, including both biodegradable and non-degradable polymers, can be used to form implants for sustained release of compounds at specific target sites.

[0224] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied to provide an amount of the active ingredient effective to achieve a therapeutic response for a particular patient, composition, and mode of administration, without causing toxicity to the patient.

[0225] The selected dosage level will depend on a variety of factors, including factors well known in the medical art, such as, for example, the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, being used, the route of administration, the time of administration, the rate of excretion of the particular compound being used, the duration of treatment, other drugs, compounds and / or substances being used in combination with the particular compound being used, the age, sex, weight, condition, general health and previous medical history of the patient being treated.

[0226] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount 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, another type of therapeutic agent administered together with the compound of the present invention. Multiple administrations of the drug can deliver a large total dose. 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).

[0227] In general, a suitable daily amount of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective amount will generally depend upon the factors described above.

[0228] If necessary, the effective daily amount of the active compound may be administered as 1, 2, 3, 4, 5, 6 or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound is administered once a day.

[0229] The patient to receive this treatment may be any animal in need of treatment, including primates, particularly humans; as well as other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and common pets.

[0230] In certain embodiments, the compounds of the invention can be used alone or can be co-administered with another type of therapeutic agent.

[0231] The present disclosure includes the use of pharma- ceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 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, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of 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, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptan ... Acid salts of carboxylic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hipprinic 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.

[0232] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0233] Wetting agents, emulsifying agents and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0234] Examples of pharma- ceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0235] definition Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. In general, the nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0236] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and described in various general and more specific references cited and discussed throughout this specification, unless otherwise indicated. See, e.g., "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).

[0237] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, Calif. (1985).

[0238] All of the above, and any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including specific definitions, will control.

[0239] The term "agent" is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of compounds), a biological macromolecule (such as nucleic acids, antibodies, portions thereof, including humanized, chimeric and human antibodies and monoclonal antibodies, proteins or portions thereof, e.g., peptides, lipids, carbohydrates), or an extract made from biological material such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Agents include, for example, agents with known structures and agents with unknown structures.

[0240] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals such as humans, primates, farm animals (including cows, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice, rats).

[0241] "Treating" a condition or patient refers to taking measures to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stable (i.e., not worsening) disease, prevention of disease spread, delay or slowing of disease progression, amelioration or palliation of disease symptoms, and remission (partial or complete). "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment.

[0242] The term "preventing" is art-recognized and, when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency or delays the onset of symptoms of the medical condition in a subject compared to subjects who do not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population by a statistically and / or clinically significant amount.

[0243] "Administering" or "administration" of a substance, compound or agent to a subject can be performed using one of a variety of methods known in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through the skin tract). The compound or agent can also be suitably introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations that provide sustained, sustained or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0244] The appropriate method of administering a substance, compound or agent to a subject also depends, for example, on the age and / or physical condition of the subject, and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the compound or agent is administered to the subject orally, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a sustained or timed release formulation or is administered using a device for such sustained or timed release.

[0245] 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 (e.g., the two agents are effective on a patient at the same time, and a synergistic effect of the two agents may be involved). For example, the 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 effect of the different therapeutic agents.

[0246] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of the drug or agent that has the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily occur in one administration, but may occur only after a series of administrations. Thus, a therapeutically effective amount can be administered in one or more administrations. The exact effective amount required by a subject depends, for example, on the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0247] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl can be substituted as well as cases where the alkyl is not substituted.

[0248] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art, as well as by the methods described below. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0249] As used herein, the term "optionally substituted" refers to the replacement of 1-6 hydrogen radicals in a given structure with a radical of a specified substituent, 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). Preferably, "optionally substituted" refers to the replacement of 1-4 hydrogen radicals in a given structure with the above substituents. More preferably, 1-3 hydrogen radicals are replaced by the above substituents. It is understood that the substituents can be further substituted.

[0250] As used herein, the term "alkyl" refers to any alkyl group having a C1-C 10 Straight chain alkyl group or C1-C 10 It refers to saturated aliphatic groups including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain 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.

[0251] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0252] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0253] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0254] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0255] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0256] The term "alkyl" refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl group has 30 or fewer alkyl groups in its backbone (e.g., C for straight chain). 1~30 , C for branched chains 3~30 ), more preferably having 20 or fewer carbon atoms.

[0257] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, and includes haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0258] "C x~y " or "C x ~C yThe term "alkyl" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. CO alkyl indicates a hydrogen in the group's terminal position, and if internal, indicates a bond. For example, C 1~6 Alkyl groups contain 1 to 6 carbon atoms in the chain.

[0259] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0260] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0261] As used herein, the term "amide" refers to the group

[0262] [ka] In the formula, R 9 and R 10 each independently represents a hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0263] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, and salts thereof, e.g.,

[0264] [ka] wherein R 9 , R 10 , and R 10‘ each independently represents a hydrogen or a hydrocarbyl group, or R 9 and R 10together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0265] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0266] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0267] The term "aryl" as used herein includes substituted or unsubstituted single-ring 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, where two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0268] The term "carbamate" is art-recognized and refers to a group

[0269] [ka] In the formula, R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0270] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0271] The term "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more than two atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, can be fused 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 carbocycle, as long as valences permit. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles 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 "carbocycle" can be substituted at any one or more positions that can retain a hydrogen atom.

[0272] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0273] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0274] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0275] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4-8 membered rings, more preferably 4-6 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, at least one of the rings is cycloalkyl, and where a substituent (e.g., R 100 ) is attached to the cycloalkyl ring, for example, the other cyclic rings can 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, tetrahydroquinoline, and the like.

[0276] As used herein, the term "ester" refers to an ester selected from the group -C(O)OR 9 In the formula, R 9 represents a hydrocarbyl group.

[0277] The term "ether" as used herein refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. Ethers can be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which can be represented by the general formula alkyl-O-alkyl.

[0278] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0279] The terms "hetarylalkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0280] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include 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 a heteroaromatic ring, 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, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0281] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0282] The term "heterocyclic alkyl," as used herein, refers to an alkyl group substituted with a heterocyclic group.

[0283] The terms "heterocyclyl", "heterocycle", and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocycle" also include 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, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0284] The term "hydrocarbyl" as used herein refers to a group that is bonded through a carbon atom that does not have =O or =S substituents, typically has at least one carbon-hydrogen bond and a predominantly carbon backbone, but can optionally include heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has =O substituent on the bonded carbon) and ethoxy (which is bonded through an oxygen rather than a carbon) are not. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0285] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0286] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer atoms, preferably 6 or fewer atoms, in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are, for example, hydroxyalkyl and aralkyl in reference (where, for example, atoms in an aryl group are not counted when counting the carbon atoms of an alkyl substituent), respectively, lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents.

