Heterocyclic compounds and their uses

Abstract

The present disclosure relates to pharmaceutical compounds, compositions and methods, and in particular to compositions and methods comprising the compounds of any one of Formulas (I), (II), (III) and (IV) as further described herein. TIFF2024527402000642.tif67117 The compounds are inhibitors of protein kinases associated with cancer and are therefore useful in the treatment and / or prevention of tumors or cancer. The present disclosure also provides novel compounds that inhibit one or more protein kinases known to be strongly associated with neurodegenerative diseases, including DYRK1 / DYRK1A, DYRK1B, LRRK2, and MLK1 / MAP3K9 kinases.

Description

Technical Field

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Application No. PCT / CN2021 / 106076, filed July 13, 2021, and International Application No. PCT / CN2022 / 098577, filed June 14, 2022, the disclosures of each of which are incorporated by reference in their entirety.

[0002] Technical Field The present disclosure relates to compounds, pharmaceutical compositions and methods of treatment, particularly compositions and methods for treating proliferative disorders, cancer or neurodegenerative diseases, or modulating immune responses or sensitivity to pain using the compounds disclosed herein. [Background Technology]

[0003] background Protein kinases are a group of enzymes that phosphorylate other proteins. Many protein kinases are involved in signal transduction within cells or between cells and their external environment. Phosphorylation of signaling molecules can "on" or "off" important cellular functions, dramatically affecting cell survival or proliferation. Dysregulation of protein kinases, particularly those involved in signal transduction and cell regulatory functions, is often associated with proliferation disorders such as cancer and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Dysregulation of protein kinases has also been implicated in modulating immune responses or pain sensitivity. Indeed, numerous protein kinase mutations that promote or induce cancer have been identified, and many protein kinase inhibitors have proven effective in treating such cancers. Acute myeloid leukemia (AML), for example, is often associated with mutations in FLT3 (fms-like tyrosine kinase 3), and FLT3 kinase inhibitors are known to be useful in treating some AML patients with such mutations. Daver, et al., Leukemia, vol. 33:299-312 (2019). Similarly, inhibitors of EGFR (epidermal growth factor receptor) kinase are useful for treating many types of cancer, including colorectal cancer. Li, et al., Gastroenterology Report vol. 8(3), 179-91 (2020). Similarly, inhibitors of neurotrophic tyrosine receptor kinase (NTRK) have been reported to be useful for treating some patients with non-small cell lung cancer. Tatematsu, et al., Molec. Clin. Oncology, vol. 2, 725-30 (2014).DYRK1 / DYRK1A, DYRK1B, LRRK2, and MLK1 / MAP3K9 inhibitors have been reported to be useful in treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Kargbo, R. Med Chem. Lett., vol. 11, 1795-1796 (2020); Abdel-Magid, A. Med Chem. Lett., vol. 10, 846-847 (2019); Craige, S. et al., Biochim. Et Biophys. Acta, vol 1862, 1581-1586 (2016)). c-SRC, FYN, LYN, SYK, JAK1, JAK3, and GLK / MAP4K1 inhibitors have been reported to be useful for modulating immune responses (Lowell, C. Cold Spring Harb Perspect Biol., vol. 3, a002352 (2011); Szilveszter, K. et al., Front. Immunol. Vol. 10, Article 1862 (2019); Scapini, P. et al., Immunol. Rev. vol. 228, 23-40 (2009)). NTRK inhibitors have been reported to be useful for treating pain in cancer patients (Drilon, A. Ann. Oncol. Vol. 30, viii23-viii30). Therefore, there is a need for novel small molecule inhibitors of protein kinases associated with cancer or neurodegenerative diseases or capable of modulating immune responses or pain sensitivity in cancer patients. The present disclosure provides novel compounds that inhibit one or more protein kinases known to be strongly associated with cancer, including FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1, and CK2a kinases, and are therefore useful in treating cancers associated with such protein kinases, including acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), thyroid cancer, mast cell tumor (MCT), and solid tumors with NTRK gene fusions.The compounds of the present disclosure often inhibit more than one cancer-associated kinase and therefore may be useful in treating cancer with a reduced risk of mutations that allow the cancer to escape from the compounds and treatments of the present disclosure. The present disclosure also provides novel compounds that inhibit one or more protein kinases known to be strongly associated with neurodegenerative diseases, including DYRK1 / DYRK1A, DYRK1B, LRRK2, and MLK1 / MAP3K9 kinases, and are therefore useful for treating neurodegenerative diseases associated with such protein kinases, including Alzheimer's disease and Parkinson's disease.The present disclosure further provides novel compounds that inhibit one or more protein kinases known to be strongly associated with immune response modulation, including c-SRC, FYN, LYN, SYK, JAK1, JAK3, and GLK / MAP4K1.The present disclosure further provides novel compounds that inhibit one or more protein kinases known to be strongly associated with modulating pain sensitivity in cancer patients, including NTRK.

Prior Technical Literature

Non-licensed literature

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Summary of the Invention

Means for Solving the Problems

[0005] Abstract In one aspect, the present disclosure provides a heterocyclic compound having a structure according to formula (I):

Chemical Formula

[0006] In another aspect, the present disclosure provides heterocyclic compounds having a structure according to formula (I):

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[0007] In another aspect, the present disclosure provides heterocyclic compounds having a structure according to formula (IC):

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[0008] In another aspect, the present disclosure provides a heterocyclic compound having a structure according to formula (ID):

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[0009] In another aspect, the present disclosure provides heterocyclic compounds having a structure according to formula (IE):

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[0010] In another aspect, the present disclosure provides a heterocyclic compound having a structure according to formula (II):

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[0011] In another aspect, the present disclosure provides a heterocyclic compound having a structure according to formula (III):

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[0012] In another aspect, the present disclosure provides a heterocyclic compound having a structure according to formula (IV):

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[0013] The compounds of formulae (I)-(IV) and subformulae thereof are described in more detail below.

