Compositions and methods for treating cancer

Abstract

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

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 173,796, filed April 12, 2021, the contents of which are incorporated by reference in their entirety herein. [Background technology]

[0002] Cancer is a complex disease characterized by uncontrolled cell division. In the United States, among cancer types, breast, lung, and colorectal cancer account for 50% of all cases in women, while prostate, lung, and colorectal cancer account for 46% of all newly diagnosed cases in men (Siegel et al., 2021). Although the U.S. Food and Drug Administration (FDA) has approved new indications for several novel drugs and therapeutic agents currently in clinical use for cancer treatment, there are still millions of cancer deaths annually worldwide.

[0003] Understanding of tumor biology has led to the continuous development of targeted drug therapy to improve patient survival. Considering the side effects of currently available chemotherapy drugs, the development of targeted therapy that causes less toxicity has become a major focus in recent years. Because cancer is characterized as abnormal and uncontrollable cell growth that has the potential to invade or spread to other parts of the body or malignant tumors, drugs or substances that target and inhibit the function of specific macromolecules involved in the growth and survival of tumor cells are used in cancer targeted therapy.

[0004] Microtubule reorganization is a critical step during cell division, and drugs that interfere with this process have become a major focus of cancer research. Antimitotic drugs disrupt the polymerization dynamics of microtubules by activating the spindle assembly checkpoint (SAC), preventing the metaphase to anaphase transition. As a result, cells stop dividing and these mitotically arrested cells die. Continued investigation of the mechanisms of mitotic events may lead to new target protein candidates and / or pathways for the treatment of cancer. Antimicrotubule agents, such as vinca alkaloids, maytansinoids and taxanes, are examples of such drugs that are widely used as chemotherapeutic agents for various tumors (Marzo & Naval, 2013). However, these compounds are toxic to non-tumorigenic cells and can result in severe side effects.

[0005] Drug resistance is another major problem that causes patients' response to these drugs to be highly unpredictable (Gascoigne & Taylor, 2009). To overcome these problems and improve chemotherapy response, antimitotic cancer-specific therapies targeting mitosis-specific kinases and microtubule motor proteins have been identified (Dominguez-brauer et al., 2015). Importantly, since phosphorylation is a key step in cell cycle regulation and spindle formation, kinases with roles in these processes have been identified as potential targets. Among these, specific inhibitors against cyclin-dependent kinases (Cdks), Aurora kinases and Polo-like kinases (PLKs) have been developed and are in clinical trials (Sanchez-martinez, Gelbert, Lallena, & De dios, 2015; Strebhardt & Ullrich, 2006; Tang et al., 2017). Compared to anti-microtubule agents, and despite their low toxicity, none of these anti-mitotic drugs have good clinical outcomes (Chan, Koh, & Li, 2012). The lack of efficacy of anti-mitotic drugs may be due, in part, to the fact that cancer cells in clinical tumors are mainly in interphase (Ogden et al., 2013). Therefore, therapeutic strategies that target not only mitosis but also interphase-specific activities such as migration or transcriptional reprogramming, and that induce anti-tumor immunity, may provide superior efficacy in tumors resistant to microtubule-targeting agents. Such therapies are expected to have high translational potential to ultimately improve clinical outcomes. Summary of the Invention

[0006] In one aspect, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; A is heteroaryl, and R 1 is H, alkyl, or benzyl.

[0007] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0008] In yet another aspect, the present disclosure provides a method of treating a TACC-mediated disease or disorder in a subject, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0009] [Figure 1] 1 shows the in vivo activity of exemplary compounds of the present disclosure. Tumor growth inhibition was observed at specific dose levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Transforming acidic coiled-coil protein (TACC) family members have emerged as important proteins for microtubule- and centrosome-related functions. Vertebrates express three different isoforms of TACC: TACC1, TACC2, and TACC3. TACC has been found to play important roles in gene regulation, cell proliferation and differentiation, mRNA processing, transcription, migration, etc. by interacting with different molecules involved in microtubule / centrosome dynamics (Ha et al., 2013). Members share a conserved domain called the TACC domain, which is required for TACC protein to interact with the spindle and centrosomal apparatus (Gergely et al., 2000). Although TACC family members were described as centrosomal proteins, they also distribute throughout the cell during interphase. For example, TACC3 and TACC2 form complexes with different histone acetyltransferases, including hGCN5L2 and pCAF, indicating their regulatory function in transcription (Gangisetty et al., 2004). Notably, TACC3 interacts with MBD2 (mCpG-binding domain 2) in interphase nuclei, where it promotes the association of MBD2 with histone acetyltransferases to reactivate methylated promoters.

[0011] TACC protein levels are elevated in many cancer types, including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, and breast cancer. The first member of the TACC family, TACC1, was independently discovered as breast cancer amplicon 8p11 (Still et al., 1999) and was later found to be capable of promoting breast tumorigenesis, possibly via activation of the Ras / PI3K signaling pathway (Cully et al., 2005). TACC2 has been found to promote androgen-mediated proliferation in prostate cancer and is associated with poor prognosis (Takayama et al., 2012). Moreover, overexpression of TACC2 results in proliferation of breast cancer cells (Cheng et al., 2010). When disrupted, TACC3 also causes a variety of different cellular outcomes, including multipolar spindle formation leading to mitotic arrest (Yao et al., 2012), chromosome misalignment leading to caspase-dependent apoptosis (Schneider et al., 2007), and in some cases senescence (Schmidt et al., 2010). Moreover, knockdown of TACC3 suppresses tumor formation and cell proliferation in renal cell carcinoma (RCC) (Guo & Liu, 2018).The aforementioned studies indicate that TACC family proteins are registered important molecules in spindle formation in cancer cells, which makes them important and potential targets for cancer targeted therapy.

[0012] However, to date, there are no inhibitors available for TACC1 and TACC2, and only two inhibitors targeting TACC3. KHS101, a small molecule TACC3 inhibitor, was first identified to promote neuronal differentiation in rats (Wurdak et al., 2010). Although tumor growth of glioblastoma (GBM) xenografts was suppressed by KHS101 treatment (Polson et al., 2018), KHS101 has many drawbacks, such as low oral systemic stability and high working dose (Wurdak et al., 2010). Another TACC3 inhibitor, SPL-B, has been shown to inhibit centrosomal microtubule nucleation in ovarian cancer cells and suppress tumor growth in ovarian cancer xenografts (Yao et al., 2014). However, similar to KHS101, SPL-B has not been approved for the treatment of cancer.

[0013] In view of the above, there is a clear unmet need for new TACC inhibitors for the treatment of cancer and other TACC-mediated diseases.

[0014] In one aspect, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; A is heteroaryl, and R 1 is H, alkyl, or benzyl.

[0015] In certain preferred embodiments, A is not an isoxazole.

[0016] In certain embodiments, A is pyrrole, furan, selenophene, thiophene, imidazole, pyrazole, oxazole, oxathiol, isoxathiol, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, or dithiazole. In certain preferred embodiments, A is pyrazole.

[0017] In certain embodiments, the compound is represented by formula Ia or Ib. [ka] [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; X 1 , CH2, NR 2 , O, and S; X 2 is selected from CH or N; X 3 CR 3 or N, R 1 and R 2 are each independently H, alkyl, or benzyl; and R 3 is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamido.

[0018] In certain embodiments, the compound is represented by formula Ia: [ka] [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; X 1 is C or N, X 2 , CH2, NR 2 , O, or S; X 3 CR 3 or N, R 1 and R 2 are each independently H, alkyl, or benzyl; and R 3 is alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

[0019] In certain embodiments, X 1 is N. In other embodiments, X 1 is CH.

[0020] In certain embodiments, X 2 is NR 2 In certain embodiments, R 2 is H. In other embodiments, R 2 is alkyl. In certain preferred embodiments, R 2 is methyl.

[0021] In certain embodiments, X 2 is S. In other embodiments, X 2 is O.

[0022] In certain embodiments, X 3 is CR 3 In certain embodiments, R 3 is H. In other embodiments, R 3 is alkyl. In certain embodiments, R 3 is methyl.

[0023] In certain embodiments, R 1 is H. In other embodiments, R 1 is alkyl. In certain embodiments, R 1 is methyl or ethyl.