[0287] 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 of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains from 3 to 10 atoms, preferably from 5 to 7 atoms, in the ring.

[0288] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharma- ceutically acceptable salt thereof.

[0289] The term "sulfonamide" is art-recognized and can be represented by the general formula

[0290] [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0291] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0292] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharma- ceutically acceptable salt thereof.

[0293] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0294] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the replacing atom and substituent, as well as the implicit proviso that the substitution results in a stable compound that does not spontaneously undergo transformation, such as, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and can be the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate.

[0295] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0296] As used herein, the term "thioester" refers to the group -C(O)SR 9 Or -SC(O)R 9 Refers to, In the formula, R 9 represents hydrocarbyl.

[0297] The term "thioether" as used herein is equivalent to an ether where the oxygen is replaced with a sulfur.

[0298] The term "urea" is art-recognized and has the general formula

[0299] [ka] In the formula, R 9 and R 10 is independently hydrogen or hydrocarbyl.

[0300] As used herein, the term "modulate" includes the inhibition or suppression of a function or activity (such as cell proliferation), as well as the enhancement of a function or activity.

[0301] The phrase "pharmacologically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0302] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible for the treatment of a patient.

[0303] As used herein, the term "pharmaceutical acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochloride, hydrobromide, sulfate, and phosphate salts, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, 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. Either mono- or di-acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms. The selection of an appropriate salt is known to one skilled in the art. Other non-pharmaceutical 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 a pharmaceutical acceptable acid addition salt.

[0304] As used herein, the term "pharmaceutically acceptable basic addition salt" refers to 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 suitable salts is known to those skilled in the art.

[0305] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may exist in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl.Chem.(1976),45,11-30. The present disclosure contemplates all stereoisomeric forms, such as enantiomeric and diastereoisomeric forms, of the compounds, salts, prodrugs, or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO 01 / 062726.

[0306] Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers, and in each case the present disclosure includes both mixtures and the separate individual isomers.

[0307] "Prodrug" or "Pharmaceutically acceptable prodrug" refers to a compound that is metabolized in the host after administration, e.g., hydrolyzed or oxidized, to form a compound of the present disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on the functional moiety 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 generate the active compound. Examples of prodrugs that use esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to generate a compound of formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs”, Ed. H. Bundgaard, Elsevier, 1985.

[0308] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharma- ceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, that is useful in formulating a drug for medicinal or therapeutic use.

[0309] As used herein, the term "logarithm of solubility", "LogS" or "logS" is used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution properties. Low solubility often leads to poor absorption. The LogS value is the unit stripped logarithm (decimal) of solubility measured in mol / liter. EXAMPLES

[0310] The following representative examples are intended to help illustrate the present invention, and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including the following examples and references to the scientific and patent literature cited herein. Furthermore, it should be understood that the contents of these cited references are incorporated herein by reference to help describe the state of the art. The following examples contain important additional information, exemplification, and guidance that can be adapted to the practice of the present invention in its various embodiments and equivalents thereof.

[0311] Example 1: Synthesis of exemplary compounds of the present disclosure General Procedure A.

[0312] [ka] General Procedure B.

[0313] [ka] General Procedure C.

[0314] [ka] E=Ar, HetAr Representative examples of D:

[0315] [ka] Representative examples of E:

[0316] [ka]

[0317] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine.

[0318] [ka] A mixture of compound 2-chloropyrimidin-4-amine (2.0 g, 15.4 mmol, 1.0 equiv.), compound (2R,6S)-2,6-dimethylmorpholine (5.33 g, 46.3 mmol, 3.0 equiv.), and DIEA (10.0 g, 77.0 mmol, 5.0 equiv.) in IPA (40 mL) was stirred at 80° C. under N2 for 16 h. The reaction 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 to DCM:MeOH=40:1) to give 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-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).

[0319] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine

[0320] [ka] To a solution of compound 2-chloro-5-fluoropyrimidin-4-amine (50 g, 338.9 mmol, 1.0 eq.), compound (2R,6S)-2,6-dimethylmorpholine (78 g, 667.8 mmol, 2.0 eq.) in IPA (500 mL), DIEA (87.6 g, 667.8 mmol, 2.0 eq.) was added, and the reaction mixture was stirred at 80° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:EtOAc=20:1 to give 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0321] Synthesis of 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine

[0322] [ka] To a solution of compound 2-chloro-5-fluoropyrimidin-4-amine (325 mg, 2.2 mmol, 1.5 eq.) and compound (2S,6S)-2,6-dimethylmorpholine (170 mg, 1.47 mmol, 1.0 eq.) in IPA (3 mL) was added DIEA (569 mg, 4.4 mmol, 2.0 eq.). The reaction mixture was stirred at 80° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC using DCM / MeOH=40 / 1 to give 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (92 mg, 18%) as a white solid. LCMS: 227.10 [M+1]+; 1 H 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).

[0323] Synthesis of 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine

[0324] [ka] To a solution of compound 2-chloro-5-fluoropyrimidin-4-amine (200 mg, 1.36 mmol, 1.0 equiv.) in IPA (4 mL) was added compound (2R,6R)-2,6-dimethylmorpholine (391 mg, 3.40 mmol, 2.5 equiv.) and DIEA (526 mg, 4.08 mmol, 3.0 equiv.). The reaction mixture was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (DCM / MeOH / NH3·H2O=50 / 1 / 0.5) to give 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (70 mg, white solid). LC-MS: 227.12 [M+1] + ; 1H 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).

[0325] Synthesis of 5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-amine

[0326] [ka] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (200 mg, 1.36 mmol, 1.0 equiv) in IPA (4 mL) was added pyrrolidine (290 mg, 4.08 mmol, 3.0 equiv) and DIEA (526 mg, 4.08 mmol, 3.0 equiv). The reaction mixture was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=1 / 1) to give 5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-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).