[0014] Any one of the compounds of formulas (I) to (IV) above can be used for any suitable purpose. In some embodiments, the compounds are used in therapy or for manufacturing a medicament for treating the conditions referred to herein, particularly for treating cancers associated with kinases selected from FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1, and CK2a.

[0015] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising any one of the compounds of Formulas (I)-(IV) described herein in admixture with at least one pharmaceutically acceptable carrier or excipient, such pharmaceutical compositions being useful for treating cancers such as those disclosed herein.

[0016] In yet another aspect, the present disclosure provides methods for treating and / or preventing a proliferation disorder, cancer, or tumor, comprising administering to a subject in need thereof an effective amount of a compound of any one of Formulas (I)-(IV) described herein, or a pharmaceutical composition comprising such a compound. In some embodiments, the methods are useful for treating cancers associated with protein kinases, including FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1, and CK2a kinases, particularly acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), thyroid cancer, mast cell tumor (MCT), and solid tumors with NTRK gene fusions.

[0017] In yet another aspect, the present disclosure provides use of a compound of any one of the above formulas (I) to (IV) for the manufacture of a medicament. Typically, the medicament is for treating a condition described herein, such as cancer or a similar proliferative disorder. In some embodiments, the medicament is useful for treating cancers associated with protein kinases, including FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1, and CK2a kinases, for example, acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), thyroid cancer, mast cell tumor (MCT), and solid tumors with NTRK gene fusions, among others.

[0018] In yet another aspect, the present disclosure provides a pharmaceutical combination for treating and / or preventing a proliferation disorder, cancer, or tumor in a subject, the pharmaceutical combination comprising an effective amount of a compound of any one of Formulas (I) to (IV) above or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing a proliferation disorder in a subject in need of such treatment. In some embodiments, the medicament is useful for treating cancers associated with protein kinases, including FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1, and CK2a kinases, for example, acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), thyroid cancer, mast cell tumor (MCT), and solid tumors with NTRK gene fusions, among others. The second therapeutic agent can be a small molecule or a biologic. The second therapeutic agent can be a kinase inhibitor, a cytotoxin, or a checkpoint (PD-1, PD-L1) inhibitor.

[0019] In yet another aspect, the present disclosure provides a method for treating and / or preventing a proliferative disorder, cancer, or tumor in a subject, comprising administering to a subject in need thereof an effective amount of the above-described pharmaceutical combination. In some embodiments, the proliferative condition is selected from the group consisting of sarcoma, epidermoid carcinoma, fibrosarcoma, cervical cancer, gastric cancer, skin cancer, leukemia including acute myeloid leukemia, lymphoma including non-Hodgkin's lymphoma, lung cancer, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, thyroid cancer, prostate cancer, breast cancer, liver cancer, head and neck cancer, pancreatic cancer, mast cell tumor, and solid tumors with NTRK gene fusions.

[0020] In yet another aspect, the present disclosure provides a method for inhibiting the activity of cancer-associated kinases and individual pathways, including FLT3, ALK, EGFR, VEGFR, NTRK, RET, ROS / ROS1, DYRK1, and CK2a kinases, in a cell or subject, comprising administering to a cell or subject in need thereof an effective amount of a compound of any one of Formulas (I)-(IV) described herein, or a pharmaceutical composition comprising such a compound, or a combination described herein containing such a compound. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention General definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications and other publications mentioned herein are incorporated by reference in their entirety. If the definitions set forth in this section are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications or other publications incorporated herein by reference, the definitions set forth in this section shall prevail over the definitions incorporated herein by reference.

[0022] As used herein, "a" or "an" means "at least one" or "one or more."

[0023] The term "alkyl," as used herein, refers to a saturated hydrocarbon group of a linear, branched, or cyclic configuration, or any combination thereof; specifically contemplated alkyl groups include those having 10 or fewer carbon atoms, particularly those having 1 to 6 carbon atoms, and lower alkyl groups having 1 to 4 carbon atoms. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, and the like.

[0024] The term "alkylene," by itself or as part of another substituent, unless otherwise stated, includes, but is not limited to, -CH 2 CH 2 CH 2 CH 2 "Alkyl" refers to a divalent radical derived from alkyl, as exemplified by -. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0025] Alkyl groups can be unsubstituted or they can be substituted to the extent that such substitution is chemically justified. Typical substituents include, but are not limited to, halo, ═O, ═N—CN, ═N—OR a , =NR a , -OR a , -NR a 2 , -SR a , -SO 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , -NR a CONRa 2 , -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2 , -OOCR a , -COR a and -NO 2 R a are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl; R a are halo, =O, =N-CN, and =N-OR, respectively. b , =NR b , OR b , N.R. b 2 , S.R. b , SO 2 R b , SO 2 NR b 2 , N.R. b SO 2 R b , N.R. b CONR b 2 , N.R. b COOR b , N.R. b COR b , CN, COOR b ,CONR b 2 ,OOCR b , C.O.R. b and NO 2 and optionally substituted by R b are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl. The alkyl, alkenyl, and alkynyl groups can also be substituted with C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl, each of which can be substituted with a substituent appropriate for the particular group. When the substituent is present on the same atom or adjacent atoms, two R a group or R b When the group contains a -NR b 2 or -NR b -C(O)R b ), these two R a group or R b Groups can optionally be joined together with atoms in the substituent to which they are attached to form a ring having 5 to 8 ring members, which ring can be joined by R a or R b It may be substituted as allowed by itself and may contain additional heteroatoms (N, O or S) as ring members.

[0026] The term "alkenyl," as used herein, refers to an alkyl, as defined above, having at least two carbon atoms and at least one carbon-carbon double bond. Thus, particularly contemplated alkenyl groups include linear, branched, or cyclic alkenyl groups having 2 to 10 carbon atoms (e.g., ethenyl, propenyl, butenyl, pentenyl, etc.), or, in the case of cyclic alkenyl groups, 5 to 10 atoms. Alkenyl groups are optionally substituted with groups suitable for alkyl groups, as described herein.

