Compositions and methods for treating cancer

Abstract

The present invention relates to compositions and methods for treating cancer. Inhibitors of TACC and methods of treating certain diseases and disorders (e.g., diseases and disorders associated with TACC) are disclosed.

Description

[0001] This application is a divisional application of the invention patent application with the Chinese patent application number 202380041923.9 and the invention title "Compositions and Methods for Treating Cancer", which is the Chinese national phase entry of the PCT international application PCT / US2023 / 016132 filed on March 23, 2023 and entered the Chinese national phase on November 21, 2024.

[0002] Related Applications

[0003] This application claims the priority of U.S. Provisional Application No. 63 / 323,339, filed on March 24, 2022; the content of which is incorporated herein by reference in its entirety. Technical Field

[0004] The present invention relates to compositions and methods for treating cancer. Background Art

[0005] Cancer is a complex disease characterized by uncontrolled cell division. In the United States, among cancer types, breast cancer, lung cancer, and colorectal cancer account for 50% of all cases in women, while prostate cancer, lung cancer, and colorectal cancer account for 46% of all newly diagnosed cases in men (Siegel et al., 2021). In addition, many of the available treatment methods have many drawbacks and limited efficacy, thus requiring a variety of new cancer treatment methods. Summary of the Invention

[0006] In one aspect, the present disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein,

[0009] E and B are each independently aryl, heteroaryl, or heterocyclyl;

[0010] D is amino or heterocyclyl;

[0011] A is a six-membered heteroaryl; and

[0012] R 1 is H, alkyl, or benzyl.

[0013] In some embodiments, A is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, A is pyridyl. In some embodiments, A is pyridazinyl.

[0014] In some embodiments, the compound is represented by formula Ia or a pharmaceutically acceptable salt thereof:

[0015]

[0016] wherein,

[0017] E and B are each independently aryl, heteroaryl or heterocyclic group;

[0018] D is amino or heterocyclic group;

[0019] X 1 is N or CR 2 ;

[0020] X 2 is N or CR 3 ;

[0021] X 3 is N or CR 4 ;

[0022] X 4 is N or CR 5 ;

[0023] R 1 is H, alkyl or benzyl; and

[0024] R 2 、R 3 、R 4 and R 5 are each independently H, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl or sulfonamido.

[0025] In some embodiments, the compound is represented by formula IIb or a pharmaceutically acceptable salt thereof:

[0026]

[0027] In some embodiments, R 3 is halogen (e.g., fluorine).

[0028] In some embodiments, the compound is represented by formula IIb or a pharmaceutically acceptable salt thereof:

[0029]

[0030] In some embodiments, R 4 is halogen (e.g., fluorine). In some embodiments, R 4 is hydroxy or alkoxy (e.g., methoxy).

[0031] In some embodiments, the compound is represented by Formula IIc or a pharmaceutically acceptable salt thereof:

[0032]

[0033] In some embodiments, R 2 is H, alkyl (such as methyl or ethyl), halogen (such as chlorine), hydroxy, alkoxy (such as methoxy), amino (such as aminoalkyl, such as methylamino), amido (such as N-methylamido), acetyl, carboxy or ester (such as methyl ester). In some embodiments, R 2 is halogen (such as fluorine). In some embodiments, R 2 is H.

[0034] In some embodiments, R 5 is H or alkyl (such as methyl). In some embodiments, R 5 is H.

[0035] In some embodiments, R 1 is H. In some embodiments, R 1 is alkyl (such as methyl or ethyl).

[0036] In some embodiments, B is heteroaryl (such as pyridyl, pyrimidinyl or triazinyl). In some embodiments, B is pyrimidinyl.

[0037] In some embodiments, B is substituted by at least one R 4 and each R 4 is independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido.

[0038] In some embodiments, B is substituted by at least one R 4 and each R 4 is independently selected from alkyl (such as methyl), oxo and halogen (such as chlorine or fluorine).

[0039] In some embodiments, B is substituted by 1 or 2 R 4 groups.

[0040] In some embodiments, the compound is represented by Formula Ia or a pharmaceutically acceptable salt thereof:

[0041]

[0042] wherein,

[0043] E and B are each independently aryl, heteroaryl or heterocyclyl;

[0044] D is an amino group or a heterocyclic group;

[0045] X 1 Is N or CR 2 ;

[0046] X 2 Is N or CR 3 ;

[0047] X 3 Is N or CR 4 ;

[0048] X 4 Is N or CR 5 ;

[0049] X 5 Is N or CR 8 ;

[0050] X 6 Is N or CR 9 ;

[0051] R 1 is H, alkyl or benzyl; and

[0052] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 Each is independently H, alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amide, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfone or sulfonamide.

[0053] In some embodiments, the compound is represented by Formula IIIa or is a pharmaceutically acceptable salt thereof:

[0054]

[0055] In some embodiments, the compound is represented by Formula IIIb or is a pharmaceutically acceptable salt thereof:

[0056]

[0057] In some embodiments, the compound is represented by Formula IIIc or is a pharmaceutically acceptable salt thereof:

[0058]

[0059] In some embodiments, X 5 is CR 8 .

[0060] In some embodiments, R 8 is H or a halogen (e.g., fluorine).

[0061] In some embodiments, X 5 is N.

[0062] In some embodiments, X 6 is CR 9 .

[0063] In some embodiments, R 9 is H or a halogen (e.g., fluorine).

[0064] In some embodiments, X 6 is N.

[0065] In some embodiments, the compound is represented by Formula IVa or a pharmaceutically acceptable salt thereof:

[0066]

[0067] In some embodiments, the compound is represented by Formula IVb or a pharmaceutically acceptable salt thereof:

[0068]

[0069] In some embodiments, the compound is represented by Formula IVc or a pharmaceutically acceptable salt thereof:

[0070]

[0071] In some embodiments, the compound is represented by Formula IVd or a pharmaceutically acceptable salt thereof:

[0072]

[0073] In some embodiments, the compound is represented by Formula IVd or a pharmaceutically acceptable salt thereof:

[0074]

[0075] In some embodiments, R 6 is H, hydroxy, oxo, a halogen (e.g., fluorine), an alkyl (e.g., methyl, a hydroxyalkyl such as hydroxymethyl, or an alkoxyalkyl such as methoxyethyl), or an alkoxy (e.g., methoxy). In some embodiments, R 6 is H. In some embodiments, R 6 is a halogen (e.g., fluorine).

[0076] In some embodiments, R 7 is H, alkyl (such as methyl), halogen (such as fluorine), acyl (such as acetyl), or amido (such as formamido). In some embodiments, R 7 is halogen (such as fluorine).

[0077] In some embodiments, D is an N-linked heterocyclic group (such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azabicyclooctyl, oxazabicyclooctane, hexahydrofuropyrrolyl, or azabicyclohexyl).

[0078] In some embodiments, D is amino (such as NH 2 or alkylamino, such as dimethylamino, diethylamino, or methylethylamino).

[0079] In some embodiments, D is substituted by at least one R 10 and each R 10 is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or D is substituted by at least two R 5 and two of the R 5 combine to complete a bicyclic heterocyclic group.

[0080] In some embodiments, D is substituted by at least one R 10 and each R 10 is independently selected from alkyl (such as methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), halogen (such as fluorine), cycloalkyl (such as cyclopropyl or cyclobutyl), or heterocyclic group (such as oxetanyl).

[0081] In some embodiments, D is substituted by 1 or 2 R 10 groups.

[0082] In some embodiments, D has a structure represented by formula V:

[0083]

[0084] wherein,

[0085] R 10a and R 10b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0086] In some embodiments, R 10a is alkyl (such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl), halogen (such as fluorine), cycloalkyl (such as cyclopropyl or cyclobutyl) or heterocyclic group (such as oxetanyl). In some embodiments, R 10a is methyl.

[0087] In some embodiments, R 10b is alkyl (such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl), halogen (such as fluorine), cycloalkyl (such as cyclopropyl or cyclobutyl) or heterocyclic group (such as oxetanyl). In some embodiments, R 10b is methyl.

[0088] In some embodiments, D is

[0089]

[0090] In some embodiments, E is aryl (such as phenyl, dihydrobenzofuran or benzodioxole). In some embodiments, E is phenyl. In some embodiments, E is heteroaryl (such as pyridyl, pyrazinyl, benzofuranyl or benzodioxolyl).

[0091] In some embodiments, E is substituted by at least one R 11 and each R 11 is independently selected from alkyl and alkyl, alkenyl, alkynyl, halogen, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido.

[0092] In some embodiments, E is substituted by at least one R 11 and each R 11 is independently selected from alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), hydroxyl, halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl) and hydroxyl.

[0093] In some embodiments, E is substituted by 1 R 11 In some embodiments, E is substituted by 2 R 11 In some embodiments, E is substituted by 3 R 11Substituted.

[0094] In some embodiments, E has a structure represented by Formula VIa, VIb, or VIc:

[0095]

[0096]

[0097] wherein,

[0098] R 11a and R 11b are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0099] In some embodiments, E has a structure represented by Formula VIa:

[0100]

[0101] In some embodiments, E has a structure represented by Formula VIb:

[0102]

[0103] In some embodiments, E has a structure represented by Formula VIc:

[0104]

[0105]

[0106] In some embodiments, R 11a is selected from alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl), and hydroxy. In some embodiments, R 11a is difluoromethoxy.

[0107] In some embodiments, R 11b is selected from alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl), and hydroxy.

[0108] In some embodiments, E is

[0109] In some embodiments, the compound is represented by Formula VIIa, VIIb or a pharmaceutically acceptable salt thereof:

[0110]

[0111] wherein,

[0112] R 4 and R 7 are each independently H, alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl

[0113] or sulfonamide;

[0114] R 10a and R 10b are each H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamide; and

[0115] R 11a is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl or sulfonamido.

[0116] In some embodiments, the compound has a structure represented by Formula VIIa or a pharmaceutically acceptable salt thereof:

[0117]

[0118] In some embodiments, R 4 is alkyl (such as methyl), oxo or halogen (such as chlorine or fluorine). In some embodiments, R 4 is halogen (such as chlorine or fluorine).

[0119] In some embodiments, the compound has a structure represented by Formula VIIa or a pharmaceutically acceptable salt thereof:

[0120]

[0121] In some embodiments, R 7is H, alkyl (such as methyl), halogen (such as fluorine), acyl (such as acetyl), or amide (such as methylamide). In some embodiments, R 7 is halogen (such as fluorine).

[0122] In some embodiments, R 10a is alkyl (such as methyl).

[0123] In some embodiments, R 10b is alkyl (such as methyl).

[0124] In some embodiments, R 11a is alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), hydroxy, halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl), and hydroxy.

[0125] In some embodiments, R 11a is difluoromethyl. In some embodiments, the compounds are selected from:

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] or a pharmaceutically acceptable salt thereof.

[0148] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0149] 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 pharmaceutically acceptable salt thereof.

[0150] In yet another aspect, the present disclosure provides a method of treating a disease or disorder characterized by TACC dysregulation in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0151] In yet another aspect, the present disclosure provides a method of treating a disease or disorder associated with TACC in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, TACC is TACC1.

[0153] In some embodiments, TACC is TACC2.

[0154] In some embodiments, TACC is TACC3.

[0155] In some embodiments, the disease or disorder mediated by TACC is cancer.

[0156] 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 pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia, kidney cancer, or prostate cancer.

[0158] In some 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0159] Figure 1 Shows the exemplary biological activity of the exemplary compounds of the present disclosure. Compared to the standard of care, Compound 80 shows excellent tumor growth inhibitory effects in xenograft models. DETAILED DESCRIPTION

[0160] Transforming acidic coiled-coil proteins (TACCs) are emerging as important proteins for microtubule- and centrosome-related functions. Vertebrates exhibit three distinct TACC isoforms: TACC1, TACC2, and TACC3. TACCs play key 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). Each member shares a conserved domain, called the TACC domain, which is essential for the interaction of TACC proteins with the spindle and centrosome apparatus (Gergely et al., 2000). Although TACC family members are described as centrosomal proteins, they are also distributed throughout the cell during interphase. For example, TACC3 and TACC2 form complexes with different histone acetyltransferases, including hGCN5L2 and pCAF, showing their regulatory functions in transcription (Gangisetty et al., 2004). Notably, TACC3 interacts with MBD2 (methyl-CpG binding domain 2) in the interphase nucleus, promoting the binding of MBD2 to histone acetyltransferases to reactivate methylated promoters.

[0161] TACC protein levels are elevated in many cancer types, including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, and breast cancer, etc. TACC1, the first member of the TACC family, was independently discovered as a breast cancer amplicon 8p11 (Still et al., 1999), and was later found to potentially promote breast tumorigenesis by activating the Ras / PI3K signaling pathway (Cully et al., 2005). TACC2 has been found to promote androgen-mediated prostate cancer growth and is associated with poor prognosis (Takayama et al., 2012). In addition, overexpression of TACC2 leads to the proliferation of breast cancer cells (Cheng et al., 2010). Disruption of TACC3 also results in a series of different cellular outcomes, including the formation of multipolar spindles that cause mitotic arrest (Yao et al., 2012), chromosomal misalignment that causes caspase-dependent apoptosis (Schneider et al., 2007), and senescence in some cases (Schmidt et al., 2010). In addition, knockdown of TACC3 inhibits the tumorigenesis and cell growth of renal cell carcinoma (RCC) (Guo & Liu, 2018). The above studies show that the TACC protein family is a key molecule involved in the spindle assembly of cancer cells, making it an important and potential target for cancer targeted therapy.