[0024] In certain embodiments, B is heteroaryl. In certain embodiments, B is pyridinyl, pyrimidinyl, or triazinyl. In certain preferred embodiments, B is pyrimidinyl.

[0025] In certain embodiments, B is selected from the group consisting of at least one R 4 Each R 4 is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido. 4Each R 4 is independently selected from alkyl and halo. In certain preferred embodiments, R 4 is methyl. In another preferred embodiment, R 4 is chloro or fluoro. In certain embodiments, B is selected from one or two R 4 has been replaced with.

[0026] In certain embodiments, D is an N-linked heterocyclyl, such as a monocyclic or bicyclic heterocyclyl. In certain embodiments, D is aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, pyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, dioxidethiomorpholinyl, oxazabicycloheptanyl, azabicyclooctanyl, oxazabicyclooctanyl, hexahydrofuropyrrolyl, or azabicyclohexanyl. In certain embodiments, D is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxidethiomorpholinyl, azabicyclooctanyl, oxazabicyclooctane, hexahydrofuropyrrolyl, or azabicyclohexanyl. In certain embodiments, D is oxazabicycloheptanyl, azabicyclooctanyl, or oxazabicyclooctanyl.

[0027] In certain embodiments, D is selected from the group consisting of at least one R 5 Each R 5 is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido. 5 is replaced by R 5 and two of R are combined to complete a bicyclic heterocyclyl. In certain embodiments, D is selected from the group consisting of at least one R 5 Each R5 is independently selected from alkyl, halo, cycloalkyl, or heterocyclyl. In certain embodiments, R 5 is methyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoro, cyclopropyl, cyclobutyl, or oxetanyl. In certain embodiments, D is selected from one or two R 5 In certain embodiments, D is substituted with one R 5 In another embodiment, D is substituted with two R 5 has been replaced with.

[0028] In certain embodiments, E is aryl. In certain embodiments, E is phenyl, dihydrobenzofuranyl, benzodioxolyl, or dihydroindenyl. In certain embodiments, E is phenyl, dihydrobenzofuran, or benzodioxole. In certain preferred embodiments, E is phenyl. In other embodiments, E is heteroaryl. In certain embodiments, E is pyridinyl, pyrazinyl, indolyl, e.g., N-methylindolyl, or benzofuranyl. In certain embodiments, E is pyridinyl or pyrazinyl. In yet other embodiments, E is heterocyclyl. In certain embodiments, E is pyrrolidinyl.

[0029] In certain embodiments, E is selected from the group consisting of at least one R 6 Each R 6 is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and alkyl with sulfomide.

[0030] In certain embodiments, E is selected from the group consisting of at least one R 6 Each R 6is independently selected from alkyl (e.g., deuteroalkyl), alkyloxy (e.g., deuteroalkyloxy), alkylthio, amino, halo, cyano, heterocyclyl, and hydroxyl. In certain embodiments, R 6 is methyl, ethyl, butyl, isopropyl, difluoromethyl, trifluoromethyl, difluoroethyl, methoxy, ethoxy, difluoromethyoxy, trifluoromethyoxy, methylthio, dimethylamino, fluoro, chloro, or azetidinyl. 6 In another embodiment, E is substituted with two R 6 In yet other embodiments, E is substituted with 3 R 6 has been replaced with.

[0031] In certain embodiments, the compound is represented by Formula Ic, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, Y 1 is N or CR 8a and Y 2 is N or CR 8b and Y 3 is N or CR 8c and Y 4 is N or CR 8d and X 4 CR 5c R 5d , O, or NR 7 and R 5c and R 5dare each independently selected from deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl, R 8a , R 8b , R 8c , and R 8d are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R 7 is H, alkyl, acyl, acetyl, hydroxyl, alkoxy, cycloalkyl, m is 1 to 5, and n is 1 to 8.

[0032] In certain embodiments, Y 1 is N. In another embodiment, Y 1 is CR 8a In certain embodiments, R 8a is H, alkyl (e.g., methyl), or halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8a is fluoro.

[0033] In certain embodiments, Y 2 is N. In another embodiment, Y 2 is CR 8b In certain embodiments, R 8b is H, alkyl (e.g., methyl), or halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8b is fluoro.

[0034] In certain embodiments, Y 3 is N. In another embodiment, Y 3 is CR 8c In certain embodiments, R 8c is H, alkyl (e.g., methyl), or halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8c is fluoro.

[0035] In certain embodiments, Y 4 is N. In another embodiment, Y 4 is CR 8d In certain embodiments, R 8d is H, alkyl (e.g., methyl), or halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8d is fluoro.

[0036] In certain embodiments, the compound is represented by Formula II, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, X 4 CR 5c R 5d , O, or NR 7 and R 5c and R 5d are each independently selected from deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl, R 7 is H, alkyl, acyl, acetyl, hydroxyl, alkoxy, cycloalkyl, m is 1 to 5, and n is 1 to 8.

[0037] In certain embodiments, X 4 is NR 7 In certain preferred embodiments, X 4 is O. In another preferred embodiment, X 4 is CR 5c R 5d It is.

[0038] In certain embodiments, the compound is represented by Formula IIIa, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 6a and R 6b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0039] In certain embodiments, the compound is represented by formula IIIb: or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 6a and R 6b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0040] In certain embodiments, n is at least 2 and there are two or more R5 combine to form a cycloalkyl or heterocyclyl (eg, oxazabicycloheptanyl, azabicyclooctanyl, or oxazabicyclooctanyl).

[0041] In certain embodiments, the compound is represented by Formula IVa, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0042] In certain embodiments, the compound is represented by formula IVb, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0043] In certain embodiments, the compound is represented by formula IVc, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0044] In certain embodiments, the compound is represented by formula IVd, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0045] In certain embodiments, the compound is represented by formula IVe, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6bare each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R 8a is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0046] In certain embodiments, R 8a is halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8a is fluoro. In other embodiments, R 8a is alkyl (e.g., methyl).

[0047] In certain embodiments, the compound is represented by formula IVf, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R 8cis selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0048] In certain embodiments, R 8c is halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8c is fluoro. In other embodiments, R 8c is alkyl (e.g., methyl).

[0049] In certain embodiments, the compound is represented by formula IVg, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R 8d is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0050] In certain embodiments, R 8d is halo (e.g., fluoro or chloro). In certain preferred embodiments, R 8dis fluoro. In other embodiments, R 8d is alkyl (e.g., methyl).

[0051] In certain embodiments, the compound is represented by formula IVh, or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5a , R 5b , R 6a , and R 6b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0052] In certain embodiments, R 5a is alkyl. In certain preferred embodiments, R 5a is methyl.

[0053] In certain embodiments, R 5b is alkyl. In certain preferred embodiments, R 5b is methyl.

[0054] In certain embodiments, the compound is represented by formula Va: or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5c and R 5dare each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl; R 6a and R 6b are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0055] In certain embodiments, the compound is represented by formula Vb: or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5c and R 5d are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl; R 6a and R 6bare each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0056] In certain embodiments, the compound is represented by Formula VIa: or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5c and R 5d are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl; and R 6a and R 6b are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0057] In certain embodiments, the compound is represented by formula VIb: or a pharma- ceutically acceptable salt thereof. [ka] [In the formula, R 5c and R 5dare each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R 5c and R 5d and combine to form a cycloalkyl; R 6a and R 6b are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

[0058] In certain embodiments, R 6a is halo. In certain embodiments, R 6a is fluoro, chloro, or bromo. In certain preferred embodiments, R 6a is fluoro. In other embodiments, R 6a is alkyl (e.g., deuteroalkyl).

[0059] In certain embodiments, R 6b is alkoxy (e.g., deuteroalkyloxy). In certain embodiments, R 6b is deuteroalkoxy, methoxy, or fluoromethyoxy, e.g., monofluoromethyoxy or difluoromethyoxy. In other embodiments, R 6b is alkyl (e.g., deuteroalkyl). In certain embodiments, R 6bis methyl, ethyl, fluoroalkyl, such as monofluoromethyl, difluoromethyl, or difluoroethyl. In certain preferred embodiments, R 6b is fluoroalkyl. In a further preferred embodiment, R 6b is difluoromethyl. In another embodiment, R 6b is alkylsulfonyl. In certain embodiments, R 6b is methylsulfonyl.