[0327] Synthesis of 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-amine

[0328] [ka] Step a: To a solution of 2-chloro-5-fluoropyrimidin-4-amine (300 mg, 2.03 mmol, 1.0 equiv), Boc2O (1.77 g, 8.13 mmol, 4.0 equiv) and TEA (821 mg, 8.13 mmol, 4.0 equiv) in DCM (3 mL) was added DMAP (12 mg, 0.10 mmol, 0.05 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE:EtOAc=100:1 to give the 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 the bis-N-Boc protected compound (512 mg, 1.47 mmol, 1.0 equiv.) was added 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (200 mg, 1.47 mmol, 1.0 equiv.) in DIEA (3 mL). The reaction mixture was stirred at 100° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC using PE / EA=3 / 1 to give 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 equiv) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 mL). The reaction mixture was stirred at 40° C. for 16 h. 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 with DCM / MeOH=40 / 1 to give 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-amine (12 mg, 21%) as a white solid. 1H 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).

[0329] Synthesis of (2R,6S)-4-(4,6-difluoropyrimidin-2-yl)-2,6-dimethylmorpholine

[0330] [ka] To a solution of 2,4,6-trifluoropyrimidine (300 mg, 2.24 mmol, 1.0 equiv.), K2CO3 (619 mg, 4.48 mmol, 2.0 equiv.) in ACN (30 mL) was added (2R,6S)-2,6-dimethylmorpholine (258 mg, 2.24 mmol, 1.0 equiv.). The reaction mixture was stirred for 10 min under ice cooling and further stirred at room temperature for 1 h. The mixture was concentrated under vacuum to give a residue which was purified by column chromatography on silica gel eluted with (PE / EA=100 / 1 to 50 / 1) to give (2R,6S)-4-(4,6-difluoropyrimidin-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).

[0331] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine

[0332] [ka] 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (700 mg, 3.36 mmol, 1.0 equiv.), 3,5-dichloropyridazine (500 mg, 3.36 mmol, 1.0 equiv.), Xantphos (197 mg, 0.34 mmol, 0.1 equiv.), and C in dioxane (10 mL). S2 To a solution of CO3 (2.2 g, 6.72 mmol, 2.0 equiv) was added Pd2(dba)3 (97 mg, 0.17 mmol, 0.05 equiv) at room temperature under N2. The reaction mixture was then stirred at 110 °C under N2 for 16 h. The reaction 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 to DCM:MeOH=40:1) to give 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine (200 mg, 18.5%) as a yellow solid. LCMS: 321.00 [M+1] +

[0333] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine

[0334] [ka] To a solution of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (35.5 g, 157.08 mmol, 1.0 equiv), 3,5-dichloropyridazine (35 g, 234.90 mmol, 1.5 equiv), Xantphos (4.54 g, 7.85 mmol, 0.05 equiv), and Cs2CO3 (153.5 g, 471.15 mmol, 3.0 equiv) in Tol (500 mL) under N2 was added Pd(dppf)Cl2 (5.75 g, 7.86 mmol, 0.05 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. The reaction 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 eluting with PE:EtOAc=5:1 to give 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (29 g, 55%) as a yellow solid. LCMS: 339.11 [M+H] + ; 1 H 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).

[0335] Synthesis of 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine

[0336] [ka] To a solution of 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (92 mg, 0.41 mmol, 1.0 equiv), 3,5-dichloropyridazine (91 mg, 0.61 mmol, 1.5 equiv), Xantphos (12 mg, 0.02 mmol, 0.05 equiv), and Cs2CO3 (398 mg, 1.22 mmol, 3.0 equiv) in Tol (3 mL) under N2 was added Pd(dppf)Cl2 (15 mg, 0.02 mmol, 0.05 equiv) at room temperature. The reaction mixture was then stirred at 80 °C under N2 for 16 h. The reaction 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 (over Na2SO4 or MgSO4) and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=2 / 1 to give 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0337] Synthesis of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine

[0338] [ka] To a solution of 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (70 mg, 0.31 mmol, 1.0 equiv.) in toluene (4 mL) was added 3,5-dichloropyridazine (46 mg, 0.31 mmol, 1.0 equiv.), Cs2CO3 (202 mg, 0.62 mmol, 2.0 equiv.), Xantphos (18 mg, 0.031 mmol, 0.1 equiv.), and Pd(dppf)Cl2 (23 mg, 0.031 mmol, 0.1 equiv.). The reaction mixture was stirred at 80 °C under N2 for 16 h. 50 mL of H2O was poured into the mixture, which was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=2 / 1) to give 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (50 mg). LC-MS: 339.05[M+1] +

[0339] Synthesis of 5-chloro-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine

[0340] [ka] To a solution of 5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-amine (230 mg, 1.26 mmol, 1.0 equiv.) in toluene (5 mL) was added 3,5-dichloropyridazine (188 mg, 1.26 mmol, 1.0 equiv.), Cs2CO3 (819 mg, 2.52 mmol, 2.0 equiv.), Xantphos (73 mg, 0.126 mmol, 0.1 equiv.), and Pd(dppf)Cl2 (92 mg, 0.126 mmol, 0.1 equiv.). The reaction mixture was stirred at 80° C. for 16 h under N2. 50 mL of H2O was poured into the mixture, which was extracted with EtOAc (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=2 / 1) to give 5-chloro-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine (50 mg, crude). LC-MS: 295.00 [M+1] +

[0341] Synthesis of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-chloropyridazin-3-amine

[0342] [ka] To a solution of 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-amine (12 mg, 0.06 mmol, 1.0 equiv.), 3,5-dichloropyridazine (13 mg, 0.09 mmol, 1.5 equiv.), Xantphos (2 mg, 0.003 mmol, 0.05 equiv.), and Cs2CO3 (59 mg, 0.18 mmol, 3.0 equiv.) in Tol (3 mL) was added Pd(dppf)Cl2 (2 mg, 0.003 mmol, 0.05 equiv.) at room temperature. The reaction mixture was then stirred at 80° C. under N2 for 16 h. The reaction 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 give N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-chloropyridazin-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).

[0343] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine

[0344] [ka] A reaction mixture of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (100 mg, 0.44 mmol, 1.0 equiv), 4,6-dichloro-3-methylpyridazine (71 mg, 0.44 mmol, 1.0 equiv), Xantphos (35 mg, 0.044 mmol, 0.1 equiv), Pd2(dba)3 (56 mg, 0.044 mmol, 0.1 equiv), and Cs2CO3 (380 mg, 0.88 mmol, 2.0 equiv) in toluene (5 mL) was stirred at 110 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=7 / 1 to 4 / 1) to give 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-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).

[0345] Synthesis of N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)-5-(2-fluoro-4-methoxyphenyl)pyridazin-3-amine - compound 3

[0346] [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine (100 mg, 0.31 mmol, 1.0 equiv), (2-fluoro-4-methoxyphenyl)boronic acid (80 mg, 0.47 mmol, 1.5 equiv), and K2CO3 (86 mg, 0.62 mmol, 2.0 equiv) in dioxane / HO (5 mL / 0.5 mL) under N2 was added Pd(PPh3)4 (36 mg, 0.031 mmol, 0.1 equiv) at room temperature. The reaction mixture was then stirred at 110 °C under N2 for 16 h. The reaction 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 give N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-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).