[0162] However, to date, there are no available TACC1 and TACC2 inhibitors, and there are only two inhibitors targeting TACC3. KHS101 is a small molecule TACC3 inhibitor that was first discovered to promote neuronal differentiation in rats (Wurdak et al., 2010). Although treatment with KHS101 inhibits the tumor growth of glioblastoma (GBM) xenografts (Polson et al., 2018), KHS101 has many drawbacks, such as low oral systemic stability and high working doses (Wurdak et al., 2010). Another TACC3 inhibitor, SPL-B, has been shown to inhibit centrosomal microtubule nucleation in multiple ovarian cancer cells and inhibit tumor growth in ovarian cancer xenografts (Yao et al., 2014). However, like KHS101, SPL-B has not been approved for the treatment of cancer.

[0163] In view of the above, there is an obvious unmet need for novel TACC inhibitors for the treatment of cancer and other TACC-mediated diseases.

[0164] In one aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0165]

[0166] Wherein,

[0167] E and B are each independently an aryl, heteroaryl or heterocyclic group;

[0168] D is an amino group or a heterocyclic group;

[0169] A is a six-membered heteroaryl; and

[0170] R 1 is H, an alkyl group or a benzyl group.

[0171] In certain embodiments, A is pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl. In certain preferred embodiments, A is pyridyl. In a plurality of other preferred embodiments, A is pyridazinyl.

[0172] In certain embodiments, the compound is represented by Formula Ia or a pharmaceutically acceptable salt thereof:

[0173]

[0174] Wherein,

[0175] E and B are each independently an aryl, heteroaryl or heterocyclic group;

[0176] D is an amino group or a heterocyclic group;

[0177] X 1 is N or CR 2 ;

[0178] X 2 is N or CR 3 ;

[0179] X 3 is N or CR 4 ;

[0180] X 4 is N or CR 5 ;

[0181] R 1 is H, an alkyl group or a benzyl group; and

[0182] R 2 、R 3 、R 4 and R 5Each independently is H, alkyl, alkenyl, alkynyl, halogen, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl or sulfonamido.

[0183] In certain embodiments, the compound is represented by Formula IIb or a pharmaceutically acceptable salt thereof:

[0184]

[0185] In certain preferred embodiments, R 3 is halogen (such as fluorine).

[0186] In certain embodiments, the compound is represented by Formula IIb or a pharmaceutically acceptable salt thereof:

[0187]

[0188] In certain preferred embodiments, R 4 is halogen (such as fluorine). In other embodiments, R 4 is hydroxyl or alkoxy (such as methoxy).

[0189] In certain embodiments, the compound is represented by Formula IIc or a pharmaceutically acceptable salt thereof:

[0190]

[0191] In certain embodiments, R 2 is H, alkyl (such as methyl or ethyl), halogen (such as chlorine), hydroxyl, alkoxy (such as methoxy), amino (such as aminoalkyl, like methylamino), amido (such as N-methylamido), acetyl, carboxyl or ester (such as methyl ester). In certain preferred embodiments, R 2 is halogen (such as fluorine). In other preferred embodiments, R 2 is H.

[0192] In certain embodiments, R 5 is H or alkyl (such as methyl). In certain preferred embodiments, R5 is H.

[0193] In certain embodiments, R 1 is H. In certain embodiments, R 1 is alkyl (such as methyl or ethyl).

[0194] In certain embodiments, B is heteroaryl (such as pyridyl, pyrimidinyl or triazinyl). In certain preferred embodiments, B is pyrimidinyl.

[0195] In certain embodiments, B is substituted by at least one R 4 and each R 4 is independently selected from alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido. In certain embodiments, B is substituted by at least one R 4 and each R 4 is independently selected from alkyl (such as methyl), oxo and halogen (such as chlorine or fluorine). In certain preferred embodiments, B is substituted by 1 or 2 R 4 groups.

[0196] In certain embodiments, the compound is represented by Formula Ia or a pharmaceutically acceptable salt thereof:

[0197]

[0198] wherein,

[0199] E and B are each independently aryl, heteroaryl or heterocyclic group;

[0200] D is amino or heterocyclic group;

[0201] X 1 is N or CR 2 ;

[0202] X 2 is N or CR 3 ;

[0203] X 3 is N or CR 4 ;

[0204] X 4 is N or CR 5 ;

[0205] X 5 is N or CR 8 ;

[0206] X 6 is N or CR9 ;

[0207] R 1 is H, alkyl or benzyl; and

[0208] R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently H, alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl or sulfonamido.

[0209] In certain embodiments, the compound is represented by Formula IIIa or a pharmaceutically acceptable salt thereof:

[0210]

[0211] In certain embodiments, the compound is represented by Formula IIIb or a pharmaceutically acceptable salt thereof:

[0212]

[0213] In certain embodiments, the compound is represented by Formula IIIc or a pharmaceutically acceptable salt thereof:

[0214]

[0215] In certain embodiments, X 5 is CR 8 .

[0216] In certain embodiments, R 8 is H or halogen (e.g., fluorine). In certain preferred embodiments, R 8 is fluorine.

[0217] In certain embodiments, X 5 is N.

[0218] In certain embodiments, X 6 is CR 9 . In certain embodiments, X 6 is N.

[0219] In certain embodiments, R 9 is H or halogen (e.g., fluorine). In certain preferred embodiments, R 9 is fluorine.

[0220] In certain embodiments, the compound is represented by Formula IVa or a pharmaceutically acceptable salt thereof:

[0221]

[0222] In certain embodiments, the compound is represented by Formula IVb or a pharmaceutically acceptable salt thereof:

[0223]

[0224] In certain embodiments, the compound is represented by Formula IVc or a pharmaceutically acceptable salt thereof:

[0225]

[0226] In certain embodiments, the compound is represented by Formula IVd or a pharmaceutically acceptable salt thereof:

[0227]

[0228] In certain embodiments, the compound is represented by Formula IVe or a pharmaceutically acceptable salt thereof:

[0229]

[0230] In certain embodiments, R 6 is H, hydroxy, oxo, halogen (e.g., fluorine), alkyl (e.g., methyl, hydroxyalkyl such as hydroxymethyl, or alkoxyalkyl such as methoxyethyl), or alkoxy (e.g., methoxy). In certain preferred embodiments, R 6 is halogen (e.g., fluorine). In other preferred embodiments, R 6 is H.

[0231] In certain embodiments, R 7 is H, alkyl (e.g., methyl), halogen (e.g., fluorine), acyl (e.g., acetyl), or amido (e.g., formamido). In certain preferred embodiments, R 7 is halogen (e.g., fluorine).

[0232] In certain embodiments, D is an amino group. In certain embodiments, D is an N-linked heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidethiomorpholinyl, azabicyclooctanyl, oxaazabicyclooctane, hexahydrofuropyrrolyl or azabicyclohexanyl).

[0233] In certain embodiments, D is substituted by at least one R 10 and each R 10 is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido; or D is substituted by at least two R 5 and two of the R 5 combine to complete a bicyclic heterocyclic group.

[0234] In certain embodiments, D is substituted by at least one R 10 and each R 10 is independently selected from alkyl (e.g., methyl, fluoromethyl, difluoromethyl or trifluoromethyl), halogen (e.g., fluorine), cycloalkyl (e.g., cyclopropyl or cyclobutyl) or heterocyclic group (e.g., oxetanyl). In certain embodiments, D is substituted by 1 or 2 R 10 . In certain preferred embodiments, D is substituted by 2 R 10 .

[0235] In certain embodiments, D has the structure represented by Formula V or a pharmaceutically acceptable salt thereof:

[0236]

[0237] wherein,

[0238] R 10a and R 10b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido.

[0239] In certain embodiments, R 10a is alkyl (such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl), halogen (such as fluorine), cycloalkyl (such as cyclopropyl or cyclobutyl) or heterocyclic group (such as oxetanyl). In certain preferred embodiments, R 10a is methyl.

[0240] In certain embodiments, R 10b is alkyl (such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl), halogen (such as fluorine), cycloalkyl (such as cyclopropyl or cyclobutyl) or heterocyclic group (such as oxetanyl). In certain preferred embodiments, R 10b is methyl.

[0241] In certain preferred embodiments, D is

[0242] In certain embodiments, D is In certain embodiments, D is In a more preferred embodiment, D is In another more preferred embodiment, D is In another more preferred embodiment, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is In certain embodiments, D is

[0243] 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., pyridyl, pyrazinyl, benzofuranyl, or benzodioxolyl). In certain preferred embodiments, E is pyridyl. In other preferred embodiments, E is pyrazinyl.

[0244] In certain embodiments, E is substituted by at least one R 11 and each R 11 is independently selected from alkyl and alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azide, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido. In certain embodiments, E is substituted by at least one R 6 and each R 11 is independently selected from alkyl (e.g., deuterated alkyl, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, or difluoroethyl), alkoxy (e.g., deuterated alkoxy, methoxy, ethoxy, fluoromethoxy, difluoromethoxy, or trifluoromethoxy), alkylthio (e.g., methylthio), amino (e.g., dimethylamino), hydroxy, halogen (e.g., fluorine or chlorine), cyano, heterocyclic group (e.g., azetidinyl), and hydroxy.

[0245] In certain preferred embodiments, E is substituted by 1 R 11 In other preferred embodiments, E is substituted by 2 R's 11 In still other embodiments, E is substituted by 3 R's 11 substituted.

[0246] In certain embodiments, E has a structure represented by Formula VIa, VIb, or VIc:

[0247]

[0248] wherein,

[0249] R11a and R 11b are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl and sulfonamido.

[0250] In certain embodiments, E has the structure represented by Formula VIa:

[0251]

[0252] In certain embodiments, E has the structure represented by Formula VIb:

[0253]

[0254] In certain embodiments, E has the structure represented by Formula VIc:

[0255]

[0256] In certain embodiments, R 11a is selected from alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl) and hydroxy. In certain preferred embodiments, R 11a is difluoromethoxy.

[0257] In certain embodiments, R 11b is selected from alkyl (such as deuterated alkyl, methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl or difluoroethyl), alkoxy (such as deuterated alkoxy, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy), alkylthio (such as methylthio), amino (such as dimethylamino), halogen (such as fluorine or chlorine), cyano, heterocyclic group (such as azetidinyl) and hydroxy.

[0258] In certain preferred embodiments, E is

[0259] In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain preferred embodiments, E is In even more preferred embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is

[0260] In certain embodiments, the compound is represented by Formula VIIa, VIIb or a pharmaceutically acceptable salt thereof:

[0261]

[0262] Wherein,

[0263] R 4 and R 7 are each independently H, alkyl, alkenyl, alkynyl, halogen, hydroxy, oxo, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl or sulfonamide;

[0264] R 10a and R 10b is each independently H, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamide; and

[0265] R 11a is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamido.

[0266] In certain embodiments, the compound is represented by Formula VIIa or a pharmaceutically acceptable salt thereof:

[0267]

[0268] In certain embodiments of Formula VIIa, R 4 is alkyl (e.g., methyl), oxo, or halogen (e.g., chlorine or fluorine). In certain preferred embodiments of Formula VIIa, R 4 is halogen (e.g., chlorine or fluorine).

[0269] In certain embodiments, the compound is represented by Formula VIIb or a pharmaceutically acceptable salt thereof:

[0270]

[0271] In certain embodiments of Formula VIIb, R 7 is H, hydroxy, oxo, alkyl (e.g., methyl), halogen (e.g., fluorine), acyl (e.g., acetyl), or amido (e.g., methylamido). In certain embodiments of Formula VIIb, R 7 is H, alkyl (e.g., methyl), halogen (e.g., fluorine), acyl (e.g., acetyl), or amido (e.g., methylamido). In certain preferred embodiments of Formula VIIb, R 7 is halogen (e.g., fluorine).

[0272] In certain preferred embodiments of Formula VIIa or VIIb, R 10a is alkyl (e.g., methyl).

[0273] In certain preferred embodiments of Formula VIIa or VIIb, R 10b is alkyl (e.g., methyl).

[0274] In certain embodiments of Formula VIIa or VIIb, R 11ais an alkyl group (such as a deuterated alkyl group, methyl, ethyl, butyl, isopropyl, fluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl or difluoroethyl), an alkoxy group (such as a deuterated alkoxy group, methoxy, ethoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy), an alkylthio group (such as methylthio), an amino group (such as dimethylamino), a hydroxyl group, a halogen (such as fluorine or chlorine), a cyano group, a heterocyclic group (such as azetidinyl) and a hydroxyl group. In certain preferred embodiments of Formula VIIa or VIIb, R 11a is difluoromethyl.

[0275] In certain embodiments, the compound is selected from the compounds listed in Table 1 or a pharmaceutically acceptable salt thereof:

[0276] Table 1: Exemplary Compounds of the Present Disclosure

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300] Some of the compounds disclosed herein may also exist in multiple tautomeric forms. Such forms, while not explicitly depicted in the formulas described herein, are intended to be included within the scope of the present disclosure.

[0301] The present disclosure also encompasses all suitable isotopic variants of the compounds of the present disclosure. Isotopic variants of the compounds of the present disclosure are defined as those in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass typically or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 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. Accordingly, unless otherwise indicated, the term “hydrogen” or “H” shall be understood to include 1 H (protium), 2 H (deuterium) and 3 H (tritium). Certain isotopic variants of the compounds of the present disclosure, such as those incorporating one or more radioactive isotopes such as 3 H or 14 C, can be used in drug and / or substrate tissue distribution studies. Tritiated isotopes and carbon-14, namely 14C isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with multiple isotopes such as deuterium can provide certain therapeutic advantages that result from higher metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may thus be preferred in some cases. Such variants may also have favorable optical properties, for example, due to multiple changes in multiple vibrational modes caused by the heavier isotopes. Isotope variants of the compounds of the present invention can generally be prepared by conventional procedures known to those of ordinary skill in the art, such as by the illustrative methods or by using appropriate isotope variants of suitable reagents for the preparations described in the examples below.