[0060] In certain embodiments, R 5c is alkyl (e.g., deuteroalkyl). In certain preferred embodiments, R 5c is methyl or trifluoromethyl. In other embodiments, R 5c is halo. In certain preferred embodiments, R 5c is fluoro.

[0061] In certain embodiments, R 5d is hydrogen. In other embodiments, R 5d is alkyl (e.g., deuteroalkyl).

[0062] In other embodiments, R 5c and R 5d and combine to form a cycloalkyl. In certain preferred embodiments, it is cyclopropyl or cyclobutyl.

[0063] In certain embodiments, the compound is selected from the compounds listed in Table 1 or a pharma- ceutically acceptable salt thereof. Table 1: Exemplary compounds of the present disclosure [Table 1-1] [Table 1-2] [Table 1-3]

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

[0064] The present disclosure includes all suitable isotopic variations of the compounds of the present disclosure.An isotopic variation of a compound of the present invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass that is usually or predominantly found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively: 2 H (deuterium), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 17 O.18 O. 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Thus, unless otherwise specified, the reference to "hydrogen" or "H" is 1 H (protium), 2 H (deuterium), and 3 H (tritium). Specific isotopic variations of the compounds of the invention, such as 3 H or 14 Those incorporating one or more radioactive isotopes, such as C, are useful for drug and / or substrate tissue distribution studies. Tritium-labeled and carbon-14, i.e. 14 C isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced required dosage, and therefore may be preferred in some circumstances. Such variants may also have advantageous optical properties, for example, resulting from changes to vibrational modes due to the heavier isotope. Isotopic variants of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art, for example, by the exemplary method or by the preparation described in the following examples using appropriate isotopic variants of suitable reagents.

[0065] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein and a pharma- ceutically acceptable excipient.

[0066] In yet another aspect, the present disclosure provides a method of treating a TACC-mediated disease or disorder in a subject, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof.

[0067] In certain embodiments, TACC is TACC1. In other embodiments, TACC is TACC2. In other preferred embodiments, TACC is TACC3.

[0068] In certain embodiments, the TACC-mediated disease or disorder is cancer, hi certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia cancer, renal cancer, or prostate cancer.

[0069] In yet another aspect, the disclosure provides a method of treating a disease or disorder characterized by TACC dyregulation in a subject, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof.

[0070] In certain embodiments, TACC is TACC1. In other embodiments, TACC is TACC2. In other preferred embodiments, TACC is TACC3.

[0071] In certain embodiments, the disease or disorder is cancer, hi certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia cancer, renal cancer, or prostate cancer.

[0072] In yet another aspect, the disclosure provides a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein or a pharma- ceutically acceptable salt thereof, hi certain embodiments, the cancer is breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia cancer, kidney cancer, or prostate cancer.

[0073] Pharmaceutical Compositions The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition, for example, comprising the compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or 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, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide delayed release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical compositions may be in unit dosage form such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The compositions may also be present in transdermal delivery systems, such as skin patches. The compositions may also be present in solutions suitable for topical administration, such as lotions, creams, or ointments.

[0074] A pharma- ceutically acceptable carrier may contain a physiologically acceptable agent that acts, for example, to stabilize a compound, such as a compound of the present invention, to increase the solubility of the compound, or to increase the absorption of the compound. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical carrier that includes a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, in which, for example, the compound of the present invention may be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers, and are relatively simple to prepare and administer.

[0075] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0076] The phrase "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can function as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and glycerin; and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0077] The pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, orally (e.g., aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin). The compounds may also be formulated for inhalation. In certain embodiments, the compounds may simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor are described, 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 patents cited therein.

[0078] The formulations may be conveniently provided in unit dosage form and may be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated, the particular mode of administration. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

[0079] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carriers and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0080] Formulations of the present invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophilized, 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 a pastille (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0081] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar, The pharmaceutical compositions may be mixed with any of the following: calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0082] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0083] Tablets, as well as other solid dosage forms of the pharmaceutical composition, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may be optionally 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 therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or any other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.

[0084] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0085] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0086] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0087] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[0088] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0089] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0090] 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 made by dissolving or dispersing the active compound in a suitable medium. Absorption 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 dispersing the compound in a polymer matrix or gel.

[0091] The phrases "parenteral administration" and "administered parenterally" as used herein 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, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that may be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0092] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0093] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by including various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like, in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0094] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This may be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a drug depends on its rate of dissolution, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0095] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0096] For use in the methods of the invention, the active compound may be provided per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0097] The introduction method may also be provided by rechargeable or biodegradable devices.For the controlled delivery of drugs, including proteinaceous biologics, various slow release polymeric devices have been developed and tested in vivo in recent years.Various biocompatible polymers, including both biodegradable and non-degradable polymers (including hydrogels), can be used to form implants for sustained release of compounds at specific target sites.

[0098] The actual dosage level of the active ingredient in the pharmaceutical composition may be varied to obtain an amount of the active ingredient that is not toxic to the patient and is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration.

[0099] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, used, the route of administration, the time of administration, the rate of excretion of the particular compound used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound used, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical arts.

[0100] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of the compound varies according to the weight, sex, age, and medical history of the subject. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13th Edition, 1814-1882, incorporated herein by reference).

[0101] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0102] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. In certain embodiments of the invention, the active compound may be administered two or three times a day. In a preferred embodiment, the active compound will be administered once a day.

[0103] The patient receiving this treatment may be any animal in need, including primates, particularly humans; other mammals, such as horses, cows, pigs, sheep, cats, and dogs; poultry; and pets in general.

[0104] In certain embodiments, the compounds of the invention may be used alone or may be administered together with another type of therapeutic agent.

[0105] The present disclosure includes the use of pharma- ceutically acceptable salts of the compounds of the present invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.In certain embodiments, contemplated salts of the present invention include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, l-ascorbic acid, l-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptan ... Acids that may be used include, but are not limited to, 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.

[0106] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be inherent in the solvent of crystallization, the solvent of preparation or crystallization, or adventitious to such solvent.

[0107] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0108] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0109] definition 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. In general, the nomenclature used in connection with and techniques of chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are those well known and commonly used in the art.

[0110] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art, unless otherwise indicated, 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 Edition", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th Edition", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th Edition", Sinauer Associates, Inc., Sunderland, MA (2000).

[0111] Chemical terms used herein, unless otherwise defined herein, are used according to conventional usage in the art as exemplified in "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., ed., McGraw-Hill, San Francisco, Calif. (1985).

[0112] All of the above, as well as 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, will control.

[0113] The term "agent" is used herein to refer to a chemical compound (e.g., an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (e.g., a nucleic acid, an antibody (including a portion thereof), as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or a portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as a cell or tissue of a bacteria, a plant, a fungus, or an animal (especially a mammal). Agents include, for example, agents of known structure and agents of unknown structure. The ability of such agents to inhibit AR or promote AR degradation may make them suitable as "therapeutic agents" in the methods and compositions of the present disclosure.

[0114] "Patient," "subject," or "individual" are used interchangeably and refer to either a human or non-human animal. These terms include mammals such as humans, primates, livestock animals (including cows, pigs, etc.), companion animals (e.g., canines, felines, etc.), and rodents (e.g., mice and rats).

[0115] "Treating" a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, diminishment of the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or complete remission). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0116] The term "preventing" is art-recognized and, when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure, or any other medical condition, is well understood in the art and includes administration of a composition that reduces the frequency of or delays the onset of symptoms of a medical condition in a subject compared to subjects not receiving the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population compared to an untreated control population, for example, by a statistically and / or clinically significant amount.

[0117] "Administering" or "administration" of a substance, compound or agent to a subject can be performed using one of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through the skin tract). The compound or agent can also be suitably introduced by rechargeable or biodegradable polymeric devices or other devices, such as patches and pumps, or formulations that provide sustained, slow or controlled release of the compound or agent. Administration can also be performed, for example, once, multiple times, and / or over one or more extended periods of time.

[0118] The appropriate method of administering a substance, compound or agent to a subject will also depend, for example, on the age and / or physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, the compound or agent is administered to the subject orally, for example, by ingestion. In some embodiments, the orally administered compound or agent is in a sustained or slow release formulation or is administered using a device for such sustained or slow release.