[0347] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine - compound 20

[0348] [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine (75 mg, 0.23 mmol, 1.0 equiv.) in dioxane / HO (2 mL / 0.2 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (80 mg, 0.46 mmol, 2.0 equiv.), KPO (149 mg, 0.7 mmol, 3.0 equiv.), and Pd(dppf)Cl (17 mg, 0.023 mmol, 0.1 equiv.). The reaction mixture was stirred at 110° C. under N for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=0 / 1) to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-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).

[0349] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine - compound 80

[0350] [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (9 g, 26.57 mmol, 1.0 equiv.), (4-(difluoromethoxy)phenyl)boronic acid (9 g, 53.13 mmol, 2.0 equiv.), and K3PO4 (16.9 g, 79.7 mmol, 3.0 equiv.) in dioxane / HO (10:1, 90 mL / 10 mL) under N2, Pd(dppf)Cl2 (1.94 g, 2.66 mmol, 0.05 equiv.) was added at room temperature. The reaction mixture was then stirred at 110 °C for 16 h. The reaction 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 eluting with PE:EtOAc=2:1 to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0351] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine - compound 91

[0352] [ka] To a solution of 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (75 mg, 0.22 mmol, 1.0 equiv), (4-(difluoromethoxy)phenyl)boronic acid (76 mg, 0.44 mmol, 2.0 equiv), and KPO (141 mg, 0.66 mmol, 3.0 equiv) in dioxane / HO (2 mL / 0.2 mL) under N was added Pd(dppf)Cl (16 mg, 0.02 mmol, 0.1 equiv) at room temperature. The reaction mixture was then stirred at 110 °C under N for 16 h. The reaction 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 (over Na2SO4 or MgSO4) and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=1 / 1 to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0353] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine - compound 90

[0354] [ka] To a solution of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (50 mg, 0.15 mmol, 1.0 equiv.) in toluene / HO (3 mL / 1 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (43 mg, 0.23 mmol, 1.5 equiv.), KPO (64 mg, 0.30 mmol, 2.0 equiv.) and Pd(dppf)Cl (11 mg, 0.015 mmol, 0.1 equiv.). The reaction mixture was stirred at 110° C. for 16 h under N. 50 mL of HO was poured into the mixture, extracted with EtOAc (15 mL×3), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=1 / 1) to give the compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine as a yellow oil (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).

[0355] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine - Compound 104

[0356] [ka] To a solution of 5-chloro-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine (50 mg, 0.17 mmol, 1.0 equiv.) in toluene / HO (3 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (48 mg, 0.26 mmol, 1.5 equiv.), KPO (72 mg, 0.0.34 mmol, 2.0 equiv.), and Pd(dppf)Cl (13 mg, 0.017 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 110° C. under N for 16 h. 50 mL of HO was poured into the mixture, extracted with EtOAc (15 mL×3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the compound 5-(4-(difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-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).

[0357] Synthesis of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine - Compound 103

[0358] [ka] To a solution of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-chloropyridazin-3-amine (10 mg, 0.03 mmol, 1.0 equiv.), (4-(difluoromethoxy)phenyl)boronic acid (10 mg, 0.06 mmol, 2.0 equiv.), and KPO (19 mg, 0.09 mmol, 3.0 equiv.) in dioxane / HOC (1 mL / 0.1 mL) was added Pd(dppf)Cl (2 mg, 0.003 mmol, 0.1 equiv.) at room temperature. The reaction mixture was then stirred at 110° C. for 16 h under N. The reaction was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water. The separated organic layer was dried (over Na2SO4 or MgSO4) and evaporated to dryness. The residue was purified by preparative TLC using PE / EA=1 / 1 to give N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-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).

[0359] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine - Compound 508

[0360] [ka] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine (70 mg, 0.20 mmol, 1.0 equiv.) in toluene (4 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (38 mg, 0.20 mmol, 1.0 equiv.), K3PO4 (85 mg, 0.40 mmol, 2.0 equiv.), and Pd(dppf)Cl2 (15 mg, 0.020 mmol, 0.1 equiv.). The reaction mixture was stirred at 110 °C under N2 for 16 h. The mixture was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=2 / 1) to obtain the compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-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).

[0361] Synthesis of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0362] [ka] To a solution of 5-chloropyridazin-3-amine (500 mg, 3.86 mmol, 1.0 equiv), (4-(difluoromethoxy)phenyl)boronic acid (1.45 g, 7.7 mmol, 2.0 equiv), and K3PO4 (2.46 g, 11.58 mmol, 3.0 equiv) in dioxane / H2O (20 mL / 2 mL) under N2, Pd(dppf)Cl2 (283 mg, 0.39 mmol, 0.1 equiv) was added at room temperature. The reaction mixture was then stirred at 110 °C under N2 for 16 h. The reaction 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 eluting with DCM / MeOH=80:1 to give 5-(4-(difluoromethoxy)phenyl)pyridazin-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).

[0363] Synthesis of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine

[0364] [ka] Pd(dppf)Cl2 (220 mg, 0.3 mmol, 0.1 equiv) was added to a solution of (4-(difluoromethoxy)phenyl)boronic acid (564 mg, 3.0 mmol, 1.0 equiv), 5-bromo-2-methoxypyridin-3-amine (609 mg, 3.0 mmol, 1.0 equiv), and K3PO4 (1.27 g, 6.0 mmol, 2.0 equiv) in dioxane / HO (8 mL / 2 mL) under N2. The reaction mixture was then stirred at 110 °C under N2 for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with (PE / EA=6 / 1 to 4 / 1) to give 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine (800 mg, white solid). 1 H 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).