[0027] Similarly, the term "alkynyl," as used herein, refers to an alkyl or alkenyl, as defined above, having at least two (preferably three) carbon atoms and at least one carbon-carbon triple bond. Particularly contemplated alkynyls include linear, branched, or cyclic alkynes having a total of 2 to 10 carbon atoms (e.g., ethynyl, propynyl, butynyl, cyclopropylethynyl, etc.). Alkynyl groups are optionally substituted with groups suitable for alkyl groups, as described herein.

[0028] The term "cycloalkyl," as used herein, refers to a cyclic alkane (i.e., a hydrocarbon chain of carbon atoms forming a ring), preferably containing 3 to 8 carbon atoms. Thus, exemplary cycloalkanes include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls also contain one or two double bonds to form "cycloalkenyl" groups. Cycloalkyl groups are optionally substituted with groups suitable for alkyl groups, as described herein.

[0029] The term "aryl" or "aromatic moiety," as used herein, refers to an aromatic ring system that may further contain one or more non-carbon atoms. These are typically 5- to 6-membered isolated rings or 8- to 10-membered bicyclic groups, which may be substituted. Thus, contemplated aryl groups include (e.g., phenyl, naphthyl, etc.) and pyridyl. Additionally, contemplated aryl groups may be fused (i.e., covalently bonded to two atoms on the first aromatic ring) with one or two 5- or 6-membered aryl or heterocyclic groups, i.e., referred to as "fused aryl" or "fused aromatic."

[0030] Aromatic groups containing one or more heteroatoms (usually N, O, or S) as ring members can be referred to as heteroaryl or heteroaromatic groups. Typical heteroaromatic groups include monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and imidazolyl, as well as fused bicyclic moieties formed by fusing one of these monocyclic groups with a phenyl ring or with any of the heteroaromatic monocyclic groups to form C8-C10 bicyclic groups such as indolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, pyrazolopyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl, and the like. Included in this definition are both monocyclic and fused-ring bicyclic systems that possess aromatic character in terms of electron distribution throughout the ring system. This definition also includes bicyclic groups in which at least the ring directly attached to the rest of the molecule possesses aromatic character. Typically, ring systems contain 5 to 12 ring atoms.

[0031] As also used herein, the terms "heterocycle," "cycloheteroalkyl," and "heterocyclic moiety" are used interchangeably herein and refer to any compound in which atoms form a ring through multiple covalent bonds, where the ring contains at least one atom other than a carbon atom as a ring member. In particular, contemplated heterocyclic rings include 5- and 6-membered rings having nitrogen, sulfur, or oxygen as the non-carbon atom (e.g., imidazole, pyrrole, triazole, dihydropyrimidine, indole, pyridine, piperazine, thiazole, tetrazole, etc.). Typically, these rings contain 0 to 1 oxygen or sulfur atom, at least 1, and usually 2 to 3, carbon atoms, and up to 4 nitrogen atoms as ring members. Further contemplated heterocycles may be fused to one or two carbocyclic or heterocyclic rings (i.e., covalently bonded to two atoms on the first heterocyclic ring), i.e., as used herein, are referred to as "fused heterocycles" or "fused heterocyclic rings" or "fused heterocyclic moieties." When the rings are aromatic, they may be referred to herein as "heteroaryl" or heteroaromatic groups.

[0032] Heterocyclic groups that are not aromatic may be substituted with groups suitable for substituting alkyl groups, as described above.

[0033] The aryl and heteroaryl groups can be substituted where permissible. Suitable substituents include, but are not limited to, halo, -OR a , -NR a 2 , -SR a , -SO 2 R a , -SO 2 NR a 2 , -NR a SO 2 R a , -NR a CONR a 2 , -NR a COOR a , -NR a COR a , -CN, -COOR a , -CONR a 2 , -OOCR a , -CORa and -NO 2 Contains R a are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8 heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, or C5-C10 heteroaryl; R a are halo, =O, =N-CN, and =N-OR, respectively. b , =NR b , OR b , N.R. b 2 , S.R. b , SO 2 R b , SO 2 NR b 2 , N.R. b SO 2 R b , N.R. b CONR b 2 , N.R. b COOR b , N.R. b COR b , CN, COOR b ,CONR b 2 ,OOCR b , C.O.R. b and NO 2 and optionally substituted by R b are each independently H, C1-C8 alkyl, C2-C8 heteroalkyl, C3-C8 heterocyclyl, C4-C10 heterocyclylalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl. The alkyl, alkenyl, and alkynyl groups can also be substituted with C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl, or C5-C10 heteroaryl, each of which can be substituted with a substituent appropriate for the particular group. When the substituent is present on the same atom or adjacent atoms, two R a group or R b When the group contains a -NR b 2 or -NR b -C(O)R b ), these two R a group or R b Groups can optionally be joined together with atoms in the substituent to which they are attached to form a ring having 5 to 8 ring members, which ring can be joined by R a or R b It may be substituted as allowed by itself and may contain additional heteroatoms (N, O or S) as ring members.

[0034] The term "alkoxy" as used herein refers to a hydrocarbon group linked via an oxygen atom, e.g., -O-Hc, where the hydrocarbon portion Hc can have any number of carbon atoms, typically 1 to 10 carbon atoms, and may further contain double or triple bonds, may contain one or two oxygen, sulfur, or nitrogen atoms in the alkyl chain, and may be substituted with aryl, heteroaryl, cycloalkyl, and / or heterocyclyl groups. For example, suitable alkoxy groups include methoxy, ethoxy, propyloxy, isopropoxy, methoxyethoxy, benzyloxy, allyloxy, and the like. Similarly, the term "alkylthio" refers to an alkyl sulfide of the general formula -S-Hc, where the hydrocarbon portion Hc is as described for an alkoxy group. For example, contemplated alkylthio groups include methylthio, ethylthio, isopropylthio, methoxyethylthio, benzylthio, allylthio, and the like.