[0302] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0303] In yet another aspect, the present 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 pharmaceutically acceptable salt thereof.

[0304] In yet another aspect, the present disclosure provides a method of treating a disease or disorder characterized by TACC dysregulation in a subject, the method comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0305] In certain embodiments, TACC is TACC1. In other embodiments, TACC is TACC2. In other preferred embodiments, TACC is TACC3.

[0306] 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, kidney 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.

[0307] 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 pharmaceutically acceptable salt thereof. In certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia, kidney 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.

[0308] Pharmaceutical Composition

[0309] The compositions and methods of the present invention can be used to treat an individual in need. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition, which comprises, for example, a 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 physiological 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, especially for invasive routes of administration (i.e., routes that bypass the epithelial barrier for transport or diffusion, such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to affect the delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in the form of dosage units, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized agents for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as a skin patch. The composition can also be present in a solution suitable for topical application, such as a lotion, cream, or ointment.

[0310] The pharmaceutically acceptable carrier can comprise physiologically acceptable agents, which, for example, serve to stabilize, increase solubility, or increase the absorption of the compound, such as a 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 the pharmaceutically acceptable carrier (including the physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can also be a liposome or other polymeric matrix, in which, for example, a 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 their preparation and administration are relatively simple.

[0311] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0312] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can be used as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (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) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0313] The pharmaceutical compositions (formulations) can be administered to a subject by any of the routes of administration, including, for example, orally (e.g., as a rinse, tablet, capsule (including sprinkle capsules and gelatin capsules), bolus, powder, granule, paste for the tongue in an aqueous or non-aqueous solution or suspension); by buccal mucosa absorption (e.g., sublingually); subcutaneously; transdermally (e.g., as a patch for the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and the compositions suitable for them 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.

[0314] The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well-known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host to be 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 the amount of the compound that produces a therapeutic effect. Generally, on a weight-for-weight basis, the amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, and most preferably from about 10% to about 30%.

[0315] The methods of preparing these formulations or compositions include the step of bringing together the active compound, such as a compound of the present disclosure, with the carrier and, optionally, one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing together the compound of the invention with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0316] The formulations of the invention suitable for oral administration can be in the form of capsules (including spouted capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as tablets (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and / or as a mouthwash, etc., each containing a predetermined amount of the compound of the invention as an active ingredient. The compositions or compounds can also be administered as boluses, electuaries or pastes.

[0317] For the preparation of solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or calcium hydrogen phosphate, and / or with any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution blockers, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0318] Tablets can be made by compression or molding, optionally with the use of one or more accessory ingredients. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or croscarmellose sodium), surfactants or dispersing agents. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0319] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide slow or controlled release of the active ingredient, for example, using different proportions of hydroxypropyl methylcellulose to provide the desired release profile, other polymeric matrices, liposomes, and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter or by the addition immediately prior to use of a sterilizing agent in the form of a sterile solid composition soluble in sterile water or some other sterile injectable medium. These compositions may also optionally contain opacifying agents and may be compositions that release the active ingredient only or preferably in a particular part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. If appropriate, the active ingredient may also be in microencapsulated form together with one or more of the above excipients.

[0320] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing agents, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid ester of sorbitan, and mixtures of the foregoing.

[0321] In addition to the inert diluent, oral compositions may also include adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives.

[0322] In addition to the active compound, suspensions may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0323] Dosage forms for topical or percutaneous administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compounds can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants as may be required.

[0324] In addition to the active compound, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0325] In addition to the active compound, powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbons and unsubstituted volatile hydrocarbons such as butane and propane.

[0326] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Penetration enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0327] As used herein, the phrases "parenteral administration" and "parenterally administering" refer to modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise a combination of one or more active compounds with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions before use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0328] Examples of suitable aqueous and non-aqueous carriers for the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0329] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. By including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid, etc., the action of microorganisms can be ensured to be prevented. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, the absorption of injectable pharmaceutical forms can be prolonged by including absorption delaying agents such as aluminum monostearate and gelatin.

[0330] In some cases, in order to prolong the effect of the drug, it is necessary to slow down the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The absorption rate of the drug depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, the delayed absorption of parenterally administered pharmaceutical forms is achieved by dissolving or suspending the drug in an oil carrier.

[0331] Injectable depot forms are prepared by forming a microencapsulation matrix of the compounds of the present invention in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled according to the ratio of the drug to the polymer and the nature of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Depot injectable formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0332] For use in the methods of the present invention, the active compound can be administered per se or as a pharmaceutical composition containing, for example, from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0333] The introduction method can also be provided by a refillable or biodegradable device. In recent years, various sustained-release polymer devices have been developed and tested in vivo for the controlled delivery of drugs, including protein biopharmaceuticals. Biocompatible polymers (including hydrogels) including biodegradable and non-biodegradable polymers can be used to form implants for the sustained release of compounds at specific target sites.

[0334] The actual dosage level of the active ingredient in the pharmaceutical composition can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0335] The selected dosage level will depend on factors including the activity of the specific compound or combination of compounds or their esters, salts or amides used, the route of administration, the time of administration, the excretion rate of the specific compound being used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific compound being used, the age, sex, weight, medical condition, general health and medical history of the patient being treated, and similar factors well known in the medical arts.

[0336] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the required pharmaceutical composition. For example, the physician or veterinarian can start with a level of the pharmaceutical composition or compound below the level required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" means a concentration of the compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary according to the weight, sex, age and medical history of the subject. Other factors that can affect the effective amount can include, but are not limited to, the severity of the patient's medical condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered in combination with the compounds of the present invention. Larger total doses can be delivered by multiple administrations. Methods for determining efficacy and dosage are known to those of ordinary skill in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th ed., 1814 - 1882, incorporated herein by reference).

[0337] Generally, the appropriate daily dosage of the active compound used in the compositions and methods of the present invention will be the amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective dosage will generally depend on the factors described above.

[0338] If desired, the effective daily dosage of the active compound can be administered as one, two, three, four, five, six or more sub-doses, at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments of the present invention, the active compound can be administered two or three times a day. In a preferred embodiment, the active compound will be administered once a day.

[0339] A patient receiving such treatment is any animal in need, including primates, especially humans; and other mammals such as horses, cattle, pigs, sheep, cats and dogs; poultry; and generally pets.

[0340] In certain embodiments, the compounds of the present invention can be used alone or administered in combination with another type of therapeutic agent.

[0341] The present disclosure includes the use of pharmaceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, the salts contemplated by the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, the salts contemplated by the present invention include, but are not limited to, L-arginine, aniline (benenthamine), benzathine, betaine, calcium hydroxide, choline, dimethylethanolamine (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, the salts contemplated by the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In certain embodiments, 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, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-10-camphorsulfonic 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-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, l-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, l-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, l-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid and undecylenic acid salts.;

[0342] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of these solvates can also be prepared. The source of such solvates can be from the crystallization solvent, inherent in the preparation or crystallization solvent, or foreign to such solvent.

[0343] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives and antioxidants may also be present in the composition.

[0344] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0345] Definition

[0346] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. Generally, the nomenclature and techniques related to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well-known and commonly used in the art.

[0347] Unless otherwise indicated, the methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", W.H. Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", W.H. Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0348] Unless otherwise defined herein, chemical terms used herein are used according to conventional usage in the art, such as in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0349] All of the foregoing 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 its specific definitions, shall govern.

[0350] The term "agent" as used herein is used to denote a compound (such as an organic or inorganic compound, a mixture of compounds), a biological macromolecule (such as a nucleic acid, an antibody, including portions thereof and humanized, chimeric, and human antibodies, and monoclonal antibodies, a protein or a portion thereof, such as a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (especially mammalian) cells or tissues. Agents include, for example, agents of known structure and agents of unknown structure.

[0351] The terms "patient", "subject", or "individual" are used interchangeably and refer to a human or non-human animal. These terms include mammals such as humans, primates, domestic animals (including cows, pigs, etc.), companion animals (such as dogs, cats, etc.), and rodents (such as mice and rats).

[0352] "Treating" a condition or a patient refers to taking steps to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the severity of the disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of the disease, delaying or slowing disease progression, improving or alleviating the disease state, and remission (partial or complete), whether detectable or not. "Treatment" can also refer to an extended survival as compared to the expected survival without receiving treatment.

[0353] The term "preventing" is well recognized in the art and, when used in relation to a condition such as local recurrence (e.g., pain), a disease such as cancer, a syndrome such as heart failure, or any other medical condition, is well known in the art and includes administering a composition that, relative to a subject not receiving the composition, reduces the frequency of symptoms of the medical condition in the subject or delays their onset. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving preventive treatment, relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in the treated population, relative to an untreated control population, by a statistically and / or clinically significant amount.

[0354] A substance, compound, or agent can be "administered" to a subject using one of a variety of methods known to those of ordinary skill in the art. For example, a compound or agent can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ophthalmically, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin catheter). A compound or agent can also be introduced appropriately through a refeedable or biodegradable polymeric device or other device, such as a patch and a pump, or a formulation that provides for an extended, slow, or controlled release of the compound or agent. Administration can also be, for example, once, multiple times, and / or over one or more extended periods.

[0355] The appropriate method of administering a substance, compound or agent to a subject will also depend on, for example, the age and / or physical condition of the subject and the chemical and biological properties of the compound or agent (such as solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the compound or agent is administered orally, for example, by ingestion to the subject. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or is administered using a device for such slow or extended release.

[0356] As used herein, the phrase "conjoint administration" refers to any form of administration of two or different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., both agents are effective simultaneously in the patient, which may include a synergistic effect of the two agents). For example, different therapeutic compounds can be administered simultaneously or sequentially in the same formulation or in different formulations. Thus, an individual receiving such treatment can benefit from the combined effects of different therapeutic agents.

[0357] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is the amount of the drug or agent that, when administered to a subject, has the desired therapeutic effect. The full therapeutic effect does not necessarily occur upon administration of a single dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations. The precise effective amount required for a subject will depend on, for example, the size, health and age of the subject, and the nature and extent of the condition being treated such as cancer or myelodysplastic syndrome (MDS). A person skilled in the art can readily determine the effective amount in a given case by routine experimentation.

[0358] As used herein, the term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" means that the alkyl may or may not be substituted.

[0359] It should be understood that those of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the present invention to obtain chemically stable compounds, which can be easily synthesized from readily available starting materials by techniques known in the art and those methods listed below. If the substituent itself is substituted by more than one group, it should be understood that these groups can be on the same carbon or different carbons as long as a stable structure is produced.

[0360] As used herein, the term "optionally substituted" means that one to six hydrogen groups in a given structure are substituted by the designated substituents, including but not limited to: hydroxy, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclic group, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH 2 -O-alkyl, -OP(O)(O-alkyl) 2 or -CH 2 -OP(O)(O-alkyl) 2 . Preferably, "optionally substituted" means that one to four hydrogen groups in a given structure are substituted by the above substituents. More preferably, one to three hydrogen groups are substituted by the substituents as described above. It should be understood that the substituents can be further substituted.

[0361] As used herein, the term "alkyl" refers to saturated aliphatic groups, including but not limited to C 1 -C 10 linear alkyl or C 1 -C 10 branched alkyl. Preferably, "alkyl" refers to C 1 -C 6 linear alkyl or C 1 -C 6 branched alkyl. Most preferably, "alkyl" refers to C 1 -C 4 linear alkyl or C 1 -C 4 branched alkyl. 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, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl, etc. "alkyl" can be optionally substituted.

[0362] The term "acyl" is well recognized in the art and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0363] The term "acylamino" is well recognized in the art and refers to an amino group substituted by an acyl group, and can be represented, for example, by the formula hydrocarbylC(O)NH-.

[0364] The term "acyloxy" is well recognized in the art and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0365] The term "alkoxy" refers to an alkyl group linked to oxygen. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0366] The term "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group and can be represented by the general formula alkyl-O-alkyl.

[0367] The term "alkyl" refers to saturated aliphatic groups, including straight-chain alkyls, branched-chain alkyls, cycloalkyls (alicyclics), alkyl-substituted cycloalkyls, and cycloalkyl-substituted alkyls. In a preferred embodiment, the straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its main chain (e.g., straight-chain is C 1-30 , branched-chain is C 3-30 ), more preferably 20 or fewer.

[0368] In addition, the term "alkyl" as used throughout the specification, examples, and claims is intended to include unsubstituted and substituted alkyls, the latter referring to an alkyl moiety having substituents replacing hydrogen on one or more carbons of the hydrocarbon main chain, including haloalkyls such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0369] When used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "C x-y " or "C x -C y " is intended to include groups containing x to y carbons in the chain. C 0 alkyl represents a hydrogen at the terminal position of the group and a bond if internal. For example, C 1-6 alkyl contains one to six carbon atoms in the chain.

[0370] As used herein, the term "alkylamino" refers to an amino group substituted by at least one alkyl group.

[0371] As used herein, the term "alkylthio" refers to a mercapto group substituted by an alkyl group and can be represented by the general formula alkylS-.

[0372] As used herein, the term "amido" refers to the group

[0373]

[0374] wherein R 9 and R 10 each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 together with the N atom to which they are attached form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0375] The terms "amine" and "amino group" are well recognized in the art and refer to unsubstituted and substituted amines and their salts, for example, moieties represented by the following:

[0376]

[0377] wherein R 9 , R 10 and R 10’ each independently represents hydrogen or a hydrocarbon group, or R 9 and R 10 together with the N atom to which they are attached form a heterocyclic ring having 4 to 8 atoms in the ring structure.

[0378] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0379] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0380] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom in 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 systems having two or more rings, wherein two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic groups. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, etc.