[0119] As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic agents, such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., two agents are effective in a patient at the same time, which may include a synergistic effect of the two agents). For example, different therapeutic compounds can be administered either simultaneously or sequentially, either in the same formulation or in separate formulations. Thus, an individual undergoing such treatment can benefit from the combined effect of the different therapeutic agents.

[0120] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or agent is an amount of a drug or agent that has an intended therapeutic effect when administered to a subject. A complete therapeutic effect may not necessarily occur by administration of one dose, but only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The exact effective amount required for a subject will depend, for example, on the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. Those skilled in the art can easily determine the effective amount for a given situation by routine experimentation.

[0121] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" refers to cases where the alkyl may be substituted and cases where the alkyl is not substituted.

[0122] It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by one of ordinary skill in the art to result in chemically stable compounds that can be readily synthesized from readily available starting materials by techniques known in the art and by the methods set forth below. It is understood that when a substituent is itself substituted with more than one group, these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0123] As used herein, the term "optionally substituted" refers to the replacement of 1-6 hydrogen radicals in a given structure with the radical of a particular substituent, including but not limited to hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2, or -CH2-OP(O)(O-alkyl). Preferably, "optionally substituted" refers to the replacement of 1-4 hydrogen radicals in a given structure with the above substituents. More preferably, 1-3 hydrogen radicals are replaced by the above substituents. It is understood that the substituents may be further substituted.

[0124] As used herein, the term "alkyl" refers to any alkyl group having a C1-C 10 Straight chain alkyl group or C1-C 10 It refers to saturated aliphatic groups, including but not limited to branched alkyl groups. Preferably, the "alkyl" group refers to a C1-C6 straight chain alkyl group or a C1-C6 branched chain alkyl group. Most preferably, the "alkyl" group refers to a C1-C4 straight chain alkyl group or a C1-C4 branched chain alkyl group. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, or 4-octyl. The "alkyl" group may be optionally substituted.

[0125] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0126] The term "acylamino" is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0127] The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0128] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0129] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0130] The term "alkyl" refers to saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, the straight chain or branched chain alkyl group has 30 or fewer alkyl groups in its backbone (e.g., C for straight chain). 1-30 , C for branched chain 3-30 ), more preferably having 20 or fewer carbon atoms.

[0131] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups, such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0132] "C x-y " or "C x -C yThe term "alkyl" when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. CO alkyl indicates a hydrogen in the terminal position of the group, or a bond if the group is internal. 1-6 An alkyl group contains, for example, 1 to 6 carbon atoms in the chain.

[0133] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0134] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0135] As used herein, the term "amide" refers to the group [ka] In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group, or R 9 and R 10 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0136] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] wherein R 9 , R 10 , and R 10 Each ' is independently hydrogen or a hydrocarbyl group, or R 9 and R 10together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

[0137] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0138] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0139] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings being aromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0140] The term "carbamate" is art-recognized and is intended to include [ka] In the formula, R 9 and R 10 each independently represents hydrogen or a hydrocarbyl group.

[0141] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0142] The term "carbocycle" includes 5-7 membered monocyclic rings and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Carbocycles include bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, may 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 carbocycle, as valences permit. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocycle" may be substituted at any one or more positions that may have a hydrogen atom.

[0143] The term "carbocyclylalkyl," as used herein, refers to an alkyl group substituted with a carbocycle group.

[0144] The term "carbonate" is art-recognized and refers to the group -OCO2-.

[0145] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0146] The term "cycloalkyl" includes substituted or unsubstituted non-aromatic monocyclic structures, preferably 4-8 membered rings, more preferably 4-6 membered rings. The term "cycloalkyl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is cycloalkyl and no substituents (e.g., R 100 ) is attached to the cycloalkyl ring, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0147] As used herein, the term "ester" refers to an ester selected from the group -C(O)OR 9 In the formula, R 9 represents a hydrocarbyl group.

[0148] The term "ether" as used herein refers to a hydrocarbyl group bonded to another hydrocarbyl group via oxygen. Thus, the ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or asymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

[0149] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo, and iodo.

[0150] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0151] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0152] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0153] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocycle group.

[0154] 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, whose ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is heterocyclic, e.g., the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0155] The term "hydrocarbyl" as used herein refers to a group that does not have =O or =S substituents and typically has at least one carbon-hydrogen bond and a predominantly carbon backbone, but is bonded through a carbon atom that may optionally contain heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered hydrocarbyl for the purposes of this application, while substituents such as acetyl (having =O substituent on the bonded carbon) and ethoxy (bonded through an oxygen rather than a carbon) are not hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclic, alkyl, alkenyl, alkynyl, and combinations thereof.

[0156] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0157] The term "lower" when used in combination with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer atoms, preferably 6 or fewer atoms, in the substituent. "Lower alkyl" refers, for example, to alkyl groups containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they occur alone or in combination with other substituents in the descriptions of, for example, hydroxyalkyl and aralkyl (where, for example, atoms in the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0158] The terms "polycyclyl," "polycycle," and "polycyclic" refer to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings, e.g., the rings are "fused rings." Each ring of a polycycle can be substituted or unsubstituted. In certain embodiments, each ring of a polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring.

[0159] The term "sulfate" is art-recognized and refers to the group -OSO3H, or a pharma- ceutically acceptable salt thereof.

[0160] The term "sulfonamide" is art-recognized and has the general formula [ka] In the formula, R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0161] The term "sulfoxide" is art-recognized and refers to the group --S(O)--.

[0162] The term "sulfonate" is art-recognized and refers to the group SO3H, or a pharma- ceutically acceptable salt thereof.

[0163] The term "sulfone" is art-recognized and refers to the group -S(O)2-.

[0164] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more, the same or different, for appropriate organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituents may include any of the substituents described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if desired.

[0165] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group. As used herein, the term "thioester" refers to the group -C(O)SR9 or -SC(O)R9,

[0166] In the formula, R9 represents hydrocarbyl.

[0167] The term "thioether" as used herein is equivalent to an ether where the oxygen is replaced with a sulfur.

[0168] The term "urea" is art-recognized and has the general formula [ka] where R 9 and R 10 independently represent hydrogen or hydrocarbyl.

[0169] As used herein, the term "modulate" includes inhibiting or suppressing a function or activity (eg, cell proliferation), as well as enhancing a function or activity.

[0170] The phrase "pharmacologically acceptable" is art-recognized. In certain embodiments, this term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0171] A "pharmacologically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0172] The term "pharmaceutically acceptable acid addition salts" as used herein refers to any non-toxic organic or inorganic salt of any base compound represented by formula I. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinmic acid, and salicylic acid, as well as sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts can be formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of compounds of formula I are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms. The selection of an appropriate salt will be known to one of skill in the art. Other pharma-ceutically unacceptable salts, such as oxalates, may be used, for example, in the isolation of compounds of formula I for laboratory use or for subsequent conversion to a pharma-ceutically acceptable acid addition salt.

[0173] 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. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and picoline or ammonia. The selection of appropriate salts will be known to those skilled in the art.

[0174] Many of the compounds useful in the methods and compositions of the present disclosure have at least one stereocenter in their structure. This stereocenter may be in the R or S configuration, and the R and S designations are used according to the rules set forth in Pure Appl.Chem.(1976), 45, 11-30. The present disclosure contemplates all stereoisomeric forms, e.g., enantiomeric and diastereomeric forms, of the compounds, salts, prodrugs or mixtures thereof, including all possible mixtures of stereoisomers. See, for example, WO 01 / 062726.

[0175] Furthermore, certain compounds containing alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the present disclosure includes both mixtures and the separate individual isomers.

[0176] Some of the compounds may exist in tautomeric forms. Such forms, although not explicitly shown in the formulas set forth herein, are intended to be included within the scope of the present disclosure.

[0177] "Prodrug" or "Pharmaceutically acceptable prodrug" refers to a compound that is metabolized, e.g., hydrolyzed or oxidized, in the host after administration to form a compound of the present disclosure (e.g., a compound of formula I). ​​Typical examples of prodrugs include compounds that have a biologically labile or cleavable (protecting) group on a functional moiety of an active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to generate an active compound. Examples of prodrugs that use esters or phosphoramidates as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patent Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. The prodrugs of the present disclosure are metabolized to generate a compound of formula I. The present disclosure includes within its scope prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs”, H. Bundgaard (ed.), Elsevier, 1985.