[0035] The term "amino" as used herein refers to the group -NH 2 The term "alkylamino" refers to an amino group in which one or both hydrogen atoms have been replaced by a hydrocarbon group Hc as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group. Exemplary alkylamino groups include methylamino, dimethylamino, ethylamino, diethylamino, and the like. Similarly, the term "substituted amino" refers to an amino group in which one or both hydrogen atoms have been replaced by a hydrocarbon group Hc as described above, where the amino nitrogen "N" may be substituted by one or two Hc groups as described above for the alkoxy group.

[0036] The term "acyl," as used herein, refers to a group of formula -C(=O)-D, where D represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle as defined above. Typical examples are groups where D is C1-C10 alkyl, C2-C10 alkenyl or alkynyl, or phenyl, each of which is optionally substituted. In some embodiments, D is H, Me, Et, isopropyl, propyl, butyl, C1-C4 alkyl (-OH, -OMe, or NH 2 substituted by), phenyl, halophenyl, alkylphenyl, and the like.

[0037] The term "aryloxy" as used herein refers to an aryl group linked to an oxygen atom, and the aryl group may be further substituted. For example, suitable aryloxy groups include phenyloxy and the like. Similarly, the term "arylthio" as used herein refers to an aryl group linked to a sulfur atom, and the aryl group may be further substituted. For example, suitable arylthio groups include phenylthio and the like.

[0038] Each hydrocarbon moiety, such as alkoxy, alkylthio, alkylamino, and aryloxy, may be appropriately substituted relative to the associated hydrocarbon moiety.

[0039] The term "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine. Halogen or halo, when present as a substituent, usually refers to F or Cl or Br, more typically F or Cl.

[0040] The term "haloalkyl" refers to the alkyl group described above, in which one or more hydrogen atoms on the alkyl group are replaced by a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as fluoroethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0041] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group has been replaced by a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0042] The term "sulfonyl" refers to the group SO 2 -Alkyl, SO 2 -substituted alkyl, SO 2 -Alkenyl, SO 2 -substituted alkenyl, SO 2 -cycloalkyl, SO 2 -substituted cycloalkyl, SO 2 -cycloalkenyl, SO 2 -substituted cycloalkenyl, SO 2 -aryl, SO 2 -substituted aryl, SO 2 -heteroaryl, SO 2 -substituted heteroaryl, SO 2 -heterocyclic and SO 2 -substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are each as defined herein. Sulfonyl includes, by way of example, methyl-SO.sub.2. 2 -, phenyl-SO 2 - and 4-methylphenyl-SO 2 -Includes.

[0043] The term "sulfonylamino" refers to the group -NR 21 SO 2 R 22 refers to R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the atoms to which they are bonded, form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0044] The term "aminosulfonyl" refers to the group -SO 2 NR 21 R 22 refers to R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the nitrogen to which they are attached, form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0045] The term "acylamino" refers to -NR 20 C(O) alkyl, -NR 20 C(O) substituted alkyl, -NR 20 C(O)cycloalkyl, -NR 20 C(O)-substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)-substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O) substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O) substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O) substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)-substituted heteroaryl, -NR 20 refers to the groups -C(O)heterocyclic and -NR20C(O)substituted heterocyclic, and R 20 is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0046] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0047] The term "aminocarbonylamino" refers to -NR 20 C(O)NR 21 R 22 R refers to the group 20 is hydrogen or alkyl, and R 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 optionally, together with the nitrogen to which they are attached, form a heterocyclic or substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0048] It should be further recognized that all of the above-defined groups may be further substituted with one or more substituents, which in turn may be substituted with hydroxy, amino, cyano, C1-C4 alkyl, halo, or C1-C4 haloalkyl. For example, a hydrogen atom in an alkyl or aryl may be replaced by an amino, halo, or C1-4 haloalkyl or alkyl group.

[0049] The term "substituted," as used herein, refers to a functional group replacing a hydrogen atom of an unsubstituted group; specifically contemplated functional groups are nucleophilic groups (e.g., -NH 2 , -OH, -SH, -CN, etc.), electrophilic groups (e.g., C(O)OR, C(X)OH, etc.), polar groups (e.g., -OH), non-polar groups (e.g., heterocycles, aryls, alkyls, alkenyls, alkynyls, etc.), ionic groups (e.g., -NH 3 + ) and halogens (e.g., -F, -Cl), NHCOR, NHCONH 2 , OCH 2 COOH, OCH 2 CONH 2 , OCH 2 CONHR, NHCH 2 COOH, NHCH 2 CONH 2 ,NHSO 2 R, OCH 2 -heterocycle, PO 3 H, SO 3 H, amino acids, and all chemically reasonable combinations thereof. Furthermore, the term "substituted" also includes multiple degrees of substitution, where multiple substituents are disclosed or claimed, the substituted compound may be independently substituted with one or more of the disclosed or claimed substituent moieties.

[0050] Further to the disclosure herein, in certain embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0051] It is understood that for all of the substituted groups defined above, compounds arrived at by defining a substituent that itself has a further substituent (e.g., a substituted aryl having a substituted aryl group as a substituent that is itself substituted by a substituted aryl group, which in turn is substituted by a substituted aryl group, etc.) are not intended to be encompassed herein. In such cases, the maximum number of such substitutions is 3. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl.

[0052] Unless otherwise indicated, the naming of substituents not explicitly defined herein is arrived at by naming the terminal portion of that functionality and then the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0053] With respect to any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically difficult and / or synthetically not feasible. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0054] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal, such as a human, with a counterion that is safe for the mammal for a given dosage regimen. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of a compound, which is derived from a variety of organic and inorganic counterions well known in the art, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, etc.

[0055] The term "salt thereof" refers to a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Optionally, the salt is a pharmaceutically acceptable salt, but this is not necessary for salts of intermediate compounds that are not intended for administration to a patient. For example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0056] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or more, about 70% or more, about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, the compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the subject racemate.