[0381] The term "carbamate" is well recognized in the art and refers to the group

[0382]

[0383] wherein R 9 and R 10 independently represent hydrogen or a hydrocarbon group.

[0384] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0385] The term "carbocyclic ring" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring of the bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. The carbocyclic ring includes bicyclic molecules in which one, two, three, or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each of the rings shares two adjacent atoms with the other ring. Each ring of the fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as a phenyl group, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of the carbocyclic ring, provided that the valences permit. Exemplary "carbocyclic rings" 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 carbocyclic rings 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. The "carbocyclic ring" can be substituted at any one or more positions capable of bearing a hydrogen atom.

[0386] As used herein, the term "carbocyclic ring alkyl" refers to an alkyl group substituted with a carbocyclic ring group.

[0387] The term "carbonate" is well recognized in the art and refers to the group -OCO 2 -.

[0388] As used herein, the term "carboxyl" refers to the group represented by the formula -CO 2 H.

[0389] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term "cycloalkyl" also includes polycyclic systems having two or more rings, where two or more carbons are common to two adjacent rings, where at least one of the rings is a cycloalkyl, and substituents (such as R 100) is connected to a cycloalkyl ring. For example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic group. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, benzodioxane, tetrahydroquinoline, etc.

[0390] As used herein, the term "ester" refers to the group -C(O)OR 9 , where R 9 represents a hydrocarbyl group.

[0391] As used herein, the term "ether" refers to a hydrocarbyl group linked to another hydrocarbyl group through oxygen. Thus, the ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include the "alkoxyalkyl" group, which can be represented by the general formula alkyl-O-alkyl.

[0392] The terms "halo and halogen" as used herein refer to halogens and include chlorine, fluorine, bromine and iodine.

[0393] As used herein, the term "hetaralkyl and heteroaralkyl" refers to an alkyl group substituted by a heteroaryl group.

[0394] The terms "heteroaryl and hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic systems having two or more rings, where two or more carbons are common to two adjacent rings, and at least one of the rings is heteroaromatic. For example, other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic group. Heteroaryl includes, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc.

[0395] As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0396] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0397] 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, the ring structure of which includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are common to two adjacent rings, wherein at least one of the rings is heterocyclic, e.g., the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl includes, for example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, etc.

[0398] As used herein, the term "hydrocarbyl" refers to a group bonded through a carbon atom not having an =O or =S substituent and generally having at least one carbon-hydrogen bond and a predominantly carbon backbone, but may optionally include heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl, but substituents such as acetyl (which has an =O substituent on the linking carbon) and ethoxy (which is linked through oxygen rather than carbon) are not. Hydrocarbyl includes, but is not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0399] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0400] When used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" is intended to include groups in which there are ten or fewer atoms, preferably six or fewer atoms, in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer carbon atoms, preferably six or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, e.g., in the description of hydroxyalkyl and aralkyl (in which case, for example, when counting the carbon atoms in the alkyl substituent, the atoms within the aryl are not counted).

[0401] The terms "polycyclyl", "polycycle" and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl), where two or more atoms are common to two adjacent rings, such that the rings are "fused rings". Each ring of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably 5 to 7 atoms.

[0402] The term "sulfate" is well recognized in the art and refers to the group -OSO 3 H or a pharmaceutically acceptable salt thereof.

[0403] The term "sulfonamido" is well recognized in the art and refers to a group represented by the following general formula:

[0404]

[0405] wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.

[0406] The term "sulfoxide" is well recognized in the art and refers to the group -S(O)-.

[0407] The term "sulfonate" is well recognized in the art and refers to the group SO 3 H or a pharmaceutically acceptable salt thereof.

[0408] The term "sulfone" is well recognized in the art and refers to the group -S(O) 2 -.

[0409] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It should be understood that "substitution" or "substituted with" includes the implicit conditions that such substitution is consistent with the allowed valences of the substituting atoms and substituents and that the substitution results in a stable compound, e.g., one that does not spontaneously undergo rearrangement, cyclization, elimination, etc. conversions. As used herein, it is contemplated that the term "substituted" includes all allowed substituents of an organic compound. In a broad aspect, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, the allowed substituents may be one or more and the same or different. For the purposes of this invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any allowed substituent of the organic compounds described herein that satisfies the valence of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic, aralkyl or aromatic or heteroaromatic moieties. One of ordinary skill in the art will understand that, if appropriate, the moieties substituted on a hydrocarbon chain may themselves be substituted.

[0410] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a mercapto group.

[0411] As used herein, the term "thioester" refers to the group -C(O)SR 9 or -SC(O)R 9 ,

[0412] wherein R 9 represents a hydrocarbon group.

[0413] As used herein, the term "thioether" is equivalent to an ether in which oxygen is replaced by sulfur.

[0414] The term "urea" is well recognized in the art and may be represented by the following general formula:

[0415]

[0416] wherein R 9 and R 10 each independently represents hydrogen or a hydrocarbon group.

[0417] As used herein, the term "modulate" includes inhibition or suppression as well as enhancement of a function or activity such as cell proliferation.

[0418] The phrase "pharmaceutically acceptable" is well recognized in the art. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0419] As used herein, "pharmaceutically acceptable salt" or "salt" refers to acid addition salts or base addition salts that are suitable for or compatible with the treatment of multiple patients.

[0420] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any basic compound represented by Formula I. Illustrative inorganic acids for forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate, potassium bisulfate. Illustrative organic acids for forming suitable salts include monocarboxylic, dicarboxylic, 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. Mono- or di-salts can be formed, and such salts can exist in hydrated, solvated, or substantially anhydrous forms. Generally, the acid addition salts of the 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 suitable salts will be known to those of ordinary skill in the art. Other non-pharmaceutically acceptable salts, such as oxalates, can be used, for example, for the isolation of the compounds of Formula I in the laboratory or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0421] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound represented by Formula I or any of its intermediates. Illustrative inorganic bases for forming suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Illustrative organic bases for forming suitable salts include aliphatic, cycloaliphatic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline, or ammonia. The selection of suitable salts will be known to those of ordinary skill in the art.

[0422] A variety of compounds useful in the methods and compositions of the present disclosure have at least one stereoisomeric center in their structure. This stereoisomeric center can exist in the R or S configuration, and the R and S symbols are used to correspond to the rules described in Pure Appl. Chem. (1976), 45, 11 - 30. The present disclosure encompasses all stereoisomeric forms of the compounds, salts, prodrugs, or mixtures thereof (including mixtures of all possible stereoisomers), such as enantiomeric and diastereomeric forms. See, for example, WO 01 / 062726.

[0423] In addition, certain compounds containing alkenyl may exist as Z (zusammen) or E (entgegen) isomers. In each case, the present disclosure includes mixtures and isolated individual isomers.

[0424] A "prodrug" or "pharmaceutically acceptable prodrug" refers to a compound that is metabolized in a host, such as by hydrolysis or oxidation, after administration to form a compound of the present disclosure (e.g., a compound of Formula I). Typical examples of prodrugs include compounds having a biolabile or cleavable (protecting) group on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolized, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. Examples of prodrugs using esters or aminophosphates as biolabile or cleavable (protecting) groups are disclosed in U.S. Pat. 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 produce compounds of Formula I. Prodrugs of the compounds described herein are included within the scope of the present disclosure. Conventional procedures for selecting and preparing suitable prodrugs are described, for example, in "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.

[0425] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material useful in formulating a pharmaceutical composition for a drug or therapeutic use.

[0426] As used herein, the terms "Log of solubility", "LogS", or "logS" are used in the art to quantify the water solubility of a compound. The water solubility of a compound significantly affects its absorption and distribution characteristics. Poor solubility is generally associated with poor absorption. The LogS value is the base-10 logarithm of the solubility in units of moles per liter (mol / liter).

[0427] Example

[0428] The following representative examples are intended to assist in illustrating the invention and are not intended nor should they be construed as limiting the scope of the invention. In fact, various modifications of the invention and many further embodiments thereof will become apparent to those of ordinary skill in the art in light of the entire disclosure herein, including the following examples and references to scientific and patent literature cited herein. It should also be understood that the content of those cited references is incorporated herein by reference to assist in describing the state of the art. The following examples contain important additional information, exemplification, and guidance that can be applied to the practice of the invention in its various embodiments and their equivalents.

[0429] Example 1: Synthesis of Exemplary Compounds of the Present Disclosure

[0430] General Procedure A.

[0431]

[0432] General Procedure B

[0433]

[0434] General Procedure C

[0435]

[0436] Representative examples of D:

[0437] Representative examples of E:

[0438] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (2-((2R,6S)-2,6- dimethylmorpholino)pyrimidin-4-amine)

[0439]

[0440] A mixture of 2-chloropyrimidin-4-amine (2.0 g, 15.4 mmol, 1.0 eq), (2R,6S)-2,6-dimethylmorpholine (5.33 g, 46.3 mmol, 3.0 eq), and N,N-diisopropylethylamine (DIEA; 10.0 g, 77.0 mmol, 5.0 eq) in isopropanol (IPA; 40 mL) was stirred at 80 °C under N 2 for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water, dried over anhydrous sodium sulfate (Na 2 SO 4 2) and evaporated to dryness. The residue was purified by column chromatography (petroleum ether (PE):ethyl acetate (EA) = 5:1 to dichloromethane (DCM):methanol (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] + ; 1 1H NMR (400 MHz, CD3OD) δ 7.76 (d, J = 5.9 Hz, 1H), 5.86 (d, J = 5.9 Hz, 1H), 4.49–4.36 (m, 2H), 3.61 (ddd, J = 10.5, 6.3, 2.5 Hz, 2H), 3.38 (s, 1H), 2.48 (dd, J = 13.2, 10.7 Hz, 2H), 1.22 (d, J = 6.2 Hz, 6H).

[0441] Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-amine)

[0442]

[0443] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (50 g, 338.9 mmol, 1.0 eq.) and (2R,6S)-2,6-dimethylmorpholine (78 g, 667.8 mmol, 2.0 eq.) in IPA (500 mL) was added DIEA (87.6 g, 667.8 mmol, 2.0 eq.), 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:ethyl acetate (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 (400 MHz, DMSO-d 6 ): δ 7.76 (d, J = 3.5 Hz, 1H), 6.83 (s, 2H), 4.28 (d, J = 12.0 Hz, 2H), 3.46 (dd, J = 7.9, 6.3 Hz, 2H), 2.32 (dd, J = 12.7, 10.9 Hz, 2H), 1.07 (d, J = 6.2 Hz, 6H).

[0444] Synthesis of 2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (2-((2S,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-amine)

[0445]

[0446] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (325 mg, 2.2 mmol, 1.5 eq) and (2S,6S)-2,6-dimethylmorpholine ((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 thin layer chromatography (Prep-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 (400 MHz, DMSO-d 6) δ 7.76 (d, J = 3.5 Hz, 1H), 6.82 (s, 2H), 3.96–3.83 (m, 2H), 3.61 (dd, J = 12.9, 3.2 Hz, 2H), 3.24 (dd, J = 12.9, 6.2 Hz, 2H), 1.07 (d, J = 6.4 Hz, 6H).

[0447] Synthesis of 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (2-((2R,6R)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-amine)

[0448]

[0449] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (200 mg, 1.36 mmol, 1.0 eq) and (2R,6R)-2,6-dimethylmorpholine (391 mg, 3.40 mmol, 2.5 eq) in IPA (4 mL) was added DIEA (526 mg, 4.08 mmol, 3.0 eq). The reaction mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM / MeOH / NH 3 . H 2 O = 50 / 1 / 0.5) to afford 2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (70 mg, white solid). LC-MS: 227.12 [M+1] + ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.77 (d, J = 3.6 Hz, 1H), 6.84 (s, 2H), 3.92 (td, J = 6.3, 3.5 Hz, 2H), 3.63 (dd, J = 12.9, 3.3 Hz, 2H), 3.26 (dd, J = 12.9, 6.2 Hz, 2H), 1.08 (d, J = 6.4 Hz, 6H).

[0450] Synthesis of 5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-amine (5-fluoro-2-(pyrrolidin-1-yl)pyrimidin- 4-amine)

[0451]

[0452] To a solution of 2-chloro-5-fluoropyrimidin-4-amine (200 mg, 1.36 mmol, 1.0 eq) in IPA (4 mL) was added pyrrolidine (290 mg, 4.08 mmol, 3.0 eq) and DIEA (526 mg, 4.08 mmol, 3.0 eq). The reaction mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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 (400 MHz, DMSO-d 6 ) δ 7.75 (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).

[0453] Synthesis of 2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-amine (2-(2-oxa-5- azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-amine)

[0454]

[0455] Step a: At room temperature, to a solution of 2-chloro-5-fluoropyrimidin-4-amine (300 mg, 2.03 mmol, 1.0 eq), di-tert-butyl dicarbonate (Boc 2 O; 1.77 g, 8.13 mmol 4.0 eq) and triethylamine (TEA; 821 mg, 8.13 mmol 4.0 eq) in DCM (3 mL) was added 4-dimethylaminopyridine (DMAP; 12 mg, 0.10 mmol 0.05 eq). 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 column 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 (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), 1.44 (s, 18H).

[0456] Step b: To a solution of bis-N-Boc protected compound (512 mg, 1.47 mmol, 1.0 eq) was added 2-oxa-5-azabicyclo[4.1.0]heptane hydrochloride (200 mg, 1.47 mmol, 1.0 eq) 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 Prep-TLC using PE / EA = 3 / 1 to give the product (110 mg, crude) as a white solid. LCMS: 411.35 [M+1] + 。

[0457] Step c: To a solution of the bis-N-Boc product from step b (110 mg crude, 0.268 mmol, 1.0 eq) in dioxane (1 mL) was added hydrochloric acid / 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 Na 2 CO 3 solution (50 mL). The separated organic layer was dried over (Na 2 SO 4 or MgSO 4 ) and evaporated to dryness. The residue was purified by Prep-TLC using DCM / MeOH = 40 / 1 to give 2-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-5-fluoropyrimidin-4-amine (12 mg, 21%) as a white solid. 1 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 3.0 Hz, 1H), 4.85 (s, 2H), 3.85–3.65 (m, 3H), 3.40 (dt, J = 7.4, 4.4 Hz, 2H), 2.92 (td, J = 6.9, 5.0 Hz, 1H), 0.92 (q, J = 6.8 Hz, 1H), 0.57 (ddd, J = 6.9, 4.8, 3.6 Hz, 1H).