[0178] As used herein, the phrase "pharmaceutical acceptable carrier" means a pharma- ceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material, useful in formulating a drug for pharmaceutical or therapeutic use.

[0179] As used herein, the terms "Log of solubility", "LogS" or "logS" are used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound greatly affects its absorption and distribution properties. Low solubility is often associated with poor absorption. The LogS value is the unit stripped logarithm (base 10) of the solubility measured in moles / liter.

[0180] example Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention.

[0181] Example 1: Synthesis of exemplary compounds of the present disclosure General procedure for the preparation of compounds 5-41 [ka] Scheme 1. Synthesis of compounds 5-41. Reagents and conditions: (A) SOCl2, EtOH, reflux, 3 h; (B) NaH, MeCN, toluene, reflux, 2 h; (C) NH2NH2·H2O, EtOH:HCl, reflux, 4 h; (D), 2,4-dichloropyrimidine, DMSO, 60 °C, 24 h; (E) morpholine, n-BuOH, reflux, 4 h. The synthesis of compounds 5-41 is shown in Scheme 1, which includes the following process steps: i) The appropriate acid derivatives were esterified by refluxing in EtOH (ethanol) in the presence of SOCl2 (thionyl chloride) to give compounds 1aa-bn. ii) A solution of compounds 1aa-bn in toluene was refluxed with acetonitrile in the presence of NaH (sodium hydride; 60% dispersion in mineral oil) to give the β-ketonitrile derivatives 2aa-bn. iii) Compounds 2aa-bn were reacted with NH2NH2·H2O (hydrazine monohydrate) in EtOH:concentrated HCl (8:1) solution at 95 °C to give 1H-pyrazol-5-amine analogues 3aa-bn. iv) Compounds 3aa-bn were reacted with 2,4-dichloropyrimidine in DMSO (dimethylsulfoxide) in the presence of DIEA (N,N-diisopropylethylamine) at 60° C. to give compounds 4aa-bn. Compounds 4aa-bn in n-BuOH (butanol) were refluxed with morpholine to give compounds 5-41. For compounds 137 and 138, intermediates 4aj and 4bn in n-BuOH (butanol) were refluxed with 2,6-dimethylmorpholine instead of morpholine to give the final compounds. Preparation of compound 43. [ka]

[0182] Scheme 2. Synthesis of compound 43. Reagents and conditions: (A) BBr3, DCM, 0 °C, 24 h; (B) morpholine, n-BuOH, reflux, 5 h. The synthesis of compound 43 is shown in Scheme 2, which includes the following process steps: i) Demethylation of compound 4aa in the presence of BBr3 (boron tribromide) in DCM (dichloromethane) at 0° C. gave compound 42. ii) Compound 42 in n-BuOH was refluxed with morpholine to give compound 43.

[0183] General procedure for the preparation of compounds 56-58. [ka] Scheme 3. Synthesis of compounds 56-58. Reagents and conditions: (A) TBAB, MeCN, rt, 24 h; (B) KCN, EtOH:H2O, rt, 5 h; (C) NH2NH2·H2O, EtOH:HCl, reflux, 4 h; (D), 2,4-dichloropyrimidine, DMSO, 60 °C, 24 h; (E) morpholine, n-BuOH, reflux, 4 h. The synthesis of compounds 56-58 is shown in Scheme 1, which includes the following process steps: i) A solution of the appropriate acetophenone derivative in acetonitrile was brominated with TBAB (tetrabutylammonium bromide) to give compounds 44-46. ii) A solution of compounds 44-46 (0.2 M) in EtOH:H2O was reacted with KCN (potassium cyanide) to give the β-ketonitrile derivatives 47-49. iii) Compounds 47–49 were reacted with NH2NH2·H2O in EtOH:concentrated HCl (8:1) solution at 95 °C to give 1H-pyrazol-5-amine analogs 50–52. iv) Compounds 50-52 were reacted with 2,4-dichloropyrimidine in DMSO in the presence of DIEA at 60° C. to give compounds 53-55. v) Compounds 53-55 in n-BuOH were refluxed with morpholine to give compounds 56-58.

[0184] General procedure for the preparation of compounds 59-73. [ka] Scheme 4. Synthesis of compounds 59-73. Reagents and conditions: (A) appropriate amine derivative, n-BuOH, reflux, 5 h; (B) appropriate amine derivative, DIPEA, n-BuOH, reflux, 5 h. For the synthesis of derivatives with R5 modification, the synthetic procedure shown in Scheme 4 was utilized. Compound 4aa was used as a starting intermediate and then reacted with various amines to give the final compounds (59-73) by method A or B. When the amine derivative was in the form of an HCl salt, method B was used (for 60-65). The synthetic method for compounds 59-73 is shown in Scheme 4, which includes the following process steps: i) Compound 4aa and the appropriate amine derivative not in HCl (hydrogen chloride) salt form were refluxed in BuOH to give compounds 59, 66-73 (Method A). For compound 72, N-Boc protected piperazine was used and the protecting group was then hydrolyzed with TFA (trifluoroacetic acid) in DCM to give the final compound. ii) When the amine derivative was in salt form, the appropriate HCl salt of the amine was dissolved in BuOH in the presence of DIPEA to give the free amine, which was then reacted with compound 4aa under reflux to give the final compounds 60-65 (Method B).

[0185] General procedure for the preparation of compounds 77-83 For derivatives bearing B-ring modifications, the synthetic procedures outlined in Schemes 5 and 6 were utilized. Compound 3aa was used as the starting material and was subjected to nucleophilic aromatic substitution reactions with various pyrimidine derivatives such as 2,4,5-trichloropyrimidine, 2,4-dichloro-5-fluoropyrimidine, and 2,4-dichloro-6-methylpyrimidine (77-79). Also, the final compounds 81-83 were obtained by coupling reactions of compound 3aa with morpholinopyridine or morpholinopyrazine derivatives such as 4-(4-bromopyridin-2-yl)morpholine, 4-(6-bromopyridin-2-yl)morpholine, and 4-(6-bromopyrazin-2-yl)morpholine (81-83). [ka] Scheme 5. Synthesis of compounds 77-80. Reagents and conditions: (A) appropriate pyrimidine or 4-(4-chloro-1,3,5-triazin-2-yl)morpholine derivative, DIEA, DMSO, 60° C., 24 h; (B) morpholine, n-BuOH, reflux, 5 h. The synthesis of compounds 77-80 is shown in Scheme 5, which includes the following process steps: i) Compound 3aa was reacted with an appropriate pyrimidine derivative (for compound 80, 4-(4-chloro-1,3,5-triazin-2-yl)morpholine derivative was used instead of the pyrimidine derivative) in DMSO in the presence of DIEA at 60° C. to give compounds 74-76 and 80. ii) Compounds 74-76 were refluxed with morpholine to give compounds 77-79. [ka]

[0186] Scheme 6. Synthesis of compounds 81-83. Reagents and conditions: (A) appropriate morpholinopyridine or morpholinopyridazine derivative t-BuONa and [PdXanthPos]Cl2Me-THF at 75 °C for 24 hours. The synthesis of compounds 81-83 is shown in Scheme 6, which includes the following process steps: i) Compound 3aa was reacted with an appropriate morpholinopyridine or morpholinopyrazine derivative in Me-THF (methyl-tetrahydrofuran) in the presence of t-BuONa (sodium tert-butoxide) and [PdXanthPos]Cl2 at 75°C to give compounds 81-83.

[0187] General procedure for the preparation of compounds 84-85. [ka] Scheme 7. Synthesis of compounds 84-85. Reagents and conditions: (A) CH3I or C2H5I, Cs2CO3, DMF, room temperature, 3 hours. For the synthesis of compounds 84-85, the synthetic procedure outlined in Scheme 7 was utilized. Compound 5 was used as the starting material, which was alkylated to give the N-methylated and N-ethylated derivatives 84-85.

[0188] The synthesis of compounds 84-85 is shown in Scheme 7, which includes the following process steps: i) Compound 5 was dissolved in DMF (N,N-dimethylformamide) and reacted with CH3I (iodomethane) or C2H5I (iodoethane) in the presence of Cs2CO3 (cesium carbonate) at room temperature to obtain compounds 84 to 85.