[0057] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) are used to denote the compound's optical rotation, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light left-handed or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light right-handed or clockwise. However, the optical rotation symbols (+) and (-) are independent of the molecule's absolute configuration, i.e., R and S.

[0058] The term "isotopically enriched" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, isotopically enriched compounds contain isotopes of atoms such as, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 In certain embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. In certain embodiments, the isotopically enriched compound is an isotopically enriched compound containing, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79(79 Br), Bromine-81( 81 Br) and iodine-127( 127 In certain embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In certain embodiments, the isotopically enriched compound is an isotope enriched compound containing, but not limited to, tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), Fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I) and iodine-131( 131 In the compounds provided herein, where feasible according to the judgment of one skilled in the art, any of the hydrogen atoms, for example, 2 H or any of the carbons, e.g. 13 C or nitrogen, as examples. 15 It can be either N or Oxygen, for example 18 It is understood that the number of ions in the sieve may be O.

[0059] The term "isotopic enrichment" refers to the amount of an element's more commonly occurring isotope (e.g., in the case of hydrogen, 1 "H" refers to the percentage that incorporates a less commonly occurring isotope of that element (e.g., D for hydrogen) in place of the less commonly occurring isotope of that element (e.g., H). As used herein, when an atom at a particular location in a molecule is designated as a particularly less commonly occurring isotope, it is understood that the abundance of that isotope at that location is substantially greater than its natural abundance.

[0060] The term "isotopic enrichment factor" refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specified isotope.

[0061] The term "hydrogen" or the symbol "H" refers to protium ( 1 H), deuterium ( 2 H or D) and tritium ( 3 H) at their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance of greater than 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0062] The term "deuterium enrichment" refers to the percentage of deuterium incorporated into a molecule at a given position instead of hydrogen. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium is about 0.0156% on average, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a specific position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

[0063] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 Carbon-12 refers to the composition of naturally occurring carbon isotopes, including carbon-12, carbon-13, and carbon-14, carbon-15, carbon-16, carbon-17, carbon-18, carbon-19, carbon-20, carbon-21, carbon-22, carbon-23, carbon-24, carbon-25, carbon-26, carbon-27, carbon-28, carbon-29, carbon-30, carbon-31, carbon-32, carbon-33, carbon-34, carbon-35, carbon-36, carbon-37, carbon-38, carbon-39, carbon-40, carbon-41, carbon-42, carbon-43, carbon-44, carbon-45, carbon-46, carbon-47, carbon-48, carbon-49, carbon-50, carbon-51, carbon-52, carbon-53, carbon-54, carbon-55, carbon-56, carbon-57, carbon-58, carbon-

[0064] The term "carbon-13 enrichment" or " 13 "C enrichment" refers to the proportion of carbon-13 incorporated in place of carbon at a given position in a molecule. For example, a 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at the specified position. Because the natural distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).

[0065] The phrase "enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referenced herein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound referenced herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, tautomer, a mixture of two or more tautomers, or an isotopic variant of a compound referenced herein."

[0066] The compounds and compositions described herein can be administered to a subject in need of treatment for a cell proliferation disorder, such as cancer, particularly a cancer selected from AML, leukemia, lymphoma, lung cancer including non-small cell lung cancer, colon and colorectal cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, head and neck cancer, and pancreatic cancer. The subject is usually a mammal diagnosed with the need for treatment for one or more of such proliferation disorders, and in most cases, the subject is a human. The method includes administering an effective amount of at least one compound of the present disclosure, and optionally, the compound can be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful in treating cancer or proliferation disorders suffered by a particular subject.

[0067] The embodiments listed below are representative of some aspects of the present disclosure. 1. A compound of formula (I):

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[0023] The compound of any one of the preceding embodiments, wherein each represents H, or a pharmaceutically acceptable salt thereof. 10. R 1

[0023] The compound of any one of the preceding embodiments, wherein is H; or a pharmaceutically acceptable salt thereof. 11. R 2

[0023] The compound of any one of the preceding embodiments, wherein is H; or a pharmaceutically acceptable salt thereof. 12. Compounds of formula (IA):

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[0068] In an embodiment, a compound of formula (I):

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[0069] In an embodiment, a compound of formula (I):

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[0070] In embodiments, Y is H, halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 In an embodiment, Y is a group selected from haloalkyl and amino. In an embodiment, Y is H. In an embodiment, Y is halo. In an embodiment, Y is C 1 ~C 3 In an embodiment, Y is C 1 ~C 3 In an embodiment, Y is C 1 ~C 3 In an embodiment, Y is haloalkyl. In an embodiment, Y is amino.

[0071] In embodiments, Y is H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, amino, -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 and -CH 2 In an embodiment, Y is a group selected from H, fluoro, chloro, methoxy, and —CF 3 In embodiments, Y is a group selected from fluoro, chloro, methoxy, and -CF 3 is a group selected from

[0072] In embodiments, Y is H. In embodiments, Y is fluoro. In embodiments, Y is chloro. In embodiments, Y is -CF 3 In an embodiment, Y is methoxy.

[0073] In embodiments, Y' is H, halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 In an embodiment, Y' is a group selected from haloalkyl and amino. In an embodiment, Y' is H. In an embodiment, Y' is halo. In an embodiment, Y' is C 1 ~C 3 In embodiments, Y' is C 1 ~C 3 In embodiments, Y' is C 1 ~C 3 In embodiments, Y' is H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, amino, -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 and -CH 2 In an embodiment, Y' is a group selected from H, methoxy and amino.

[0074] In embodiments, Y' is H. In embodiments, Y' is methoxy. In embodiments, Y' is amino.

[0075] In embodiments, X is halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, X represents one or two optional substituents independently selected from halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, X represents two optional substituents independently selected from halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl is one optional substituent selected from

[0076] In embodiments, X is fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, -CF 3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 and -CH 2 is one optional substituent selected from Cl.