[0458] (2R,6S)-4-(4,6-difluoropyrimidin-2-yl)-2,6-dimethylmorpholine ((2R,6S)-4-(4,6- difluoropyrimidin-2-yl)-2,6-dimethylmorpholine)

[0459]

[0460] To 2,4,6-trifluoropyrimidine (300 mg, 2.24 mmol, 1.0 eq), potassium carbonate (K 2 CO 3;A solution of (2R,6S)-2,6-dimethylmorpholine (258 mg, 2.24 mmol, 1.0 eq) was added to a solution of 619 mg, 4.48 mmol, 2.0 eq) in acetonitrile (ACN; 1 mL). The reaction mixture was stirred for over 10 minutes under ice-cooling and then stirred for an additional 1 hour at room temperature. The mixture was concentrated under vacuum to give a residue, which was purified by silica gel column chromatography, eluting with (PE / EA = 100 / 1 to 50 / 1), to afford (2R,6S)-4-(4,6-difluoropyrimidin-2-yl)-2,6-dimethylmorpholine (250 mg, 49%) as a white solid. 1 H NMR(400MHz,CDCl 3 )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).

[0461] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine (5-chloro-N- (2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine)

[0462]

[0463] At room temperature, N 2 To a solution of 2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine (700 mg, 3.36 mmol, 1.0 eq), 3,5-dichloropyridazine (500 mg, 3.36 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 197 mg, 0.34 mmol, 0.1 eq) and cesium carbonate (Cs 2 CO 3 ; 2.2 g, 6.72 mmol, 2.0 eq) in dioxane (1 mL) was added tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ; 97 mg, 0.17 mmol, 0.05 eq). The reaction mixture was then stirred at 110 °C under N 2 for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water and dried over anhydrous Na 2 SO 4Dry and evaporate 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] +

[0464] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (5- chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) pyridazin-3-amine)

[0465]

[0466] At room temperature, N 2 To a solution of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine; 35.5 g, 157.08 mmol, 1.0 eq), 3,5-dichloropyridazine (3,5-dichloropyridazine; 35 g, 234.90 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene (4.54 g, 7.85 mmol, 0.05 eq) and cesium carbonate (153.5 g, 471.15 mmol, 3.0 eq) in toluene (Tol.; 500 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl 2 ; 5.75 g, 7.86 mmol, 0.05 eq). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water. The separated organic layer was washed with water and dried over Na 2 SO 4 and evaporated to dryness. The residue was purified by silica gel column 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 (400 MHz, DMSO-d 6): δ 10.69 (s, 1H), 9.05 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 3.2 Hz, 1H), 4.20 (d, J = 12.5 Hz, 2H), 3.52 (d, J = 7.3 Hz, 2H), 2.51 (s, 2H), 1.10 (d, J = 6.1 Hz, 6H).

[0467] Synthesis of 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (5- chloro-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) pyridazin-3-amine)

[0468]

[0469] At room temperature, N 2 To a solution of 2-((2S,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-amine (92 mg, 0.41 mmol, 1.0 eq), 3,5-dichloropyridazine (91 mg, 0.61 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol, 0.05 eq) and cesium carbonate (398 mg, 1.22 mmol, 3.0 eq) in toluene (3 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15 mg, 0.02 mmol, 0.05 eq). Then the reaction mixture was stirred at 80 °C for 16 h under N 2 under. The reaction mixture 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 and dried over (Na 2 SO 4 or MgSO 4 ) and evaporated to dryness. The residue was purified by Prep-TLC using PE / EA = 2 / 1 to give 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (75 mg, 54%) as a yellow solid. LCMS: 339.10 [M+1] + ; 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.68 (s, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.17 (d, J = 3.3 Hz, 1H), 4.01–3.91 (m, 2H), 3.67 (dd, J = 13.0, 3.3 Hz, 2H), 3.33 (m, 1H), 3.29 (m, 1H), 1.10 (d, J = 6.4 Hz, 6H).

[0470] Synthesis of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) pyridazin-3-amine)

[0471]

[0472] To a solution of 2-((2R,6R)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-amine (70 mg, 0.31 mmol, 1.0 eq) in toluene (4 mL) was added 3,5-dichloropyridazine (46 mg, 0.31 mmol, 1.0 eq), cesium carbonate (202 mg, 0.62 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg, 0.031 mmol, 0.1 eq), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.031 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 h under N 2 atmosphere. 50 mL of water was poured into the mixture and the mixture was extracted three times with ethyl acetate (20 mL), dried over anhydrous Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE / EA = 2 / 1), to give 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (50 mg). LC-MS: 339.05 [M+1] +

[0473] Synthesis of 5-chloro-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine (5-chloro-N-(5-fluoro- 2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine)

[0474]

[0475] To a solution of 5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-amine (230 mg, 1.26 mmol, 1.0 eq) in toluene (5 mL) was added 3,5-dichloropyridazine (188 mg, 1.26 mmol, 1.0 eq), cesium carbonate (819 mg, 2.52 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (73 mg, 0.126 mmol, 0.1 eq), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (92 mg, 0.126 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 h under N 2 atmosphere. 50 mL of water was poured into the mixture and the mixture was extracted three times with ethyl acetate (20 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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] + 。

[0476] Synthesis of N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-chloropyridazin-3-amine (N-(2-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5- chloropyridazin-3-amine)

[0477]

[0478] 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 eq), 3,5-dichloropyridazine (13 mg, 0.09 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2 mg, 0.003 mmol, 0.05 eq) and cesium carbonate (59 mg, 0.18 mmol, 3.0 eq) in toluene (3 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2 mg, 0.003 mmol, 0.05 eq) at room temperature. Then the reaction mixture was stirred at 80 °C for 16 h under N 2 2. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water. The separated organic layer was washed with water, dried over (Na 2 2 4 SO 4 4 or MgSO4) and evaporated to dryness. The residue was purified by Prep-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 1H NMR (400 MHz, CDCl 3 3) δ 9.12 (s, 1H), 8.85 (s, 1H), 8.10 (s, 2H), 3.88 (m, 3H), 3.46 (m, J = 25.7 Hz, 2H), 2.88 (s, 1H), 1.08 (d, J = 6.2 Hz, 1H), 0.66 (s, 1H).

[0479] Synthesis of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine (5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine)

[0480]

[0481] The reaction mixture of 2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-amine (100 mg, 0.44 mmol, 1.0 eq), 4,6-dichloro-3-methylpyridazine (71 mg, 0.44 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.044 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium(0) (56 mg, 0.044 mmol, 0.1 eq) and cesium carbonate (380 mg, 0.88 mmol, 2.0 eq) in toluene (5 mL) was stirred at 110 °C for 16 h under N 2 The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE / EA = 7 / 1 to 4 / 1) to afford 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine (70 mg, 45%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.70 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 4.35 (d, J = 12.9 Hz, 2H), 3.67 (s, 2H), 2.74 (s, 3H), 2.65 (t, J = 11.5 Hz, 2H), 1.28 (d, J = 6.1 Hz, 6H).

[0482] Synthesis of N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)-5-(2-fluoro-4-methoxyphenyl)pyridazin- 3-amine (N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)-5-(2-fluoro-4- methoxyphenyl)pyridazin-3-amine) - Compound 3

[0483]

[0484] At room temperature, under N 2Downward 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine (5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin-3-amine; 100 mg, 0.31 mmol, 1.0 eq), (2-fluoro-4-methoxyphenyl)boronic acid ((2-fluoro-4-methoxyphenyl)boronic acid; 80 mg, 0.47 mmol, 1.5 eq) and potassium carbonate (86 mg, 0.62 mmol, 2.0 eq) were added to a solution of tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 (36 mg, 0.031 mmol, 0.1 eq) in dioxane / water (5 mL / 0.5 mL). The reaction mixture was then stirred at 110 °C under N 2 for 16 h. The reaction mixture 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 Na 2 SO 4 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 (400 MHz, CD 3 OD) δ 9.03 (d, J = 2.3 Hz, 1H), 8.68 (s, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.83 (t, J = 8.9 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 6.81 (dd, J = 13.0, 2.3 Hz, 1H), 6.17 (d, J = 5.7 Hz, 1H), 4.40 (d, J = 13.1 Hz, 2H), 3.85 (s, 3H), 3.65–3.57 (m, 2H), 2.59–2.49 (m, 2H), 1.17 (d, J = 6.2 Hz, 6H).

[0485] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)pyridazin- 3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino) Synthesis of (pyrimidin-4-yl)pyridazin-3-amine) - Compound 20

[0486]

[0487] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl)pyridazin-3-amine (75 mg, 0.23 mmol, 1.0 eq) in dioxane / water (5 mL / 0.5 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (80 mg, 0.46 mmol, 2.0 eq), potassium phosphate (149 mg, 0.7 mmol, 3.0 eq), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (17 mg, 0.023 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 h under N 2 and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA = 0 / 1) to afford 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholin-4-yl)pyrimidin-4-yl)pyridazin-3-amine (68 mg, 68%). LCMS: [M+1]: 429.10; 1 H NMR (400 MHz, CD 3 OD) δ 9.12 (s, 1H), 8.72 (s, 1H), 8.10 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 73.6 Hz, 1H), 6.21 (d, J = 5.6 Hz, 1H), 4.45 (d, J = 12.5 Hz, 2H), 3.65 (m, 2H), 2.67–2.57 (m, 2H), 1.19 (d, J = 6.2 Hz, 6H).

[0488] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) Pyridazin-3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine) - Synthesis of Compound 80

[0489]

[0490] At room temperature under N 2Downward 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (9 g, 26.57 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (9 g, 53.13 mmol, 2.0 eq) and potassium phosphate (16.9 g, 79.7 mmol, 3.0 eq) were added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.94 g, 2.66 mmol, 0.05 eq) in dioxane / water (10:1, 90 mL / 10 mL). The reaction mixture was then stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water. The separated organic layer was washed with water and dried over Na 2 SO 4 and evaporated to dryness. The residue was purified by silica gel column chromatography, eluting with PE:EtOAc = 20:1, to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (5.2 g, 44%), as a yellow solid. LCMS: 447.35 [M+H] + ; 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.42 (s, 1H), 9.31 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 3.0 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.55–7.12 (m, 3H), 4.20 (d, J = 12.5 Hz, 2H), 3.49 (t, 2H), 2.42 (d, J = 12.6 Hz, 2H), 0.96 (d, J = 5.0 Hz, 6H).

[0491] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) Pyridazin-3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine) - Synthesis of Compound 91

[0492]

[0493] At room temperature N 2Downward 5-chloro-N-(2-((2S,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (75 mg, 0.22 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (76 mg, 0.44 mmol, 2.0 eq) and potassium phosphate (141 mg, 0.66 mmol, 3.0 eq) were added to a solution in dioxane / water (2 mL / 0.2 mL) of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.02 mmol, 0.1 eq). Then the reaction mixture was stirred at 110 °C for 16 h under N 2 under reduced pressure. The reaction mixture 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 and dried over (Na 2 SO 4 or MgSO 4 ) and evaporated to dryness. The residue was purified by Prep-TLC using PE / EA = 1 / 1 to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2S,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (63 mg, 64%), as a yellow solid. LCMS: 447.35 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) δ 9.17 (s, 1H), 8.83 (s, 1H), 8.03 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.95 (t, J = 73.3 Hz, 1H), 4.02 (s, 2H), 3.75 (d, J = 13.0 Hz, 2H), 3.40 (dd, J = 12.8, 6.3 Hz, 2H), 1.11 (d, J = 6.3 Hz, 6H).

[0494] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl) Pyridazin-3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazin-3-amine) - Synthesis of Compound 90

[0495]

[0496] To a solution of 5-chloro-N-(2-((2R,6R)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine (50 mg, 0.15 mmol, 1.0 eq) in toluene / water (3 mL / 1 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (43 mg, 0.23 mmol, 1.5 eq), potassium phosphate (64 mg, 0.30 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.015 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 h under N 2 and 50 mL of water was poured into the mixture and the mixture was extracted three times with ethyl acetate (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE / EA = 1 / 1) to give 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6R)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)pyridazin-3-amine as a yellow oil (21 mg). LC-MS: 447.20 [M+1] + ; 1 H NMR (400 MHz, CD 3 OD) δ 9.16 (d, J = 2.0 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 3.3 Hz, 1H), 7.89–7.81 (m, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.97 (t, J = 73.5 Hz, 1H), 4.08–3.98 (m, 2H), 3.75 (dd, J = 12.9, 3.3 Hz, 2H), 3.40 (dd, J = 12.9, 6.5 Hz, 2H), 1.13 (d, J = 6.4 Hz, 6H).