[0365] Synthesis of N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0366] [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 equiv) in toluene (4 mL) was added 2-bromo-4-iodopyridine (180 mg, 0.063 mmol, 1.5 equiv), Cs2CO3 (273 mg, 0.82 mmol, 2.0 equiv), Xantphos (24 mg, 0.042 mmol, 0.1 equiv), and Pd2(dba)3 (39 mg, 0.042 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C under N2 for 16 h. 50 mL of H2O was poured into the mixture, extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (DCM / MeOH=30 / 1) to give N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (80 mg, yellow solid). LC-MS: 393.00 [M+1] +

[0367] Synthesis of N-(2-chloro-5-fluoropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0368] [ka] To a solution of compound 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 equiv.), 4-bromo-2-chloro-5-fluoropyridine (134 mg, 0.64 mmol, 1.5 equiv.), Xantphos (25 mg, 0.04 mmol, 0.1 equiv.), and Cs2CO3 (414 mg, 1.27 mmol, 3.0 equiv.) in dioxane (2 mL) was added Pd2(dba)3 (39 mg, 0.04 mmol, 0.1 equiv.) at room temperature under N2. The reaction mixture was then stirred at 80° C. for 16 h. The reaction 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 give N-(2-chloro-5-fluoropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-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).

[0369] Synthesis of N-(6-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0370] [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 equiv.) in toluene (4 mL) was added 2,6-dichloro-3-fluoropyridine (105 mg, 0.42 mmol, 1.0 equiv.), Cs2CO3 (273 mg, 0.82 mmol, 2.0 equiv.), Xantphos (24 mg, 0.042 mmol, 0.1 equiv.), and Pd2(dba)3 (39 mg, 0.042 mmol, 0.1 equiv.). The reaction mixture was stirred at 100° C. for 16 h under N2. 50 mL of H2O was poured into the mixture, which was extracted with EtOAc (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (DCM / MeOH=30 / 1) to give N-(6-chloro-3-fluoropyridin-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).

[0371] Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)pyrimidin-4-amine

[0372] [ka] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine (300 mg, 1.12 mmol, 1.0 equiv), 2,4-dichloropyrimidine (184 mg, 1.24 mmol, 1.1 equiv), and DIEA (434 mg, 3.36 mmol, 3.0 equiv) in DMSO (5 mL) was stirred at 80° C. for 16 h. The mixture was poured into 60 mL of H2O, extracted with EtOAc (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=3 / 1) to give 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)pyrimidin-4-amine (150 mg). LC-MS: 379.00 [M+1] + .

[0373] Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-5-fluoropyrimidin-4-amine

[0374] [ka] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine (300 mg, 1.12 mmol, 1.0 equiv), 2,4-dichloro-5-fluoropyrimidine (207 mg, 1.24 mmol, 1.1 equiv), and DIEA (434 mg, 3.36 mmol, 3.0 equiv) in DMSO (5 mL) was stirred at 80° C. for 16 h. The mixture was poured into 60 mL of H2O, extracted with EtOAc (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=3 / 1) to give 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-5-fluoropyrimidin-4-amine (300 mg, crude). LC-MS: 397.00 [M+1] + .

[0375] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyridin-4-yl)pyridazin-3-amine - Compound 428

[0376] [ka] To a solution of N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-pyridazin-3-amine (80 mg, 0.20 mmol, 1.0 equiv.) in toluene (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (47 mg, 0.40 mmol, 2.0 equiv.), Cs2CO3 (130 mg, 0.4 mmol, 2.0 equiv.), Xantphos (12 mg, 0.020 mmol, 0.1 equiv.), and Pd2(dba)3 (18 mg, 0.020 mmol, 0.1 equiv.). The reaction mixture was stirred at 100° C. for 16 h under N2. 50 mL of H2O was poured into the mixture, which was extracted with EtOAc (20 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyridin-4-yl)pyridazin-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).

[0377] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyridin-4-yl)pyridazin-3-amine - Compound 469

[0378] [ka] To a solution of N-(2-chloro-5-fluoropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (135 mg, 0.37 mmol, 1.0 equiv.), (2R,6S)-2,6-dimethylmorpholine (85 mg, 0.74 mmol, 1.0 equiv.) in NMP (5 mL), DIEA (143 mg, 1.11 mmol, 3.0 equiv.) was added and the reaction mixture was stirred at 200° C. for 2 h under microwave. 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 give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyridin-4-yl)pyridazin-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).

[0379] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)pyridazin-3-amine - Compound 223

[0380] [ka] To a solution of N-(6-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.27 mmol, 1.0 equiv.) in NMP (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (95 mg, 0.82 mmol, 3.0 equiv.) and DIEA (109 mg, 0.82 mmol, 3.0 equiv.). The reaction mixture was stirred at 200 °C in a microwave for 1. 50 mL of H2O was poured into the mixture and extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the compound 5-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)pyridazin-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).

[0381] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine - Compound 305

[0382] [ka] To a solution of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)pyrimidin-4-amine (150 mg, 0.40 mmol, 1.0 equiv.) in IPA (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (137 mg, 1.20 mmol, 3.0 equiv.), DIEA (154 mg, 1.20 mmol, 3.0 equiv.). The reaction mixture was then stirred at 90° C. overnight under N2. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=5 / 1 to 2 / 1) to give N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-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).

[0383] Synthesis of 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)pyridin-2(1H)-one - Compound 264

[0384] [ka] To a solution of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (50 mg, 0.109 mmol, 1.0 equiv) in DMF (1.5 mL) was added LiBr (95 mg, 1.090 mmol, 10.0 equiv), then the reaction mixture was stirred at 120° C. under N2 overnight. H2O (7 mL) was added, extracted with EA (10 mL*3) and dried with Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)pyridin-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.

[0385] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine - Compound 387

[0386] [ka] To a solution of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-5-fluoropyrimidin-4-amine (300 mg, 0.76 mmol, 1.0 equiv.) in IPA (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (261 mg, 2.27 mmol, 3.0 equiv.) and DIEA (293 mg, 2.27 mmol, 3.0 equiv.). The reaction mixture was then stirred at 90° C. overnight under N2. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=5 / 1-2 / 1) to give N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0387] Synthesis of 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridin-2(1H)-one - Compound 346

[0388] [ka] To a solution of N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (50 mg, 0.105 mmol, 1.0 equiv) in DMF (1.5 mL) was added LiBr (92 mg, 1.050 mmol, 10.0 equiv), then the reaction mixture was stirred at 120° C. under N2 overnight. H2O (7 mL) was added, extracted with EA (10 mL*3) and dried with Na2SO4. The residue was concentrated under reduced pressure. The residue was purified by TLC (DCM / MeOH=20 / 1) to give 5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridin-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.

[0389] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-6-fluoropyrimidin-4-yl)pyridazin-3-amine - compound 131

[0390] [ka] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (52 mg, 0.22 mmol, 1.0 equiv) in DMF (1 mL) was added NaH (13 mg, 0.33 mmol, 1.5 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h, and then (2R,6S)-4-(4,6-difluoropyrimidin-2-yl)-2,6-dimethylmorpholine (50 mg, 0.26 mmol, 1.2 equiv) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 h. 30 mL of H2O was poured into the mixture and extracted with EtOAc (20 mL×3). The organic phases were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (PE / EA=1 / 1) to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-6-fluoropyrimidin-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).