[0189] General procedure for the preparation of compounds 86–123, 165–212. [ka] Scheme 8. Synthesis of compounds 86-128, 129-171. Reagents and conditions: (A) appropriate amine derivative, n-BuOH, reflux, 5 h; (B) appropriate amine derivative, DIPEA, n-BuOH, reflux, 5 h. For the synthesis of derivatives bearing R5 modifications, the synthetic procedure outlined in Scheme 8 was utilized. Thus, compound 4av or compound 53 were used as starting intermediates and then treated with various amine derivatives to give the final compounds via Method A or B. When the amine derivative was in the form of a salt form, Method B was used.

[0190] The synthesis of compounds 86-171 is shown in Scheme 8, which includes the following process steps: i) Compound 4av or compound 53 and the appropriate amine derivative not in salt form were refluxed in BuOH to give the final compound (Method A). ii) When the amine derivative is in salt form, the appropriate salt of the amine was dissolved in BuOH in the presence of DIPEA to give the free amine, which was then reacted with compound 4av or compound 53 reacted with morpholine under reflux to give the final compound (Method B).

[0191] Preparation of compound 174. [ka] Scheme 9. Synthesis of compound 174. Reagents and conditions: (A) thiourea, EtOH, reflux, 95 °C, 2 h; (B) 2,4-dichloropyrimidine, Na2CO3, xantphos, Pd2(dba)3, toluene:H2O, sealed tube, oil bath, 100 °C, 24 h; (C) morpholine, n-BuOH, reflux, 5 h. For the synthesis of derivatives with thiazole ring modification instead of 1H-pyrazole, the synthetic procedure shown in Scheme 9 was utilized. 2-Bromo-1-(4-methoxyphenyl)ethan-1-one was used as the starting material and then reacted with thiourea to give the thiazole-2-amine ring. The amine derivative was treated with 2,4-dichloropyrimidin via a coupling reaction to give the starting intermediate. Finally, the intermediate was reacted with morpholine under reflux to give the final compound 174.

[0192] A method for the synthesis of compound 174 is shown in Scheme 9, which includes the following process steps: i) A solution of 2-bromo-1-(4-methoxyphenyl)ethan-1-one in EtOH was reacted with thiourea to give compound 172. ii) A solution of compound 172 in toluene:H2O (4:1) was degassed under nitrogen atmosphere and then reacted with 2,4-dichloropyrimidine in the presence of Na2CO3, xantphos, Pd2(dba)3 to give compound 173. iii) Compound 173 was treated with morpholine under reflux to give final compound 174.

[0193] Preparation of compound 177. [ka] Scheme 10. Synthesis of compound 177. Reagents and conditions: (A) urea, DMF, MW, 120 °C, 3 min; (B) 2,4-dichloropyrimidine, Na2CO3, xantphos, Pd2(dba)3, toluene:H2O, sealed tube, oil bath, 100 °C, 24 h; (C) morpholine, n-BuOH, reflux, 5 h. For the synthesis of derivatives with oxazole ring modification instead of 1H-pyrazole, the synthetic procedure shown in Scheme 10 was utilized. 2-Bromo-1-(4-methoxyphenyl)ethan-1-one was used as the starting material and then reacted with urea under MW conditions to give the oxazole-2-amine ring. The amine derivative was reacted with 2,4-dichloropyrimidin via a coupling reaction to give the starting intermediate. Finally, the intermediate was reacted with morpholine under reflux to give the final compound 177.

[0194] A method for the synthesis of compound 177 is shown in Scheme 10, which includes the following process steps: i) A solution of 2-bromo-1-(4-methoxyphenyl)ethan-1-one in DMF was reacted with urea under MW conditions to give compound 175. ii) A solution of oxazol-2-amine derivative (compound 175) in toluene:H2O (4:1) was degassed under nitrogen atmosphere and then reacted with 2,4-dichloropyrimidine in the presence of Na2CO3, xantphos, Pd2(dba)3 to give compound 176. iii) Compound 176 was treated with morpholine under reflux to give final compound 177.

[0195] Preparation of compound 181. [ka] Scheme 11. Synthesis of compound 181. Reagents and conditions: (A) CH3I, DMF, room temperature, 24 h; (B) NH2NH2·H2O, EtOH:HCl, reflux, 4 h; (C) 2,4-dichloropyrimidine, DMSO, 60 °C, 24 h; (D) morpholine, n-BuOH, reflux, 4 h. For the synthesis of derivatives with 4-methyl-1H-pyrazole ring modification instead of 1H-pyrazole, the synthetic procedure shown in Scheme 11 was utilized. Compound 2aa was used as the starting material which was treated with CH3I to give the methylated β-ketonitrile derivative, and then reacted with hydrazine monohydrate to give the 4-methyl-1H-pyrazol-5-amine derivative (compound 179). Compound 179 was used as the starting material which was subjected to a nucleophilic aromatic substitution reaction with 2,4-dichloropyrimidine to give intermediate compound 180. Finally, the intermediate was reacted with morpholine under reflux to give compound 181.

[0196] A method for the synthesis of compound 181 is shown in Scheme 11, which includes the following process steps: i) A solution of compound 2aa in DMF was reacted with CH3I in the presence of NaH to give compound 178. ii) A solution of compound 178 in EtOH:HCl (8:1) was treated with NH2NH2·H2O to give the amine derivative compound 179. iii) Compound 179 was dissolved in DMSO and then reacted with 2,4-dichloropyrimidine in the presence of DIEA to give compound 180. iv) A solution of compound 180 in n-BuOH was reacted with morpholine under reflux to give the final compound 181.

[0197] Preparation of compounds 184, 187 and 190. [ka] Scheme 12. Compounds 184, 187 and 190 Synthesis of. Reagents and conditions: (A) CH3NH2NH2, EtOH:HCl, reflux, 4 hours; (B) 2,4-dichloropyrimidine, DMSO, 60°C, 24 hours; (C) morpholine or (2S,6R)-2,4,6-trimethylmorpholine, n-BuOH, reflux, 4 hours. For the synthesis of derivatives with 1-methyl-1H-pyrazole ring modification instead of 1H-pyrazole, the synthetic procedure shown in Scheme 12 was utilized. Compound 2aa was used as the starting material reacted with methylhydrazine to give the 1-methyl-1H-pyrazol-5-amine derivative (compound 134). Compound 134 was used as the starting material, which was subjected to a nucleophilic aromatic substitution reaction with 2,4-dichloropyrimidine to give intermediate compound 135. Finally, the intermediate was reacted with morpholine under reflux to give compound 136.

[0198] The synthesis of compounds 184, 187 and 190 is shown in Scheme 12, which includes the following process steps: i) A solution of compound 2aa or 47 in EtOH:HCl (8:1) was treated with methylhydrazine to give the amin derivatives compounds 182, 185, 188 (minor isomers). ii) Compounds Compound 182, 185, 188 (minor isomers) were dissolved in DMSO and then reacted with 2,4-dichloropyrimidine in the presence of DIEA to give compounds Compound 183, 186, 189. iii) A solution of compounds 183, 186, 189 in n-BuOH was reacted with morpholine or (2S,6R)-2,4,6-trimethylmorpholine under reflux to give the final compounds 184, 187 and 190.

[0199]

[0023] Embodiments of the present invention include, but are not limited to, chemical structures of parent intermediate compounds that react with the amine derivatives described herein and can be selected from the compounds listed in Table 1 for the synthesis of compounds of general formula (I).

[0200] General procedure for the preparation of compounds 191-218. [ka] Scheme 13. Synthesis of compounds 191-219. Reagents and conditions: (A) (2R,6S)-2,6-dimethylmorpholine, n-BuOH, reflux, 4 hours. The synthesis method of compounds 191-219 is shown in Scheme 13. Compound 4ac-bs was obtained according to the procedure shown in Scheme 1. Compounds 4ac-cd and 55 in n-BuOH (butanol) were refluxed with (2R,6S)-2,6-dimethylmorpholine to obtain compounds 191-219.