[0497] 5-(4-(Difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl)pyridazin-3-amine (5- (4-(difluoromethoxy)phenyl)-N-(5-fluoro-2-(pyrrolidin-1-yl)pyrimidin-4-yl) Pyridazin-3-amine) - Synthesis of Compound 104

[0498]

[0499] 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 eq) in toluene / water (3 mL / 1 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (48 mg, 0.26 mmol, 1.5 eq), potassium phosphate (72 mg, 0.0.34 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13 mg, 0.017 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 h under N2 Stir at below 110 °C for 16 h. Pour 50 mL of water into the mixture and extract 3 times with ethyl acetate (15 mL). After drying over anhydrous Na 2 SO 4 and filtering, concentrate under reduced pressure. Purify the residue by preparative high performance liquid chromatography (prep-HPLC) to obtain 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 (400 MHz, CD 3 OD) δ 9.12 (dd, J = 17.1, 2.0 Hz, 2H), 8.13 (s, 1H), 7.96 (d, J = 3.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 6.99 (t, J = 73.5 Hz, 1H), 3.50 (s, 4H), 2.00 (dd, J = 7.8, 5.6 Hz, 4H).

[0500] N-(2-(2-Oxa-5-azabicyclo[4.1.0]heptan-5-yl)-5-fluoropyrimidin-4-yl)-5-(4-(difluoromethoxy yl)phenyl)pyridazin-3-amine (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 Synthesis

[0501]

[0502] Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2 mg, 0.003 mmol, 0.1 eq) to a solution of N-(2-(2-oxa-5-azabicyclo[4.1.0]hept-5-yl)-5-fluoropyrimidin-4-yl)-5-chloropyridazin-3-amine (10 mg, 0.03 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (10 mg, 0.06 mmol, 2.0 eq) and potassium phosphate (19 mg, 0.09 mmol, 3.0 eq) in dioxane / water (1 mL / 0.1 mL) at room temperature. Then stir the reaction mixture at N 2 at 110 °C for 16 h. Concentrate the reaction mixture under reduced pressure. Partition the residue between ethyl acetate (50 mL) and water. The separated organic layer is dried over (Na 2 SO 4 or MgSO 4)Dry and evaporate to dryness. Purify the residue by Prep-TLC with PE / EA = 1 / 1 to obtain N-(2-(2-oxa-5-azabicyclo[4.1.0]hept-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 (400 MHz, CDCl 3 ) δ 9.09 (s, 2H), 8.12 (s, 2H), 7.62 (d, J = 7.4 Hz, 2H), 7.26 (s, 1H), 6.59 (t, J = 72.9 Hz, 1H), 3.81 (d, J = 13.6 Hz, 3H), 3.51 (d, J = 27.5 Hz, 2H), 2.92 (s, 1H), 0.87 (s, 1H), 0.62 (s, 1H).

[0503] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4- (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine)-Compound Synthesis of Compound 508 Synthesis of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0504]

[0505] To a solution of 5-chloro-N-(2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine (70 mg, 0.20 mmol, 1.0 eq) in toluene (4 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (38 mg, 0.20 mmol, 1.0 eq), potassium phosphate (85 mg, 0.40 mmol, 2.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15 mg, 0.020 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 h under N 2 2. The mixture was extracted with ethyl acetate (20 mL) three times, dried over anhydrous Na 2 2 4 SO + 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE / EA = 2 / 1) to obtain the compound 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)-6-methylpyridazin-3-amine (25 mg, 27%), as a white solid. LC-MS: 461.15 [M+1] + ; 1 1HNMR (400 MHz, CD 3OD) δ 8.56 (s, 1H), 8.03 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 6.95 (t, J = 73.6 Hz, 1H), 4.21 (d, J = 12.9 Hz, 2H), 3.60–3.47 (m, 2H), 2.60 (s, 3H), 2.44 (dd, J = 12.8, 10.8 Hz, 2H), 1.02 (d, J = 6.2 Hz, 6H).

[0506] Synthesis of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine Synthesis of N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0507]

[0508] At room temperature, under N 2 to a solution of 5-chloropyridazin-3-amine (500 mg, 3.86 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (1.45 g, 7.7 mmol, 2.0 eq) and potassium phosphate (2.46 g, 11.58 mmol, 3.0 eq) in dioxane / water (20 mL / 2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (283 mg, 0.39 mmol, 0.1 eq). The reaction mixture was then stirred at 110 °C for 16 h under N 2 and 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 and dried over (Na 2 SO 4 or MgSO 4 ) 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 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.53–7.10 (m, 3H), 6.92 (s, 1H), 6.40 (s, 2H).

[0509] Synthesis of N-(2-chloro-5-fluoropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine Synthesis of N-(6-chloro-3-fluoropyridin-2-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine

[0510]

[0511] Under N 2A solution of (4-(difluoromethoxy)phenyl)boronic acid (564 mg, 3.0 mmol, 1.0 eq), 5-bromo-2-methoxypyridin-3-amine (609 mg, 3.0 mmol, 1.0 eq), and potassium phosphate (1.27 g, 6.0 mmol, 2.0 eq) in dioxane / water (8 mL / 2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (220 mg, 0.3 mmol, 0.1 eq). The reaction mixture was then stirred at 110 °C for 16 h under N 2 under reduced pressure. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, 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 (400 MHz, CDCl 3 ) δ 7.74 (d, J = 2.1 Hz, 1H), 7.52–7.45 (m, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 2.1 Hz, 1H), 6.53 (t, J = 73.9 Hz, 1H), 4.02 (s, 3H), 3.87 (s, 2H).

[0512] Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)pyrimidin-4-amine Synthesis of 2-chloro-N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-5-fluoropyrimidin-4-amine

[0513]

[0514] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 eq) in toluene (4 mL) was added 2-bromo-4-iodopyridine (180 mg, 0.63 mmol, 1.5 eq), cesium carbonate (273 mg, 0.82 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.042 mmol, 0.1 eq), and tris(dibenzylideneacetone)dipalladium (39 mg, 0.042 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 16 h under N 2 under reduced pressure. 50 mL of water was poured into the mixture and extracted 3 times with ethyl acetate (20 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM / MeOH = 30 / 1) to afford N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (80 mg, yellow solid). LC-MS: 393.00 [M+1] +

[0515] Synthesis of 5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)pyridin-4-yl)pyridazin- ​

[0516]

[0517] At room temperature, N 2 To a solution of compound 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 eq), 4-bromo-2-chloro-5-fluoropyridine (134 mg, 0.64 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.04 mmol, 0.1 eq) and cesium carbonate (414 mg, 1.27 mmol, 3.0 eq) in dioxane (2 mL) was added tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.04 mmol, 0.1 eq). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water. The separated organic layer was washed with water, dried over (Na 2 SO 4 or MgSO 4 ) and evaporated to dryness. The residue was purified by Prep-TLC using DCM / MeOH = 20 / 1 to afford 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 1H NMR (400 MHz, DMSO) δ 9.84 (s, 1H), 9.30 (s, 1H), 8.78 (d, J = 6.1 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 7.94–7.81 (m, 3H), 7.56–7.15 (m, 3H).

[0518] ​ ​

[0519]

[0520] To a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (100 mg, 0.42 mmol, 1.0 eq) in toluene (4 mL) was added 2,6-dichloro-3-fluoropyridine (105 mg, 0.42 mmol, 1.0 eq), cesium carbonate (273 mg, 0.82 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.042 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 16 h under N 2 and then 50 mL of water was poured into the mixture and the mixture was extracted with ethyl acetate (20 mL) three times. It was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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 (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.26 (s, 1H), 8.24 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.56–7.10 (m, 4H).

[0521] ​ ​ ​

[0522]

[0523] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine (300 mg, 1.12 mmol, 1.0 eq), 2,4-dichloropyrimidine (184 mg, 1.24 mmol, 1.1 eq) and DIEA (434 mg, 3.36 mmol, 3.0 eq) in DMSO (5 mL) was stirred at 80 °C for 16 h. The mixture was poured into 60 mL of water and extracted with ethyl acetate (20 mL) three times. It was dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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] + 。

[0524] ​ ​ ​

[0525]

[0526] A mixture of 5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-amine (300 mg, 1.12 mmol, 1.0 eq), 2,4-dichloro-5-fluoropyrimidine (207 mg, 1.24 mmol, 1.1 eq) and DIEA (434 mg, 3.36 mmol, 3.0 eq) in DMSO (5 mL) was stirred at 80 °C for 16 h. The mixture was poured into 60 mL of water and extracted 3 times with ethyl acetate (20 mL), dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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] + 。

[0527] ​ 3-Amine(5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino) Pyridin-4-yl)pyridazin-3-amine)-Synthesis of Compound 428

[0528]

[0529] To a solution of N-(2-bromopyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-pyridazin-3-amine (80 mg, 0.20 mmol, 1.0 eq) in toluene (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (47 mg, 0.40 mmol, 2.0 eq), cesium carbonate (130 mg, 0.4 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.020 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.020 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 16 h under N 2 2. 50 mL of water was poured into the mixture and the mixture was extracted three times with ethyl acetate (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 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 (400 MHz, CD 3 OD) δ 9.15 (s, 1H), 7.97 (s, 1H), 7.87 (d, J = 7.4 Hz, 3H), 7.45 (s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 6.96 (m, J = 81.4, 65.7 Hz, 2H), 3.99 (d, J = 12.4 Hz, 2H), 3.77 (s, 2H), 2.66 (s, 2H), 1.28 (d, J = 6.0 Hz, 6H).

[0530] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyridin-4-yl) Pyridazin-3-amine(5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6- Dimethylmorpholino)-5-fluoropyridin-4-yl)pyridazin-3-amine)-Synthesis of Compound 469

[0531]

[0532] 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 eq) and (2R,6S)-2,6-dimethylmorpholine (85 mg, 0.74 mmol, 1.0 eq) in N-methyl-2-pyrrolidone (NMP, 5 mL) was added DIEA (143 mg, 1.11 mmol, 3.0 eq). 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 and dried over (Na 2 SO 4 or MgSO 4 ) and evaporated to dryness. The residue was purified by Prep-TLC using DCM / MeOH = 40 / 1 to afford 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 (400 MHz, CD 3 OD) δ 9.10 (s, 1H), 8.29 (d, J = 5.9 Hz, 1H), 7.87 (dd, J = 23.4, 5.9 Hz, 3H), 7.64 (d, 1H), 7.32 (d, J = 8.6 Hz, 2H), 6.94 (t, J = 73.5 Hz, 1H), 3.97 (d, J = 12.0 Hz, 2H), 3.70 (d, J = 6.4 Hz, 2H), 2.49–2.37 (m, 2H), 1.23 (d, J = 6.2 Hz, 6H).

[0533] 5-(4-(Difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl) Pyridazin-3-amine(5-(4-(difluoromethoxy)phenyl)-N-(6-((2R,6S)-2,6- Dimethylmorpholino)-3-fluoropyridin-2-yl)pyridazin-3-amine)-Synthesis of Compound 223

[0534]

[0535] 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 eq) was added (2R,6S)-2,6-dimethylmorpholine (95 mg, 0.82 mmol, 3.0 eq), and DIEA (109 mg, 0.82 mmol, 3.0 eq) in NMP (4 mL). The reaction mixture was stirred at 200 °C under microwave for 1 h. 50 mL of water was poured into the mixture and extracted 3 times with ethyl acetate (20 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 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 (400 MHz, CD 3 OD) δ 9.03 (s, 1H), 8.75 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 21.2, 9.2 Hz, 3H), 6.94 (t, J = 73.6 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 12.2 Hz, 2H), 3.64 (s, 2H), 2.38 (t, J = 11.4 Hz, 2H), 1.08 (d, J = 6.1 Hz, 6H).

[0536] N-(5-(4-(Difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpho Lino)pyrimidin-4-amine(N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2- ((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine)-Synthesis of Compound 305

[0537]

[0538] 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 eq) in IPA (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (137 mg, 1.20 mmol, 3.0 eq), DIEA (154 mg, 1.20 mmol, 3.0 eq). Then the reaction mixture was in N 2Stir overnight at below 90 °C. Concentrate the mixture under reduced pressure. Purify the residue by silica gel column chromatography, eluting with (PE / EA = 5 / 1 to 2 / 1) to obtain 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 (400 MHz, CD 3 OD) δ 8.95 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 16.0, 4.0 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.85 (t, J = 74.0 Hz, 1H), 6.27 (d, J = 5.8 Hz, 1H), 4.36 (d, J = 13.0 Hz, 2H), 4.06 (s, 3H), 3.56 (d, J = 6.2 Hz, 2H), 2.57–2.46 (m, 2H), 1.07 (d, J = 6.2 Hz, 6H).

[0539] 5-(4-(Difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)ami No)pyridin-2(1H)-one(5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6- Dimethylmorpholino)pyrimidin-4-yl)amino)pyridin-2(1H)-one)-Synthesis of Compound 264

[0540]

[0541] 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 eq) in dimethylformamide (DMF; 1.5 mL) was added lithium bromide (95 mg, 1.090 mmol, 10.0 eq), and then the reaction mixture was stirred overnight at 120 °C under N 2 2. Add water (7 mL), and extract 3 times with ethyl acetate (10 mL). Dry over Na 2 SO 4 4. Concentrate the filtrate under reduced pressure. Purify the residue by HPLC to obtain 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 (400 MHz, CD 3OD) δ 8.92 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 5.8 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.22 (dd, J = 16.5, 5.5 Hz, 3H), 6.84 (t, J = 70.2 Hz, 2H), 6.27 (d, J = 5.8 Hz, 2H), 4.38 (d, J = 11.3 Hz, 2H), 3.58 (d, J = 6.3 Hz, 2H), 2.55 (dd, J = 13.0, 10.7 Hz, 2H), 1.11 (d, J = 6.2 Hz, 6H); 19 19F NMR (400 MHz, DMSO-d 6 ) δ -83.55, δ -83.74.