[0391] Synthesis of 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxy-pyridazine

[0392] [ka] To a solution of 6-chloro-4-iodo-3-methoxypyridazine (200 mg, 0.74 mmol, 1.0 equiv), (4-(difluoromethoxy)phenyl)boronic acid (139 mg, 0.74 mmol, 1.0 equiv), and K3PO4 (471 mg, 2.22 mmol, 3.0 equiv) in dioxane / HO (6 mL / 0.6 mL) under N2, Pd(dppf)Cl2 (16 mg, 0.07 mmol, 0.1 equiv) was added at room temperature. The reaction mixture was then stirred at 80 °C for 16 h. The reaction 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 give 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxy-pyridazine (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).

[0393] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methoxypyridazin-3-amine - Compound 526

[0394] [ka] To a solution of 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (120 mg, 0.42 mmol, 1.0 equiv), 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (142 mg, 0.63 mmol, 1.5 equiv), Xantphos (25 mg, 0.04 mmol, 0.1 equiv), and CsCO (409 mg, 1.26 mmol, 3.0 equiv) in dioxane (2 mL) under N was added Pd(dba) (39 mg, 0.04 mmol, 0.1 equiv) at room temperature. The reaction mixture was then stirred at 80 °C for 16 h. The reaction 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 preparative TLC with PE / EA=2 / 1 to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methoxypyridazin-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).

[0395] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N3-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazine-3,6-diamine - compound 598

[0396] [ka] Step a: To a solution of 4-bromo-6-chloropyridazin-3-amine (1.2 g, 5.77 mmol, 1.0 equiv.) in THF (10 mL), Boc2O (2.5 g, 11.54 mmol, 2.0 equiv.), TEA (1.75 g, 17.31 mmol, 3.0 equiv.) were added. The reaction mixture was stirred at 60 °C for 3 h. 100 mL of H2O was poured into the mixture, extracted with EtOAc (30 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA = 10 / 1 to 5 / 1) to give 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 equiv) in toluene / H2O (5 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 equiv), K3PO4 (636 mg, 3.0 mmol, 3.0 equiv), and Pd(dppf)Cl2 (73 mg, 0.1 mmol, 0.1 equiv) were added. The reaction mixture was stirred at 110 °C under N2 for 16 h. Then it was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to give bis-N-Boc protected 6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazin-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)pyridazin-3-amine (150 mg, 0.32 mmol, 1.0 equiv.) in toluene (5 mL) was added 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (72 mg, 0.32 mmol, 1.0 equiv.), Cs2CO3 (208 mg, 0.64 mmol, 2.0 equiv.), Xantphos (19 mg, 0.032 mmol, 0.1 equiv.), and Pd(dppf)Cl2 (24 mg, 0.032 mmol, 0.1 equiv.). The reaction mixture was stirred at 100° C. under N2 for 16 h. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to give 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: The Boc-protected compound (90 mg, 0.136 mmol, 1.0 equiv) was added to HCl / EA (4 M, 5 mL). The reaction mixture was stirred at 40° C. for 1 h. Then it was concentrated under reduced pressure. 50 mL of NaHCO3(aq) was poured into the residue, extracted with EtOAc (30 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1 / 1) to give the final product 5-(4-(difluoromethoxy)phenyl)-N 3 -(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0397] Synthesis of 4-(4-(difluoromethoxy)phenyl)-N6-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-N3-methylpyridazine-3,6-diamine - compound 544

[0398] [ka] Step a: To a solution of 6-chloro-N-methylpyridazin-3-amine (1.0 g, 7.0 mmol, 1.0 equiv) in AcOH / H2O (5 mL / 5 mL) was added Br2 (3.36 g, 21 mmol, 3.0 equiv), KBr (2.5 g, 21 mmol, 3.0 equiv), and KOAc (1.03 g, 10.5 mmol, 1.5 equiv). The reaction mixture was stirred at 80 °C for 16 h. 100 mL of H2O was poured into the mixture, extracted with EtOAc (35 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA = 5 / 1 to 2 / 1) to give 4-bromo-6-chloro-N-methylpyridazin-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-methylpyridazin-3-amine (400 mg, 1.79 mmol, 1.0 equiv) in THF (7 mL) was added Boc2O (782 mg, 3.59 mmol, 2.0 equiv), TEA (542 mg, 5.37 mmol, 3.0 equiv), and DMAP (22 mg, 0.179 mg, 0.1 equiv). The reaction mixture was stirred at 60° C. for 3 h. 100 mL of H2O was poured into the mixture, extracted with EtOAc (30 mL×3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with (PE / EA=10 / 1) to give tert-butyl (4-bromo-6-chloropyridazin-3-yl)(methyl)carbamate (640 mg, colorless oil). 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 equiv.) in toluene / HO (5 mL / 1 mL), (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 equiv.), KPO (636 mg, 3.0 mmol, 3.0 equiv.), and Pd(dppf)Cl (73 mg, 0.1 mmol, 0.1 equiv.) were added. The reaction mixture was stirred at 110° C. under N for 16 h. Then it was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=3 / 1) to give 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 equiv.) in toluene (5 mL) was added 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (41 mg, 0.18 mmol, 1.0 equiv.), Cs2CO3 (117 mg, 0.36 mmol, 2.0 equiv.), Xantphos (11 mg, 0.018 mmol, 0.1 equiv.), and Pd(dppf)Cl2 (14 mg, 0.018 mmol, 0.1 equiv.). The reaction mixture was stirred at 100° C. under N2 for 16 h. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=2 / 1) to give tert-butyl (4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazin-3-yl)(methyl)carbamate (50 mg, yellow oil). 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-fluoropyrimidin-4-yl)amino)pyridazin-3-yl)(methyl)carbamate (50 mg, 0.087 mmol, 1.0 equiv) was added in HCl / EA (4M, 5 mL). The reaction mixture was stirred at 40° C. for 1 h. Then it was concentrated under reduced pressure. 50 mL of NaHCO3(aq) was poured into the residue, extracted with EtOAc (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=1 / 1) to give 4-(4-(difluoromethoxy)phenyl)-N,N-dimethylmorpholino-4-yl (50 mg, 0.087 mmol, 1.0 equiv). 6-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0399] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylate methyl ester - Compound 616