[0077] In embodiments, X is halo. In embodiments, X is C 1 ~C 3 In an embodiment, X is C 1 ~C 3 In an embodiment, X is C 1 ~C 3 In embodiments, X is haloalkyl. In embodiments, X is fluoro. In embodiments, X is chloro. In embodiments, X is methyl. In embodiments, X is ethyl. In embodiments, X is methoxy. In embodiments, X is ethoxy. In embodiments, X is -CF 3 In an embodiment, X is -CCl 3 is.

[0078] In embodiments, R 1 is H and C 1 ~C 3 In embodiments, R 1 is H. In an embodiment, R 1 is C 1 ~C 3 In embodiments, R 1 is methyl. In embodiments, R 1 is ethyl. In embodiments, R 1 is propyl. In embodiments, R 1 is isopropyl.

[0079] In embodiments, R 2 is H and C 1 ~C 3 In embodiments, R 2 is H. In an embodiment, R 2 is C 1 ~C 3 In embodiments, R 2 is methyl. In embodiments, R 2 is ethyl. In embodiments, R 2 is propyl. In embodiments, R 2 is isopropyl.

[0080] In embodiments, R 3 is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and -C(O)-R 11 In embodiments, R 3 is H, methyl, ethyl, propyl, isopropyl, C 1 ~C 3 In an embodiment, R is selected from haloalkyl, —C(O)Me, and —C(O)Et. 3 is H. In an embodiment, R 3 is methyl. In embodiments, R 3 is ethyl. In embodiments, R 3 is propyl. In embodiments, R 3 is isopropyl. In embodiments, R 3 is C 1 ~C 3 In embodiments, R 3 is —C(O)Me. In embodiments, R 3 is -C(O)Et.

[0081] In embodiments, R 3 -CF 3 In an embodiment, R 3 is -CHF 2 In an embodiment, R 3 is -CH 2 F. In an embodiment, R 3 is -CH 2 CF 3 In an embodiment, R 3 is -CH 2 CH 2 CF 3 is.

[0082] In embodiments, R 4 is H and C 1 ~C 3 In embodiments, R 4 is H. In an embodiment, R 4 is C 1 ~C 3 In embodiments, R 4 is methyl. In embodiments, R 4 is ethyl. In embodiments, R 4 is propyl. In embodiments, R 4 is isopropyl.

[0083] In embodiments, R 5 is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl and -C(O)-R 12 In embodiments, R 5 is H, methyl, ethyl, propyl, isopropyl, C 1~C 3 In an embodiment, R is selected from haloalkyl, —C(O)Me, and —C(O)Et. 5 is H. In an embodiment, R 5 is methyl. In embodiments, R 5 is ethyl. In embodiments, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is C 1 ~C 3 In embodiments, R 5 is —C(O)Me. In embodiments, R 5 is -C(O)Et.

[0084] In embodiments, R 6 is H, C 1 ~C 3 Alkyl and -C(O)-R 13 In embodiments, R 6 is selected from H, methyl, ethyl, propyl, isopropyl, —C(O)Me, and —C(O)Et. 6 is H. In an embodiment, R 6 is methyl. In embodiments, R 6 is ethyl. In embodiments, R 6 is propyl. In embodiments, R 6 is isopropyl. In embodiments, R 6 is —C(O)Me. In embodiments, R 6 is -C(O)Et.

[0085] In embodiments, R 11 is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 11 is H. In an embodiment, R 11 is C 1 ~C 3 In embodiments, R 11 is selected from methyl, ethyl, propyl, and isopropyl. 11 is methyl. In embodiments, R 11 is ethyl. In embodiments, R 11 is propyl. In embodiments, R 11 is isopropyl.

[0086] In embodiments, R 12 is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 12 is H. In an embodiment, R 12 is C 1 ~C 3 In embodiments, R 12 is selected from methyl, ethyl, propyl, and isopropyl. 12 is methyl. In embodiments, R 12 is ethyl. In embodiments, R 12 is propyl. In embodiments, R 12 is isopropyl.

[0087] In embodiments, Z is —O—, —NR 6 -, -C(=O)-, -SO 2 -, -C(=O)NR 6 -, -NR 6 C(=O)-, -SO 2 NR 6 - and -(CH 2 ) 1~2 In embodiments, Z is selected from -O-, -NH-, -NMe-, -NEt-, -N(CH 2 ) 2 CH 3 -, -NC(=O)CH 3 -, -NC(=O)CH 2 CH 3 -, -C(O)-, -SO 2 -, -NHC(=O)-, -(Me)NC(=O)-, -(Et)NC(=O)-, -SO 2 NH-, -SO 2 NMe-, -(CH 2 )- and -(CH 2 ) 2 In an embodiment, Z is selected from -O-, -NH-, -NMe-, -NEt-, -NHC(=O)-, -(Me)NC(=O)-, -(Et)NC(=O)-, -(CH 2 )- and -(CH 2 ) 2 - is selected from.

[0088] In embodiments, Z is -O-. In embodiments, Z is -NR 6 In embodiments, Z is -CO-. In embodiments, Z is -SO 2 In an embodiment, Z is —C(═O)NR 6 In embodiments, Z is -NR 6 In an embodiment, Z is -SO 2 NR 6 In an embodiment, Z is -(CH 2 In an embodiment, Z is -(CH 2 CH 2 )-. In embodiments, Z is -NH-. In embodiments, Z is -NMe-. In embodiments, Z is -NEt-. In embodiments, Z is -NHC(=O)-. In embodiments, Z is -(Me)NC(=O)-. In embodiments, Z is -(Et)NC(=O)-. In embodiments, Z is -C(=O)NCH 3 -It is.

[0089] In embodiments, R 13 is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 13 is H. In an embodiment, R 13 is C 1 ~C 3 In embodiments, R 13 is selected from methyl, ethyl, propyl, and isopropyl. 13 is methyl. In embodiments, R 13 is ethyl. In embodiments, R 13 is propyl. In embodiments, R 13 is isopropyl.