[0542] N-(5-(4-(Difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpho Lino)-5-fluoropyrimidin-4-amine(N-(5-(4-(difluoromethoxy)phenyl)-2-methoxypyridin-3-yl)- Synthesis of 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine)-Compound 387

[0543]

[0544] 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 eq) in IPA (4 mL) was added (2R,6S)-2,6-dimethylmorpholine (261 mg, 2.27 mmol, 3.0 eq) and DIEA (93 mg, 2.27 mmol, 3.0 eq). Then the reaction mixture was stirred at 90 °C overnight under N 2 2. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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)-5-fluoropyrimidin-4-amine (200 mg, white solid). LC-MS: 476.35 [M+1] + ; 1 1H NMR (400 MHz, CDCl 3 ) δ 9.01 (s, 1H), 7.98 (d, J = 17.6 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 6.53 (t, J = 73.6 Hz, 1H), 4.37 (d, J = 13.0 Hz, 2H), 4.11 (s, 3H), 3.64 (s, 2H), 2.60 (t, J = 11.7 Hz, 2H), 1.19 (d, J = 6.1 Hz, 6H).

[0545] 5-(4-(Difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridin-2(1H)-one (5-(4-(difluoromethoxy)phenyl)-3-((2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridin-2(1H)-one)-Synthesis of Compound 346 Synthesis

[0546]

[0547] 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 eq) in DMF (1.5 mL) was added lithium bromide (92 mg, 1.050 mmol, 10.0 eq), and then the reaction mixture was stirred at 120 °C under N 2 overnight. Water (7 mL) was added, and the mixture was extracted three times with ethyl acetate (10 mL) and dried over Na 2 SO 4 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 (400 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 8.73 (s, 1H), 8.19–8.10 (m, 2H), 7.62 (d, J = 8.6 Hz, 2H), 7.44 (s, 1H), 7.19 (dd, J = 41.4, 32.7 Hz, 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 (400 MHz, DMSO-d 6 ) δ -82.26, δ -82.46, δ -169.61.

[0548] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-6-fluoropyrimidin-4-yl) Pyridazin-3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6- dimethylmorpholino)-6-fluoropyrimidin-4-yl)pyridazin-3-amine)-Synthesis of Compound 131

[0549]

[0550] At 0 °C, sodium hydride (13 mg, 0.33 mmol, 1.5 eq) was added to a solution of 5-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (52 mg, 0.22 mmol, 1.0 eq) in DMF (1 mL). The mixture was stirred at 0 °C for 0.5 h, then DMF (0.5 mL) containing (2R,6S)-4-(4,6-difluoropyrimidin-2-yl)-2,6-dimethylmorpholine (50 mg, 0.26 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 2 h. 30 mL of water was poured into the mixture and it was extracted 3 times with ethyl acetate (20 mL). The organic phases were combined, washed with brine, dried over anhydrous Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-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 (400 MHz, DMSO-d 6 ) δ 10.69 (s, 1H), 9.25 (s, 1H), 8.49 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.54–7.15 (m, 3H), 6.30 (s, 1H), 4.29 (d, J = 12.4 Hz, 2H), 3.53 (s, 2H), 2.55 (s, 2H), 1.05 (s, 6H).

[0551] Synthesis of 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (6-chloro-4-(4- (difluoromethoxy)phenyl)-3-methoxy-pyridazine)

[0552]

[0553] At room temperature, N 2A solution of 6-chloro-4-iodo-3-methoxypyridazine (200 mg, 0.74 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (139 mg, 0.74 mmol, 1.0 eq) and potassium phosphate (471 mg, 2.22 mmol, 3.0 eq) in dioxane / water (6 mL / 0.6 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.07 mmol, 0.1 eq). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (90 mL) and water (150 mL). The separated organic layer was washed with water, dried over anhydrous Na 2 SO 4 and evaporated to dryness. The residue was purified by Prep-TLC with PE / EA = 5 / 1 to give 6-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (120 mg, 57%) as a yellow solid. LCMS: 287.03 [M+1] + ; 1 H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.54–7.09 (m, 3H), 4.04 (s, 3H).

[0554] 5-(4-(Difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4- yl)-6-methoxypyridazin-3-amine (5-(4-(difluoromethoxy)phenyl)-N-(2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)-6-methoxypyridazin-3-amine)-Synthesis of Compound 526

[0555]

[0556] At room temperature, in N 26-chloro-4-(4-(difluoromethoxy)phenyl)-3-methoxypyridazine (120 mg, 0.42 mmol, 1.0 eq), 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (142 mg, 0.63 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.04 mmol, 0.1 eq), and cesium carbonate (409 mg, 1.26 mmol, 3.0 eq) were added to a solution of tris(dibenzylideneacetone)dipalladium (39 mg, 0.04 mmol, 0.1 eq) in dioxane (2 mL). The reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture 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 Na 2 SO 4 and evaporated to dryness. The residue was purified by Prep-TLC using PE / EA = 2 / 1 to afford 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 (400 MHz, DMSO) δ 10.25 (s, 1H), 8.31 (s, 1H), 8.09 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.50–7.11 (m, 3H), 4.09 (s, 2H), 4.02 (s, 3H), 3.41 (s, 2H), 2.34 (t, J = 11.5 Hz, 2H), 0.88 (s, 6H).

[0557] 5-(4-(Difluoromethoxy)phenyl)-N3-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4- yl)pyridazine-3,6-diamine (5-(4-(difluoromethoxy)phenyl)-N3-(2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)pyridazine-3,6-diamine)-Synthesis of Compound 598 Synthesis

[0558]

[0559] Step a: To a solution of 4-bromo-6-chloropyridazin-3-amine (1.2 g, 5.77 mmol, 1.0 eq) in tetrahydrofuran (THF; 10 mL) was added di-tert-butyl dicarbonate (2.5 g, 11.54 mmol, 2.0 eq), TEA (1.75 g, 17.31 mmol, 3.0 eq). The reaction mixture was stirred at 60 °C for 3 h. 100 mL of water was poured into the mixture and extracted 3 times with ethyl acetate (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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 (400 MHz, CDCl 3 ) δ 7.86 (s, 1H), 1.41 (s, 18H).

[0560] Step b: To a solution of the bis-N-Boc compound (408 mg, 1.0 mmol, 1.0 eq) in toluene / water (5 mL / 1 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 eq), potassium phosphate (636 mg, 3.0 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (73 mg, 0.1 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C for 16 h under N 2 . Then the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA = 3 / 1) to give the bis-N-Boc protected 6-chloro-4-(4-(difluoromethoxy)phenyl)pyridazin-3-amine (255 mg, crude). LCMS: [M+1]: 472.15

[0561] 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 eq) in toluene (5 mL) was added 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (72 mg, 0.32 mmol, 1.0 eq), cesium carbonate (208 mg, 0.64 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg, 0.032 mmol, 0.1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (24 mg, 0.032 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C under N 2 for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA = 3 / 1) to give the coupling product (90 mg). LCMS: [M+1]: 662.2; 1 H NMR (400 MHz, CDCl 3 ) δ 8.77 (s, 1H), 8.17 (s, 1H), 8.06 (s, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.26–7.23 (m, 2H), 6.55 (t, J = 72.0 Hz, 1H), 4.26 (d, J = 12.0 Hz, 2H), 3.59 (s, 2H), 2.56 (t, J = 12.2 Hz, 2H), 1.32 (s, 18H), 1.12 (d, J = 6.0 Hz, 6H).

[0562] Step d: The Boc-protected compound was added to hydrochloric acid / ethyl acetate (HCl / EA; 4 M, 5 mL). The reaction mixture was stirred at 40 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure. 50 mL of sodium bicarbonate (aqueous) was poured into the residue and extracted 3 times with ethyl acetate (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by prep-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). LCMS: [M+1]: 462.15; 1 H NMR (400 MHz, CD 3OD) δ 8.46 (s, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 6.99 (t, J = 73.2 Hz, 1H), 4.06 (d, J = 13.0 Hz, 2H), 3.58 (s, 2H), 2.64 (t, J = 11.8 Hz, 2H), 1.05 (d, J = 5.2 Hz, 6H).

[0563] 4-(4-(Difluoromethoxy)phenyl)-N6-(2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4- 4-(4-(difluoromethoxy)phenyl)-N6-(2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)-N3-methylpyridazine-3,6-diamine)- Synthesis of compound 544

[0564]

[0565] Step a: To a solution of 6-chloro-N-methylpyridazin-3-amine (1.0 g, 7.0 mmol, 1.0 eq) in acetic acid / water (AcOH / H 2 O; 5 mL / 5 mL) was added bromine (3.36 g, 21 mmol, 3.0 eq), potassium bromide (2.5 g, 21 21 mmol, 3.0 eq) and potassium acetate (1.03 g, 10.5 mmol, 1.5 eq). The reaction mixture was stirred at 80 °C for 16 h. 100 mL of water was poured into the mixture and it was extracted 3 times with ethyl acetate (35 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 6.98 (s, 1H), 2.90 (d, J = 3.9 Hz, 3H).

[0566] Step b: To a solution of 4-bromo-6-chloro-N-methylpyridazin-3-amine (400 mg, 1.79 mmol, 1.0 eq) in THF (7 mL) was added di-tert-butyl dicarbonate (782 mg, 3.59 mmol, 2.0 eq), TEA (542 mg, 5.37 mmol, 3.0 eq) and DMAP (22 mg, 0.179 mg, 0.1 eq). The reaction mixture was stirred at 60 °C for 3 h. 100 mL of water was poured into the mixture and it was extracted 3 times with ethyl acetate (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting 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] +

[0567] Step c: To a solution of tert-butyl (4-bromo-6-chloropyridazin-3-yl)(methyl)carbamate (320 mg, 1.0 mmol, 1.0 eq) in toluene / water (5 mL / 1 mL) was added (4-(difluoromethoxy)phenyl)boronic acid (188 mg, 1.0 mmol, 1.0 eq), potassium phosphate (636 mg, 3.0 mmol, 3.0 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (73 mg, 0.1 mmol, 0.1 eq). The reaction mixture was stirred at 110 °C under N 2 for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-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 1H NMR (400 MHz, CDCl 3 ) δ 7.52–7.40 (m, 3H), 7.27 (d, J = 7.1 Hz, 2H), 6.56 (t, J = 73.0 Hz, 1H), 3.48 (s, 3H), 1.08 (s, 3H).

[0568] 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 eq) in toluene (5 mL) was added 2-((2R,6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-amine (41 mg, 0.18 mmol, 1.0 eq), cesium carbonate (117 mg, 0.36 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg, 0.018 mmol, 0.1 eq) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (14 mg, 0.018 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C under N 2 for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-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 (400 MHz, CDCl 3 ) δ 8.71 (s, 0H), 8.06 (d, J = 14.0 Hz, 1H), 7.47 (s, 2H), 6.53 (t, J = 73.0 Hz, 1H), 4.27 (s, 2H), 3.59 (s, 2H), 3.43 (s, 3H), 2.56 (t, J = 11.7 Hz, 2H), 1.10 (d, J = 37.3 Hz, 5H).

[0569] 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 eq) was added to HCl / EA (4 M, 5 mL). The reaction mixture was stirred at 40 °C for 1 h. Then the reaction mixture was concentrated under reduced pressure. 50 mL of sodium bicarbonate (aqueous) was poured into the residue and extracted 3 times with ethyl acetate (30 mL), over anhydrous Na 2 SO 4Dry, filter, and concentrate under reduced pressure. Purify the residue by prep-TLC (PE / EA = 1 / 1) to obtain 4-(4-(difluoromethoxy)phenyl)-N 6 -(2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)-N 3 -methylpyridazine-3,6-diamine (18.5 mg). LCMS: [M+1]: 476.20; 1 H NMR (400 MHz, CD 3 OD) δ 8.33 (s, 1H), 8.02 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.96 (t, J = 73.3 Hz, 1H), 4.20 (d, J = 13.0 Hz, 2H), 3.52 (s, 2H), 3.02 (s, 3H), 2.42 (t, J = 11.5 Hz, 2H), 1.03 (d, J = 6.1 Hz, 6H).

[0570] 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidine-4- 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylate)-chemical Synthesis of Compound 616

[0571]

[0572] Step a: At room temperature, add tris(dibenzylideneacetone)dipalladium (810 mg, 0.88 mmol, 0.1 eq) to a solution of 2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-amine (2 g, 8.85 mmol, 1.0 eq), methyl 4,6-dichloropyridazine-3-carboxylate (2.7 g, 13.27 mmol, 1.5 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (512 g, 0.88 mmol, 0.1 eq), and cesium carbonate (8.6 g, 26.55 mmol, 3.0 eq) in toluene (20 mL). Then stir the reaction mixture at 80 °C under N 2 for 16 h. Concentrate the reaction mixture under reduced pressure. Partition the residue between ethyl acetate (100 mL) and water. Wash the separated organic layer with water and pass through Na 2 SO 4Dry and evaporate to dryness. The residue was purified by silica gel column 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 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.63 (s, 1H), 8.23 (d, J = 2.8 Hz, 1H), 4.21 (d, J = 12.1 Hz, 2H), 3.93 (s, 3H), 3.53 (d, J = 6.3 Hz, 2H), 2.52 (m, 2H), 1.11 (d, J = 6.1 Hz, 6H).

[0573] Step b: At room temperature, add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (370 mg, 0.51 mmol, 0.1 eq) 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 eq), (4-(difluoromethoxy)phenyl)boronic acid (1.3 g, 7.58 mmol, 1.5 eq) and potassium phosphate (3.2 g, 15.15 mmol, 3.0 eq) in dioxane / water (40 mL / 4 mL). Then stir the reaction mixture at 110 °C for 16 h under N 2 2. Under nitrogen atmosphere. Concentrate the reaction mixture under reduced pressure. Partition the residue between ethyl acetate (100 mL) and water. Wash the separated organic layer with water, dry over Na 2 2SO4 and evaporate to dryness. Purify the residue 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] 2 SO 4 4.+ ; 1 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.55 (s, 1H), 8.21 (d, J = 3.1 Hz, 1H), 7.54–7.15 (m, 5H), 4.11 (s, 2H), 3.76 (s, 3H), 3.44 (s, 2H), 2.43–2.34 (t, 2H), 0.93 (s, 6H).