[0201] General procedure for the preparation of compounds 220-264 and for the preparation of compound 265. [ka] Scheme 14. Synthesis of compounds 220-264. Reagents and conditions: (A) appropriate amine derivative, n-BuOH, reflux, 5 hours; (B) appropriate amine derivative, DIPEA (or IPA), n-BuOH, reflux, 5 hours. The synthesis of compounds 220-264 is shown in Scheme 14, which includes the following process steps: iii) Compound 4al and the appropriate amine derivative not in HCl (hydrogen chloride) salt form were refluxed in BuOH to give the final compound (Method A). iv) When the amine derivative was in salt form, the appropriate HCl salt of the amine was dissolved in BuOH in the presence of DIPEA or IPA to give the free amine, which was then reacted with compound 4al under reflux to give the final compound (Method B). [ka]

[0202] Scheme 15. Synthesis of compound 265. Reagents and conditions: NMP, DIEA, 230 °C, microwave, 2 hours. The synthesis of compound 265 is shown in Scheme 15, which includes the following process steps: i) Compound 4al was reacted with 1-fluoro-2-methyl-2-propanamine hydrochloride in DMSO in the presence of DIEA and reacted under microwave at 230° C. to give compound 265.

[0203] General procedure for the preparation of compounds 274-277 [ka] Scheme 16. Synthesis of compounds 274-277. Reagents and conditions: (A) Boc2O, KOH, DCM, rt, 3 h; (B) MeI, Cs2CO3, DMF, rt, 16 h; (C) TFA, DCM, rt, 3 h. The synthesis method of compounds 274-277 is shown in Scheme 16, which includes the following process steps: i) A solution of compound 86b, 129b, 201, or 210 in DCM was treated with Boc2O and KOH to give the Boc-protected derivative. ii) The Boc-protected compound was dissolved in DMF and reacted with Cs2CO3 and MeI at room temperature for 16 h to give the methylated product. iii) The resulting compounds were treated with TFA in DCM and stirred at room temperature for 3 hours to give the final compounds 274-277.

[0204] compound 281-283 and 286-295 General procedure for the preparation of [ka] Scheme 17. Synthesis of compounds 281-283 and 286-295. Reagents and conditions: (A) appropriate pyrimidine derivative, DIEA, DMSO, 60° C., 24 h; (B) appropriate amine derivative, n-BuOH, reflux, 5 h. The synthesis of compounds 281-283 and 286-295 is shown in Scheme 17, which includes the following process steps: i) Compound 3al or 52 was reacted with an appropriate pyrimidine derivative in DMSO in the presence of DIEA at 60° C. to give compounds 278-280, 284-285. ii) Compounds 278-280, 284-285 were refluxed with appropriate amine derivatives to give compounds 281-283, 286-295.

[0205] General procedure for the preparation of compound 298 [ka] Scheme 18. Synthesis of compound 298. Reagents and conditions: (A) benzylhydrazine·HCl, EtOH:HCl, reflux, 4 h; (B) 2-bromo-6-morpholinopyridine, Xanthphos, Pd2(dba)3, t-BuOK, 1,4-dioxane, 100 °C, 24 h; (C) Pd / C (10%), MeOH:HCl, room temperature, 24 h. A method for the synthesis of compound 298 is shown in Scheme 18, which includes the following process steps: i) Compound 47 was reacted with benzylhydrazine·HCl in EtOH:concentrated HCl (8:1) solution at 95 °C to give compound 296. ii) A solution of compound 296 in dioxane was reacted with 2-bromo-6-morpholinopyridine in the presence of Xanthphos, Pd2(dba)3, and t-BuOK to give compound 297. iii) Compound 298 was obtained by acid catalyzed debenzylation of a solution of compound 297 in methanol. Compounds 299-304 follow the general procedure of Scheme 18.

[0206] General procedure for the preparation of compounds 308-311, 315-316 [ka] Scheme 19. Compound 308~311、315~316Synthesis of. Reagents and conditions: (A) benzylhydrazine·HCl, EtOH:HCl, reflux, 4 h; (B) (2R,6S)-4-(4-bromopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(3-fluoro-4-iodopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(6-bromopyrazin-2-yl)-2,6-dimethylmorpholine, [PdXanthphos)]Cl2, t-BuONa, Me-THF, 100 °C, 24 h; (C) Pd / C (10%), MeOH:HCl, room temperature, 2 4 hours; (D) (2R,6S)-4-(4-chloro-1,3,5-triazin-2-yl)-2,6-dimethylmorpholine, DIEA, DMSO, 60°C, 24 hours; (E) Boc2O, TEA, TFA, 40°C, 6 hours; (F) (2R,6S)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(6-chloro-3-fluoropyridin-2-yl)-2,6-dimethylmorpholine, Xantphos, Pd2(dba)3, Cs2CO3, toluene, 110°C, 24 hours; (G) HCl, dioxane, 40°C, 1 hour compound 308~311、315~316 A method for the synthesis of is shown in Scheme 19, which comprises the following process steps: i) Compound 2al was reacted with benzylhydrazine·HCl in EtOH:concentrated HCl (8:1) solution at 95 °C to give compound 305. ii) A solution of compound 305 in Me-THF was reacted with (2R,6S)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(3-fluoro-4-iodopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(6-bromopyrazin-2-yl)-2,6-dimethylmorpholine in the presence of [PdXanthphos]Cl2, t-BuONa to give compounds 306, 307 and 311. iii) Compounds 308 and 309 were obtained by acid catalyzed debenzylation of a solution of compounds 306 and 307 in methanol. iv) Compound 3al was reacted with (2R,6S)-4-(4-chloro-1,3,5-triazin-2-yl)-2,6-dimethylmorpholine in DMSO in the presence of DIEA at 60° C. to give compound 310. v) Compound 3al was reacted with Boc2O in the presence of TEA and TFA at 40° C. to give compound 312. vi) Compound 312 in toluene was reacted with (2R,6S)-4-(6-bromopyridin-2-yl)-2,6-dimethylmorpholine or (2R,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-2,6-dimethylmorpholine in the presence of Xanthphos, Cs2CO3 to give compounds 313 and 314. vii) Compounds 313 and 314 were deprotected with HCl in dioxane to give compounds 315 and 316.

[0207] General procedure for the preparation of compounds 317-318 [ka] Scheme 20. Synthesis of compounds 317-318. Reagents and conditions: (A) 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran, PdCl2(dppf), K2CO3, isopropanol:H2O, 100 °C, 24 h; (B) Pd / C(10%), MeOH:HCl, room temperature, 24 h. The synthesis of compounds 317-318 is shown in Scheme 20, which includes the following process steps: i) Compound 53 was reacted with 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyran in an isopropanol:water (5:1) solution in the presence of PdCl2(dppf) and K2CO3 at 100 °C in a sealed tube to give compound 317. ii) Compound 318 was obtained by acid catalyzed debenzylation of a solution of compound 317. Table 1: Intermediate compounds of the present disclosure [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0208] The present disclosure includes, but is not limited to, compounds disclosed in Table 2. Table 2: Summary of compounds of the present disclosure [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10]

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

[0209] Example 2: Exemplary Biological Activities of Compounds of the Disclosure Cell culture and reagents The human colon cancer cell line HCT-116 was a kind gift from Igor Ronninson, University of South Calif., Columbia, USA. The human breast cancer cell line JIMT-1 was kindly provided by Ali Osmay Gure, Bilkent University, Ankara, Turkey. Cells were cultured in Dulbecco's modified Eagle's medium (Lonza, NJ, USA) supplemented with 10% fetal bovine serum (FBS, Lonza), 1% non-essential amino acids (NEAA), 2 mM L-glutamine (Sigma Aldrich, MO, USA) and 50 U / ml penicillin / streptomycin (P / S). HCT-116 cells were cultured in McCoy's 5A (modified) (Gibco) medium supplemented with FBS, NEAA, L-glutamine and P / S. All cell lines were routinely tested using the MycoAlert Mycoplasma Detection Kit (Lonza). The cumulative length of time that cells were cultured between thawing and use in experiments was less than 20 passages.