[0090] In embodiments, R 7 and R 8 is H and C 1 ~C 3 alkyl, or R 7 and R 8 together can represent oxo (=O). In embodiments, R 7 and R 8 are each H. In an embodiment, R 7 and R 8 can be taken together to represent oxo (=O).

[0091] In embodiments, R 9 and R 10 is H and C 1 ~C 3 alkyl. In an embodiment, R 9 and R 10 are each independently selected from H, methyl, ethyl, propyl, and isopropyl. 9 and R 10 are H, respectively.

[0092] In embodiments, R 7 、R8 、R 9 and R 10 are H, respectively.

[0093] In an embodiment, n is 1 to 4. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0094] In an embodiment, Het represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het represents a heteroaromatic bicyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, and Het is optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het represents a heteroaromatic bicyclic group of 5 to 9 atoms containing at least one nitrogen atom as a ring member, and Het is optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and optionally substituted with 1 to 3 groups independently selected from alkyl.

[0095] In an embodiment, Het is indole. In an embodiment, Het is optionally substituted indole. In an embodiment, Het is halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and indole optionally substituted with three groups independently selected from alkyl.

[0096] In an embodiment, Het is indole optionally substituted with one group selected from fluoro, methyl, methoxy, and ethyl. In an embodiment, Het is indole optionally substituted with two groups independently selected from fluoro, methyl, methoxy, and ethyl. In an embodiment, Het is indole optionally substituted with three groups independently selected from fluoro, methyl, methoxy, and ethyl.

[0097] In an embodiment, Het represents a heteroaromatic monocyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, Het is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het represents a heteroaromatic monocyclic group of 5 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het is optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het represents a heteroaromatic monocyclic group of 5 atoms containing at least one nitrogen atom as a ring member, and Het is optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het represents a heteroaromatic monocyclic group of 5 atoms containing two nitrogen atoms as ring members, and Het is optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and optionally substituted with 1 to 3 groups independently selected from alkyl.

[0098] In an embodiment, Het is pyrazole. In an embodiment, Het is halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is a pyrazole optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is a pyrazole optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is a pyrazole optionally substituted with two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and pyrazole optionally substituted with three groups independently selected from alkyl.

[0099] In an embodiment, Het is pyrazole optionally substituted with one group selected from fluoro, methyl, methoxy, and ethyl. In an embodiment, Het is pyrazole optionally substituted with two groups independently selected from fluoro, methyl, methoxy, and ethyl. In an embodiment, Het is pyrazole optionally substituted with three groups independently selected from fluoro, methyl, methoxy, and ethyl.

[0100] In an embodiment, Het is pyrazole optionally substituted with methyl and ethyl. In an embodiment, Het is pyrazole optionally substituted with two methyl groups.

[0101] In an embodiment, Het is imidazole. In an embodiment, Het is halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is imidazole optionally substituted with 1 to 3 groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is imidazole optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an imidazole optionally substituted with two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 imidazole optionally substituted with three groups independently selected from alkyl.

[0102] In an embodiment, Het is imidazole optionally substituted with one group selected from fluoro, methyl, methoxy, isopropyl, and ethyl. In an embodiment, Het is imidazole optionally substituted with two groups independently selected from fluoro, methyl, methoxy, isopropyl, and ethyl. In an embodiment, Het is imidazole optionally substituted with three groups independently selected from fluoro, methyl, methoxy, isopropyl, and ethyl.

[0103] In an embodiment, Het is imidazole optionally substituted with methyl and isopropyl.

[0104] In an embodiment, Het is

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[0105] wherein X' is halo, C 1 ~C 3 Alkyl and C 1 ~C 3 represents up to two optional substituents independently selected from alkoxy; R 14 are H and C, respectively. 1~4 Alkyl (halo, OH, CN, C 1~3 Alkoxy and C 1~3 haloalkoxy), C 3~6 Cycloalkyl(C 1~3 Alkyl, halo, OH, CN, C 1~3 Alkoxy and C 1~3 haloalkoxy) or -C(=O)-R * represents R * is H, C 1~3 Haloalkyl or C 1~4 Alkyl (OH, CN or C 1~3 optionally substituted with alkoxy).

[0106] In an embodiment, Het is

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[0107] In an embodiment, Het is

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[0108] In an embodiment, Het is

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[0109] In an embodiment, Het is

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[0110] In embodiments, R * is H, C 1~3 Haloalkyl or C 1~4 Alkyl (OH, CN or C1~3 In embodiments, R * is H, methyl, ethyl, propyl, or isopropyl. * is H. In an embodiment, R * is methyl. In embodiments, R * is ethyl. In embodiments, R * is propyl. In embodiments, R * is isopropyl.

[0111] In embodiments, the compound of formula (IA):

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[0112] In embodiments, the compound of formula (IB):

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[0113] In an embodiment, a compound of formula (IC):

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[0114] In an embodiment, a compound of formula (ID):

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[0115] In an embodiment, a compound of formula (IE):

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[0116] In an embodiment, a compound of formula (II):

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[0117] In embodiments, R 1A is H and C 1 ~C 3 In embodiments, R 1A is H. In an embodiment, R 1A is C 1 ~C 3 In embodiments, R 1A is methyl. In embodiments, R 1A is ethyl. In embodiments, R 1A is propyl. In embodiments, R 1A is isopropyl.

[0118] In embodiments, R 2A is H and C 1 ~C 3 In embodiments, R 2A is H. In an embodiment, R 2A is C 1 ~C 3 In embodiments, R 2A is methyl. In embodiments, R 2A is ethyl. In embodiments, R 2A is propyl. In embodiments, R 2A is isopropyl.

[0119] In embodiments, R 3A is H, C 1 ~C 3 Alkyl, C 2~C 4 Alkenyl, C 1 ~C 3 Haloalkyl, -SO 2 R 7A and -C(O)-R 11A In embodiments, R 3A is H, methyl, ethyl, propyl, isopropyl, propenyl, butenyl, -SO 2 Me, -C(O)Me, -C(O)Et, -CH 2 CF 3 , -C(O)CH=CH 2 , -C(O)CH(CH 3 ) 2 and -CH 2 CH 2 In an embodiment, R 3A is H, methyl, ethyl, -SO 2 Me, -C(O)Me, -C(O)Et, -CH 2 CF 3 , -C(O)CH=CH 2 , -C(O)CH(CH 3 ) 2 and -CH 2 CH 2 Selected from F.