[0574] 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidine-4- 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6- dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylic Synthesis of Compound 562

[0575]

[0576] 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 eq) in tetrahydrofuran / water (5 mL / 5 mL) was added lithium hydroxide monohydrate (LiOH·H 2 2O; 433 mg, 10.32 mmol, 4.0 eq). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and 1 N aqueous hydrochloric acid (100 mL). The separated organic layer was washed with water, dried over Na 2 2SO 4 4 and evaporated to dryness. To the residue was added MeOH (10 mL) at room temperature and stirred for 1 h. Then the mixture was filtered, and the filter cake was diluted twice with MeOH (10 mL) 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] + ; 11H NMR (400 MHz, DMSO) δ 13.74 (s, 1H), 10.82 (s, 1H), 8.51 (s, 1H), 8.20 (d, J = 3.1 Hz, 1H), 7.56 - 7.14 (m, J = 8.6 Hz, 5H), 4.12 (s, 2H), 3.44 (s, 2H), 2.42–2.35 (t, 2H), 0.93 (s, 6H).

[0577] 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidine- 4-yl)amino)pyridazin-3-yl)ethan-1-one (1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R, 6S)-2,6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)pyridazin-3-yl) Synthesis of ethan-1-one)-compound 580

[0578]

[0579] 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 eq) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 93 mg, 0.24 mmol, 1.2 eq) in DMF (2 mL) was added N,O-dimethylhydroxylamine hydrochloride (24 mg, 0.24 mmol, 1.2 eq) and DIEA (79 mg, 0.60 mmol, 3.0 eq). 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 Na 2 SO 4 dried and evaporated to dryness. The residue was purified by prep-TLC using DCM / MeOH = 20 / 1 to afford 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. 11H NMR (400 MHz, DMSO) δ 10.70 (s, 1H), 8.56 (s, 1H), 8.19 (d, J = 3.1 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.8 Hz, 3H), 4.14 (d, J = 11.5 Hz, 2H), 3.53 (s, 3H), 3.48–3.41 (m, 2H), 3.20 (s, 3H), 2.41 (t, J = 12.7 Hz, 2H), 0.92 (s, 6H).

[0580] Step b: At N 2 under 0 °C, MeMgBr (0.18 mL, 0.18 mmol, 1.2 eq) was added to a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)amino)-N-methoxy-N-methylpyridazine-3-carboxamide (80 mg, 0.15 mmol, 1.0 eq) in THF (1 mL). The reaction mixture was stirred at room temperature for 2 h. Aqueous ammonium chloride 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 Na 2 SO 4 and evaporated to dryness. The residue was purified by prep-TLC using DCM / MeOH = 20 / 1 to give 1-(4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholin-4-yl)-5-fluoropyrimidin-4-yl)amino)pyridazin-3-yl)ethan-1-one (40 mg, 55%) as a white solid. LCMS: 489.20 [M+1] + ; 1 1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 8.42 (s, 1H), 8.22 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.22 (m, J = 41.2, 32.6 Hz, 3H), 4.10 (s, 2H), 3.43 (s, 2H), 2.73 (s, 3H), 2.41–2.33 (t, 2H), 0.93 (s, 6H).

[0581] 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidine-4- 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2, 6-dimethylmorpholino)-5-fluoropyrimidin-4-yl)amino)-N-methylpyridazine-3- Synthesis of carboxamide)-compound 634

[0582]

[0583] To a solution of 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-5-fluoropyrimidin-4-yl)amino)pyridazine-3-carboxylic acid (100 mg, 0.2 mmol, 1.0 eq) and HATU (93 mg, 0.24 mmol, 1.2 eq) in DMF (2 mL) was added methylamine hydrochloride (17 mg, 0.24 mmol, 1.2 eq) and DIEA (79 mg, 0.60 mmol, 3.0 eq). 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 and dried over Na 2 SO 4 and evaporated to dryness. The residue was purified by prep-TLC using DCM / MeOH = 20 / 1 to afford 4-(4-(difluoromethoxy)phenyl)-6-((2-((2R,6S)-2,6-dimethylmorpholinyl)-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 (400 MHz, DMSO) δ 10.73 (s, 1H), 8.79 (d, J = 4.5 Hz, 1H), 8.45 (s, 1H), 8.19 (d, J = 3.2 Hz, 1H), 7.52 (t, J = 6.6 Hz, 2H), 7.24 (m, J = 41.1, 32.6 Hz, 3H), 4.11 (s, 2H), 3.43 (s, 2H), 2.72 (d, J = 4.6 Hz, 3H), 2.42–2.35 (t, 2H), 0.92 (s, 6H).

[0584] Synthesis of N-(5-bromo-2-fluoropyridin-3-yl)-2-chloropyrimidin-4-amine yl)-2-chloropyrimidin-4-amine)

[0585]

[0586] A mixture of 5-bromo-2-fluoropyridin-3-amine (500 mg, 2.6 mmol, 1.0 eq), 2,4-dichloropyrimidine (770 mg, 5.2 mmol, 2.0 eq) in DIEA (0.5 mL) was stirred at 119 °C for 16 h. DCM (5 mL) was added and the residue was purified by silica gel column chromatography, eluting with (DCM / MeOH = 200 / 1 to 50 / 1) to give the crude product. The crude product was purified by prep-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.

[0587] Synthesis of N-(5-bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-amine bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4- amine)

[0588]

[0589] A mixture of N-(5-bromo-2-fluoropyridin-3-yl)-2-chloropyrimidin-4-amine (50 mg, 0.17 mmol, 1.0 eq), (2R,6S)-2,6-dimethylmorpholine (38 mg, 0.33 mmol 2.0 eq) and DIEA (64 mg, 0.50 mmol, 3.0 eq) in IPA (1 mL) was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-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.

[0590] Synthesis of N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholino) pyrimidin-4-amine (N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridin-3-yl)-2-((2R,6S)- 2,6-dimethylmorpholino)pyrimidin-4-amine) - Synthesis of Compound 182

[0591]

[0592] In N 2Downward N-(5-bromo-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholinyl)pyrimidin-4-amine (27 mg, 0.07 mmol, 1.0 eq), (4-(difluoromethoxy)phenyl)boronic acid (26 mg, 0.14 mmol, 2.0 eq), and potassium phosphate (45 mg, 0.21 mmol, 3.0 eq) were added to a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5 mg, 0.007 mmol, 0.1 eq) in dioxane / water (1 mL / 0.1 mL). The reaction mixture was stirred at 110 °C under N 2 for 16 h. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (DCM / MeOH = 20 / 1) to give N-(5-(4-(difluoromethoxy)phenyl)-2-fluoropyridin-3-yl)-2-((2R,6S)-2,6-dimethylmorpholinyl)pyrimidin-4-amine (2.5 mg). LCMS: [M+1] + : 446.30; 1 H NMR (400 MHz, DMSO-d 6 ): 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).

[0593] Methods for the preparation and use of related compounds are disclosed in PCT / TR2019 / 050164, PCT / TR2019 / 050951, and U.S. 63 / 173,796; the content of each of these applications is incorporated herein by reference in its entirety.

[0594] Example 2: Exemplary Biological Activity of Compounds of the Present Disclosure

[0595] Cell Culture and Reagents

[0596] Human breast cancer cell line MDA-MB-231 and human endometrial cancer cell line HEC-59 were purchased from American Type Culture Collection (ATCC, USA). MDA-MB-231 cells were cultured in Dulbecco's modified Eagle's medium (Lonza, New Jersey, USA), and HEC-59 cells were grown in Iscove's Modified Dulbecco's Medium (Lonza, New Jersey, USA) supplemented with 10% fetal bovine serum (FBS; Lonza), 1% non-essential amino acid (NEAA), 2 mM L-glutamine (Sigma Aldrich, Missouri, USA) and 50 U / ml penicillin / streptomycin (P / S). All cell lines were tested regularly using the MycoAlert Mycoplasma Detection Kit (Lonza). The cumulative time between thawing and use in the experiments was less than 20 generations.

[0597] Cell Viability Assay Protocol

[0598] MDA-MB-231 and HEC-59 cells were seeded in 96-well plates at 4000 cells / well with 80 μL of medium / well. Approximately 18 hours later, 3-fold drug solutions were prepared by serial dilution (100, 10, 5, 1, 0.5, 0.3, 0.1, 0.05, 0.01 μM), and medium containing drugs was added to each well in a volume of 40 μL. For MDA-MB-231, sulfadoxetine B (SRB) or Bioluminescent cell viability ( Luminescent Cell Viability (CTG) analysis. For HEC59, medium containing drugs was refreshed on day 4. After a total of 7 days, SRB or CTG analysis was performed.

[0599] Table 3. Cell Viability Data in MDA-MB-231 and HEC-59

[0600]

[0601]

[0602] Example 3: Further Exemplary Biological Activity of Compounds of the Present Disclosure

[0603] Six- to eight-week-old female athymic Balb / c nude mice were housed in a temperature-controlled environment with a 12-hour light / 12-hour dark cycle. For in vivo colon cancer tumor growth, 5×10 6 human colon cancer cells (RKO cells) were prepared in 100 μl of DMEM and injected into the right flank of female nude mice. The body weight and tumor volume of the mice were measured twice a week. The tumor volume was calculated as length × width 2 × 0.5. Once the tumor volume reached approximately 150 to 175 mm 3 , the xenografts were randomly grouped (8 mice per group). As mentioned in the table, the animals were treated with vehicle, compound 80, or oxaliplatin. The formulations of vehicle and compound 80 were acetate buffer solutions that ultimately contained 50% polyethylene glycol 400 (PEG400) and 20% polyoxyl 40 hydrogenated castor oil (Cremophor RH40), pH = 4. Oxaliplatin was prepared in a glucose solution. Approximately 3 weeks later or if the tumor reached a predetermined tumor volume cutoff of 2500 mm 3 , the mice were sacrificed. Compound 80 exhibited strong tumor growth inhibitory effects in a dose-dependent manner in the RKO xenograft, with 85% tumor growth inhibition (TGI) at the highest dose ( Figure 1 ).

[0604]

[0605] 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 the SKOV-3 xenograft, 200 μl of DMEM:Matrigel = 1:1 (Thermo Fisher, New Jersey, USA) containing 1.5×10 7 SKOV-3 cells, and for the MDA-MB-231 xenograft, 100 μl of DMEM:Matrigel = 1:1 (Thermo Fisher, New Jersey, USA) containing 1×10 7 MDA-MB-231 cells were injected into the right flank of six- to eight-week-old female athymic Balb / c nude mice. When the tumor volume of the SKOV-3 xenograft reached an average of approximately 200 mm 3and when the tumor volume of the MDA-MB-231 xenograft reached 150 to 175 mm 3 between, the mice were randomly grouped into groups of 8 each, and treatment with vehicle, 20 mpk BID, 25 mpk BID, and 30 mpk BID of Compound 80 was initiated. For the HEC-59 xenograft, 1 × 10 7 HEC-59 cells in 100 μl of DMEM (Lonza, New Jersey, USA) were injected into the right flank of six- to eight-week-old female athymic Balb / c nude mice. When the tumor volume reached an average of approximately 150 mm 3 , the mice were randomly grouped into groups of 8 mice each, and treatment with vehicle, 20 mpk BID, 40 mpk QD, and 30 / 40 mpk BID of Compound 80 was initiated. Statistically significant tumor growth inhibition or regression was observed.

[0606] Incorporated by Reference

[0607] All publications and patents mentioned herein are hereby 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 any definitions herein, shall control.

[0608] Equivalents

[0609] Although specific embodiments of the invention have been discussed, the above description is illustrative and not restrictive. After reading this specification and the following claims, many variations of the invention will become apparent to those of ordinary skill in the art. The full scope of the invention should be determined with reference to the full scope of the claims and their equivalents, as well as the specification and such variations.

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1, wherein the compound is 3. The compound according to claim 1, wherein the compound is 4. The compound according to claim 1, wherein the compound is 5. The compound according to claim 1, wherein the compound is 6. The compound according to claim 1, wherein the compound is 7. The compound according to claim 1, wherein the compound is 8. The compound according to claim 1, wherein the compound is 9. The compound according to claim 1, wherein the compound is 10. The compound according to claim 1, wherein the compound is 11. The compound according to claim 1, wherein the compound is 12. The compound according to claim 1, wherein the compound is 13. The compound according to claim 1, wherein the compound is 14. The compound according to claim 1, wherein the compound is 15. The compound according to claim 1, wherein the compound is 16. The compound according to claim 1, wherein the compound is 17. The compound according to claim 1, wherein the compound is 18. Use of the compound according to any one of claims 1 - 17 in the manufacture of a medicament for the treatment of cancer.

19. The use according to claim 18, wherein the cancer is breast cancer, ovarian cancer, esophageal cancer, endometrial cancer, prostate cancer, colon cancer, pancreatic cancer, head and neck cancer or lung cancer.

20. The use according to claim 18, wherein the cancer is breast cancer.

21. The use according to claim 18, wherein the cancer is ovarian cancer.

22. The use according to claim 18, wherein the cancer is esophageal cancer.

23. The use according to claim 18, wherein the cancer is endometrial cancer.

24. The use according to claim 18, wherein the cancer is prostate cancer.

25. The use according to claim 18, wherein the cancer is colon cancer.

26. The use according to claim 18, wherein the cancer is pancreatic cancer.

27. The use according to claim 18, wherein the cancer is head and neck cancer.

28. The use according to claim 18, wherein the cancer is lung cancer.

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