[0400] [ka] Step a: To a solution of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (2 g, 8.85 mmol, 1.0 equiv), methyl 4,6-dichloropyridazine-3-carboxylate (2.7 g, 13.27 mmol, 1.5 equiv), Xantphos (512 g, 0.88 mmol, 0.1 equiv), and Cs2CO3 (8.6 g, 26.55 mmol, 3.0 equiv) in toluene (20 mL) was added Pd2(dba)3 (810 mg, 0.88 mmol, 0.1 equiv) at room temperature. The reaction mixture was then stirred at 80 °C under N2 for 16 h. The reaction 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 eluting with PE:EA=2:1 to give methyl 4-chloro-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylate (2.05 g, 58%) as a white solid. 1 H 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-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylate (2 g, 5.05 mmol, 1.0 equiv), (4-(difluoromethoxy)phenyl)boronic acid (1.3 g, 7.58 mmol, 1.5 equiv), and K3PO4 (3.2 g, 15.15 mmol, 3.0 equiv) in dioxane / H2O (40 mL / 4 mL) was added Pd(dppf)Cl2 (370 mg, 0.51 mmol, 0.1 equiv) at room temperature. The reaction mixture was then stirred at 110 °C under N2 for 16 h. The reaction 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 eluting with DCM / MeOH=200:1 to give methyl 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0401] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylic acid - compound 562

[0402] [ka] To a solution of methyl 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylate (1.3 g, 2.58 mmol, 1.0 equiv.) in THF / H2O (5 mL / 5 mL) was added LiOH·H2O (433 mg, 10.32 mmol, 4.0 equiv.). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and aqueous 1N HCl (100 mL). The separated organic layer was washed with water, dried over Na2SO4 and evaporated to dryness. The residue was added MeOH (10 mL) and stirred at room temperature for 1 h. The mixture was then filtered and the cake was diluted with MeOH (10 mL x 2) and dried under reduced pressure to give 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0403] Synthesis of 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazin-3-yl)ethan-1-one - Compound 580

[0404] [ka] Step a: To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylic acid (100 mg, 0.2 mmol, 1.0 equiv.) and HATU (93 mg, 0.24 mmol, 1.2 equiv.) in DMF (2 mL), N,O-dimethylhydroxylamine hydrochloride (24 mg, 0.24 mmol, 1.2 equiv.) and DIEA (79 mg, 0.60 mmol, 3.0 equiv.) were added. The mixture was then stirred at room temperature for 16 h. 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 give 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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-fluoropyrimidin-4-yl)amino)-N-methoxy-N-methylpyridazine-3-carboxamide (80 mg, 0.15 mmol, 1.0 equiv.) in THF (1 mL) under N2 was added MeMgBr (0.18 mL, 0.18 mmol, 1.2 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 2 h. Aqueous NH4Cl solution (50 mL) was added to the reaction mixture. 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 give 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazin-3-yl)ethan-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).

[0405] Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)-N-methylpyridazine-3-carboxamide - Compound 634

[0406] [ka] To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylic acid (100 mg, 0.2 mmol, 1.0 equiv.) and HATU (93 mg, 0.24 mmol, 1.2 equiv.) in DMF (2 mL) was added methylamine hydrochloride (17 mg, 0.24 mmol, 1.2 equiv.) and DIEA (79 mg, 0.60 mmol, 3.0 equiv.). The mixture was then stirred at room temperature for 16 h. 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 with DCM / MeOH=20 / 1 to give 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-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).

[0407] Synthesis of N-(5-bromo-2-fluoropyridin-3-yl)-2-chloropyrimidin-4-amine

[0408] [ka] A mixture of 5-bromo-2-fluoropyridin-3-amine (500 mg, 2.6 mmol, 1.0 equiv.), 2,4-dichloropyrimidine (770 mg, 5.2 mmol, 2.0 equiv.) in DIEA (0.5 mL) was stirred at 119° C. for 16 h. DCM (5 mL) was added and the residue was purified by column chromatography on silica gel eluted with (DCM / MeOH=200 / 1 to 50 / 1) to give crude. The crude was purified by preparative TLC (DCM / MeOH=20 / 1) to give N-(5-bromo-2-fluoropyridin-3-yl)-2-chloropyrimidin-4-amine (50 mg crude) as a white solid. LC-MS: [M+1] + :303.05.

[0409] Synthesis of N-(5-bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine

[0410] [ka] A mixture of N-(5-bromo-2-fluoropyridin-3-yl)-2-chloropyrimidin-4-amine (50 mg, 0.17 mmol, 1.0 equiv.), (2R,6S)-2,6-dimethylmorpholine (38 mg, 0.33 mmol, 2.0 equiv.) and DIEA (64 mg, 0.50 mmol, 3.0 equiv.) in IPA (1 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give N-(5-bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (27 mg, crude). LC-MS: [M+1] + :382.15.

[0411] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine - Compound 182

[0412] [ka] To a solution of N-(5-bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (27 mg, 0.07 mmol, 1.0 equiv.), (4-(difluoromethoxy)phenyl)boronic acid (26 mg, 0.14 mmol, 2.0 equiv.), KPO (45 mg, 0.21 mmol, 3.0 equiv.) in dioxane / HO (1 mL / 0.1 mL) was added Pd(dppf)Cl (5 mg, 0.007 mmol, 0.1 equiv.) under N. The reaction mixture was stirred at 110° C. for 16 h under N. It was then concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-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).

[0413] Methods of making and using related compounds are disclosed in PCT / TR2019 / 050164, PCT / TR2019 / 050951, and U.S. Patent No. 63 / 173796, the contents of each of which are incorporated by reference in their entirety herein.

[0414] Example 2: Exemplary Biological Activities of Disclosed Compounds Cell culture and reagents Human breast cancer cell line MDA-MB-231 and 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's medium (Lonza, NJ, USA), and HEC-59 were grown in Iscove'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 routinely tested using the MycoAlert Mycoplasma Detection Kit (Lonza). The cumulative length of time that cells were thawed before use in experiments was less than 20 passages.

[0415] Cell viability assay protocol MDA-MB-231 and HEC-59 cells were seeded in 96-well plates at 4000 cells / well in 80 μL medium / well. After about 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 drug-containing medium was added to each well in a volume of 40 μL. For MDA-MB-231, SRB or CTG assays were performed 3 days after drug treatment. For HEC59, drug-containing medium was refreshed on the 4th day. After a total of 7 days, SRB or CTG assays were performed.