[0210] Cell viability assay Freshly synthesized molecules were dissolved in 100% DMSO to obtain a stock concentration of 10 mM. For cell viability assays, JIMT-1 (3 × 10 3 cells / well) and HCT-116 (4 × 10 3), cells were seeded in 96-well plates and inhibitor treatment was performed at different concentrations 24 h after cell seeding. Cell viability was measured 72 h after treatment with sulforhodamine B (SRB, Sigma Aldrich) assay as recommended by the manufacturer. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0211] Example 3: Further exemplary biological activities of compounds of the present disclosure Female athymic nude mice aged 6–8 weeks were housed in a temperature-controlled environment with a 12-h light / 12-h dark cycle. For in vivo colon cancer tumor growth, 1 × 10 6 RKO cells were prepared in 100 μL of DMEM and injected into the right flank of female nude mice. The weight of the mice and the tumor volume were measured twice a week. Tumor volume was calculated as length × width. 2 × 0.5. Tumor volume was approximately 100 mm 3 Once tumors reached 2500 mm, xenografts were randomized into groups (5 mice per group). Animals were treated with vehicle and Compound 129b. The formulation of vehicle and Compound 129b was 50% PEG400 and 20% Cremophor RH40 final (50% of 40% Cremophor) in acetate buffer (PH=4). After 4 weeks or when tumors reached 2500 mm 3 Mice were sacrificed when a predefined tumor volume cutoff of 100 mg / kg was reached. Compound 129b showed strong tumor growth inhibition in RKO xenografts. For example, at the highest dose, at least 80% TGI was observed (Figure 1). Table 4. Dosing schedules for exemplary in vivo studies [Table 5]

[0212] Compound 129b was also tested in the CT-26 mouse colon xenograft model. For CT-26 xenografts, 5×10 5 CT-26 cells were injected into the right flank of 6- to 8-week-old female Balb / c mice. Tumor volumes averaged approximately 100 mm. 3 Once the tumor volume reached 100 mg / kg, mice were randomized into groups of 5 and treatment was initiated with vehicle, 15 mpk QD, 25 mpk QD, 50 mpk QD, 5 mpk IV BIW, and 5 mpk IP QD of compound 129b. Strong and statistically significant tumor growth inhibition or regression was observed in this model.

[0213] Incorporation by Reference All publications and patents mentioned herein are herein incorporated by reference in their entirety to the same extent 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, will control.

[0214] Equivalent While specific embodiments of the invention have been described, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification and such variations.

Claims

1. A compound represented by Formula I or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; A is pyrrole, furan, selenophene, thiophene, imidazole, pyrazole, oxazole, oxathiol, isoxathiol, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, dioxazole, or dithiazole; and R １ is H, alkyl, or benzyl.

2. The compound of claim 1 , wherein the compound is represented by formula Ia or formula Ib: 【Chemistry 2】 [In the formula, E and B are each independently aryl, heteroaryl, or heterocyclyl; D is heterocyclyl; X １ is CH ２ , N.R. ２ , O, and S; X ２ is selected from CH or N; X ３ is CR ３ or N, R １ and R ２ are each independently H, alkyl, or benzyl; and R ３ is H, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, or sulfonamide.

3. X １ The compound of claim 2, wherein is NR 2 and X 2 is N.

4. 2. The compound of claim 1, wherein B is heteroaryl, preferably pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl.

5. 2. The compound of claim 1, wherein D is an N-linked heterocyclyl, preferably aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, pyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, dioxidothiomorpholinyl, oxazabicycloheptanyl, azabicyclooctanyl, oxazabicyclooctanyl, hexahydrofuropyrrolyl, or azabicyclohexanyl.

6. D is at least one R ５ and each R ５ is independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido, or D is independently selected from at least two R ５ is substituted with R ５ The compound of claim 1, wherein two of:

7. D is at least one R ５ and each R ５ is independently selected from alkyl (e.g., methyl, fluoromethyl, difluoromethyl, or trifluoromethyl), halo (e.g., fluoro), cycloalkyl (e.g., cyclopropyl or cyclobutyl), or heterocyclyl (e.g., oxetanyl).

8. 2. The compound of claim 1, wherein E is aryl, preferably phenyl, dihydrobenzofuranyl, benzodioxolyl, or dihydroindenyl.

9. 2. The compound of claim 1, wherein the compound is represented by Formula Ic, or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】 [In the formula, Y １ is N or CR ８ａ and Y ２ is N or CR ８ｂ and Y ３ is N or CR ８ｃ and Y ４ is N or CR ８ｄ and X ４ is CR ５ｃ R ５ｄ , O, or NR ７ and R5, R ５ｃ , R ５ｄ and R6 are each independently selected from deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl, R 7 is H, alkyl, acyl, acetyl, hydroxyl, alkoxy, cycloalkyl; R ８ａ , R ８ｂ , R ８ｃ , and R ８ｄ are each independently selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; m is 1 to 5; and n is 1 to 8.

10. 10. The compound of claim 1, wherein the compound is represented by Formula II: or a pharma- ceutically acceptable salt thereof. 【Chemistry 4】 [In the formula, X ４ is CR ５ｃ R ５ｄ , O, or NR ７ and R5, R ５ｃ , R ５ｄ and R6 are each independently selected from deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl, R ７ is H, alkyl, acyl, acetyl, hydroxyl, alkoxy, cycloalkyl, m is 1 to 5; and n is 1 to 8.

11. 2. The compound of claim 1, wherein the compound is represented by Formula IVa or Formula IVb, or a pharma- ceutically acceptable salt thereof. 【Chemistry 5】 【change】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

12. 2. The compound of claim 1, wherein the compound is represented by formula IVc or formula IVd, or a pharma- ceutically acceptable salt thereof. 【Chemistry 6】 【change】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

13. 10. The compound of claim 1, wherein the compound is represented by Formula IVe, or a pharma- ceutically acceptable salt thereof. 【Chemistry 7】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R ８ａ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

14. 2. The compound of claim 1, wherein the compound is represented by formula IVf or a pharma- ceutically acceptable salt thereof. 【Chemistry 8】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R ８ｃ is selected from hydrogen, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

15. 10. The compound of claim 1, wherein the compound is represented by formula IVg or a pharma- ceutically acceptable salt thereof. 【Chemistry 9】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; R ８ｄ is selected from H, deuterium, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

16. 10. The compound of claim 1, wherein the compound is represented by formula IVh or a pharma- ceutically acceptable salt thereof. 【Chemistry 10】 [In the formula, R ５ａ , R ５ｂ , R ６ａ , and R ６ｂ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

17. 2. The compound of claim 1, wherein the compound is represented by Formula Va: or a pharma- ceutically acceptable salt thereof. 【Chemistry 11】 [In the formula, R ５ｃ and R ５ｄ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl; and R ６ａ and R ６ｂ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

18. 2. The compound of claim 1, wherein the compound is represented by formula Vb: or a pharma- ceutically acceptable salt thereof. 【Chemistry 12】 [In the formula, R ５ｃ and R ５ｄ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl; and R ６ａ and R ６ｂ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

19. 2. The compound of claim 1, wherein the compound is represented by Formula VIa: or a pharma- ceutically acceptable salt thereof. 【Chemistry 13】 [In the formula, R ５ｃ and R ５ｄ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl; and R ６ａ and R ６ｂ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

20. 2. The compound of claim 1, wherein the compound is represented by formula VIb: or a pharma- ceutically acceptable salt thereof. 【Chemistry 14】 [In the formula, R ５ｃ and R ５ｄ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido; or R ５ｃ and R ５ｄ and combine to form a cycloalkyl; and R ６ａ and R ６ｂ are each independently selected from alkyl, alkenyl, alkynyl, halo, hydroxyl, carboxyl, acyl, acetyl, ester, thioester, alkoxy, phosphoryl, amino, amido, cyano, nitro, azido, alkylthio, alkenyl, alkynyl, cycloalkyl, alkylsulfonyl, and sulfonamido.

21. The compound is 【Chemistry 15-1】 【Chemistry 15-2】 【Chemistry 15-3】 【Chemistry 15-4】 【Chemistry 15-5】 【Chemistry 15-6】 【Chemistry 15-7】 【Chemistry 15-8】 【Chemistry 15-9】 【Chemistry 15-10】 【Chemistry 15-11】 【Chemistry 15-12】 【Chemistry 15-13】 【Chemistry 15-14】 【Chemistry 15-15】 【Chemistry 15-16】 【Chemistry 15-17】 2. The compound of claim 1, which is selected from:

22. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharma- ceutically acceptable excipient.

23. The pharmaceutical composition of claim 22 for use in treating a disease or disorder characterized by TACC dyregulation.

24. 24. The pharmaceutical composition of claim 23, wherein the disease or disorder is cancer, preferably breast cancer, colon cancer, melanoma cancer, lung cancer, central nervous system cancer, ovarian cancer, leukemia cancer, kidney cancer or prostate cancer.

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