[0416] [Table 2]

[0417] Example 3: Further exemplary biological activities of the disclosed compounds Female athymic Balb / c nude mice, 6-8 weeks of age, were housed in a temperature-controlled 12-h light / 12-h dark cycle environment. For in vivo colon cancer tumor growth, 5 × 10 6 RKO cells were prepared in 100 μl of DMEM and injected into the right flank of female nude mice. Mouse weights and tumor volumes were measured twice a week. Tumor volumes were calculated as length × width. 2 The tumor volume was calculated as 150–175 mm × 0.5. 3 Once tumor size reached 2500 mm, xenografts were randomized and divided into groups (8 mice per group). Animals were treated with vehicle, Compound 80, or oxaliplatin as indicated in the table. Vehicle and Compound 80 formulations were 50% PEG400 and 20% Cremophor RH40 final (50% of 40% Cremophor) in acetate buffer (PH=4). Oxaliplatin was prepared in glucose solution. After approximately 3 weeks or when tumors reached 2500 mm 3 Mice were sacrificed when a pre-defined tumor volume cut-off of 100 mg / kg was reached. Compound 80 demonstrated strong tumor growth inhibition in a dose-dependent manner in RKO xenografts, with a TGI of 85% at the highest dose (Figure 1).

[0418] [Table 3]

[0419] 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, 1.5×10 cells were cultured in 200 μl of 1:1 DMEM:Matrigel (Thermo Fisher, NJ, USA). 7 For MDA-MB-231 xenografts, 1. × 10 SKOV-3 cells were cultured at 1. × 10 in 100 μl of 1:1 DMEM:Matrigel (Thermo Fisher, NJ, USA). 7 MDA-MB-231 cells were injected into the right flank of 6- to 8-week-old female athymic Balb / c nude mice. Tumor volumes averaged approximately 200 mm for SKOV-3 xenografts.3 When the mice reached 150–175 mm for MDA-MB-231 xenografts, 3 When the mice reached 1.0 μg / mL, they were randomized into groups of 8 and treatment was initiated with vehicle, 20 mpk BID, 25 mpk BID, and 30 mpk BID of Compound 80. For HEC-59 xenografts, 1. × 10 7 HEC-59 cells were injected into the right flank of 6- to 8-week-old female athymic Balb / c nude mice. Tumor volumes averaged approximately 150 mm. 3 When mice were reached, they were randomized into groups of 8 mice and treatment was initiated with vehicle, 20mpk BID, 40mpk QD, and 30 / 40mpk BID of Compound 80. Statistically significant tumor growth inhibition or regression was observed.

[0420] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including definitions herein, will control.

[0421] Equivalent Although specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

1. A compound having the structure represented by formula I, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 During the ceremony, E and B are each independently an aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, A is a six-membered heteroaryl compound, R １ is H, alkyl, or benzyl.

2. The compound according to claim 1, wherein A is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

3. R １ The compound according to claim 1, wherein the compound is H or alkyl (for example, methyl or ethyl).

4. The compound according to claim 1, wherein B is a heteroaryl compound (e.g., pyridinyl, pyrimidinyl, or triazinyl).

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula IIIa, formula IIIb, or formula IIIc. 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 During the ceremony, E is an aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, X 5 is N or CR 8, X 6 is N or CR 9, R1 is H, alkyl, or benzyl. R2, R3, R4, R5, R6, R7, R8, and R9 are each independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, cycloalkyl, alkylsulfonyl, or sulfonamide.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula IVa, formula IVb, formula IVc, formula IVd, or formula IVe. 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 During the ceremony, E is an aryl, heteroaryl, or heterocyclyl. D is an amino or heterocycline, R1 is H, alkyl, or benzyl. R2, R3, R4, R5, R6, and R7 are each independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, cycloalkyl, alkylsulfonyl, or sulfonamide.

7. The compound according to claim 1, wherein D is an N-linked heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxydethiomorpholinyl, azabicyclooctanil, oxazabicyclooctane, hexahydroflopyrrolyl, or azabicyclohexanil) or an amino (e.g., NH2), or an alkylamino (e.g., dimethylamino, diethylamino, or methylethylamino).

8. D has a structure represented by formula V, 【Chemistry 10】 During the ceremony, R １０ａ and R １０ｂ The compound according to claim 1, 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, cycloalkyl, alkylsulfonyl, and sulfonamide.

9. D is 【Chemistry 11】 The compound according to claim 1.

10. The compound according to claim 1, wherein E is an aryl (e.g., phenyl, dihydrobenzofuran, or benzodioxol) or a heteroaryl (e.g., pyridinyl, pyrazinyl, benzofuranil, or benzodioxyl).

11. E has a structure represented by formula VIa, VIb, or VIc, 【Chemistry 12】 During the ceremony, R １１ａ and R １１ｂ The compound according to claim 1, 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, cycloalkyl, alkylsulfonyl, and sulfonamide.

12. R １１ａ The compound according to claim 11, wherein the compound is difluoromethioxy.

13. E is, 【Chemistry 13】 The compound according to claim 1.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by VIIa or VIIb. 【Chemistry 14】 During the ceremony, R ４ and R ７ are each independently H, alkyl, alkenyl, alkynyl, halo, hydroxyl, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, cycloalkyl, alkylsulfonyl, or sulfonamide, R １０ａ and R １０ｂ Each of these is independently H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, cycloalkyl, alkylsulfonyl, and sulfonamide. R １１ａ These are hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azide, alkylthio, cycloalkyl, alkylsulfonyl, or sulfonamide.

15. The aforementioned compound, 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

16. The compound is 【Transformation 38】 The compound according to claim 1.

17. The compound is 【Chemistry 39】 The compound according to claim 1.

18. The compound is 【Chemistry 40】 The compound according to claim 1.

19. The compound is 【Chemistry 41】 The compound according to claim 1.

20. The compound is 【Chemistry 42】 The compound according to claim 1.

21. The compound is 【Chemistry 43】 The compound according to claim 1.

22. The compound is 【Chemistry 44】 The compound according to claim 1.

23. The compound is 【Chemistry 45】 The compound according to claim 1.

24. The compound is 【Chemistry 46】 The compound according to claim 1.

25. The compound is 【Chemistry 47】 The compound according to claim 1.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26, for use in the treatment of a disease or disorder characterized by dysregulation of TACC, or a disease or disorder related to TACC.

28. The pharmaceutical composition according to claim 27, wherein the disease or disorder is cancer.

29. The pharmaceutical composition according to claim 28, wherein the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia, kidney cancer, prostate cancer, esophageal cancer, endometrial cancer, pancreatic cancer, or head and neck cancer.

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