[0120] In embodiments, R 3A is H. In an embodiment, R 3A is methyl. In embodiments, R 3A is ethyl. In embodiments, R 3A -SO 2 In an embodiment, R 3A is —C(O)Me. In embodiments, R 3A is —C(O)Et. In embodiments, R 3A is -CH 2 CF 3 In an embodiment, R 3A is -C(O)CH=CH 2 In an embodiment, R 3A is -C(O)CH(CH 3 ) 2 In an embodiment, R 3A is -CH 2 CH 2 It's F.

[0121] In embodiments, G A is -NR 2A R 3A , -SO 2 R 7A , halo and C 1 ~C3 In an embodiment, G is selected from haloalkyl. A is -NR 2A R 3A In an embodiment, G A -SO 2 R 7A In an embodiment, G A is halo. In embodiments, G A is C 1 ~C 3 In one embodiment, G is a haloalkyl. A is -NH 2 , -NHMe, -NHEt, -N(CH 3 ) 2 , -NHC(O)Me, -NHC(O)Et, -NHCH 2 CF 3 , -NHSO 2 Me, -SO 2 Me, -F, -Cl, -Br, -I, -NHC(O)CH=CH 2 , -NHC(O)CH(CH 3 ) 2 , -NHCH 2 CH 2 F and C 1 ~C 3 In an embodiment, G is selected from haloalkyl. A is -NH 2 , -NHMe, -NHEt, -N(Me) 2 , -NHC(O)Me, -NHC(O)Et, -NHCH 2 CF 3 , -NHSO 2 Me, -NHC(O)CH=CH 2 , -NHC(O)CH(CH 3 ) 2 , -NHCH 2 CH 2 F, -SO 2 is selected from Me and -F.

[0122] In an embodiment, G A is -NH 2 In an embodiment, G A is -NHMe. In embodiments, G A is -NHEt. In embodiments, G A is -N(Me) 2 In an embodiment, G A is —NHC(O)Me. In embodiments, G A is —NHC(O)Et. In embodiments, G A is -NHCH 2 CF 3 In an embodiment, G A -NHSO 2 In an embodiment, G A is -NHC(O)CH=CH 2 In an embodiment, G A is -NHC(O)CH(CH 3 ) 2 In an embodiment, G A is -NHCH 2 CH 2 F. In an embodiment, G A -SO 2 In an embodiment, G A is -F.

[0123] In embodiments, R 4A is H and C 1 ~C 3 In embodiments, R 4A is H. In an embodiment, R 4A is C 1 ~C 3 In embodiments, R 4A is methyl. In embodiments, R 4A is ethyl. In embodiments, R 4A is propyl. In embodiments, R 4A is isopropyl.

[0124] In embodiments, R 5A is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, -C(O)-R 12A and -SO 2 R 7A In embodiments, R 5A is H, methyl, ethyl, propyl, isopropyl, C 1 ~C 3 Haloalkyl, -SO 2 In an embodiment, R is selected from -Me, -C(O)Me, and -C(O)Et. 5A is H. In an embodiment, R 5A is methyl. In embodiments, R 5A is ethyl. In embodiments, R 5A is propyl. In embodiments, R 5A is isopropyl. In embodiments, R 5A is C 1 ~C 3 In embodiments, R 5A -SO 2 In an embodiment, R 5A is —C(O)Me. In embodiments, R5A is -C(O)Et.

[0125] In embodiments, R 6A is H and C 1 ~C 3 In embodiments, R 6A is H. In an embodiment, R 6A is C 1 ~C 3 In embodiments, R 6A is methyl. In embodiments, R 6A is ethyl. In embodiments, R 6A is propyl. In embodiments, R 6A is isopropyl.

[0126] In embodiments, R 7A is C 1 ~C 3 In embodiments, R 6A is methyl. In embodiments, R 6A is ethyl. In embodiments, R 6A is propyl. In embodiments, R 6A is isopropyl.

[0127] In embodiments, R 11A is H, C 1 ~C 3 Alkyl, C 2 ~C 4 Alkenyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 11A is C 1 ~C 3 Alkyl and C 2 ~C 4 In embodiments, R is selected from the group consisting of alkyl, aryl, methyl ... 11A is C 1 ~C 3 In embodiments, R 11A is C 2 ~C 4 In embodiments, R is an alkenyl. 11A is selected from methyl, ethyl, propyl, isopropyl, and ethenyl. 11A is methyl. In embodiments, R 11A is ethyl. In embodiments, R 11A is propyl. In embodiments, R 11A is isopropyl. In embodiments, R 11A is ethenyl.

[0128] In embodiments, R 12A is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 12A is H. In an embodiment, R 12A is C 1 ~C 3 In embodiments, R 12A is selected from methyl, ethyl, propyl, and isopropyl. 12A is methyl. In embodiments, R 12A is ethyl. In embodiments, R 12A is propyl. In embodiments, R 12A is isopropyl.

[0129] In an embodiment, Z A -O-, -NR 6A -, -C(=O)-, -SO 2 -, -C(=O)NR 6A -, -SO 2 NR 6A - and -(CH 2 ) 1~2 In an embodiment, Z A -O-, -NH-, -NMe-, -NEt-, -C(O)-, -SO 2 -, -C(=O)NH-, -C(=O)NMe-, -C(=O)NEt-, -SO 2 NH-, -SO 2 NMe-, -(CH 2 )- and -(CH 2 ) 2 In an embodiment, Z A is selected from —O—, —NH—, —NMe—, —NEt— and —C(O)—.

[0130] In an embodiment, Z A is -NR 6A In an embodiment, Z A is -C(=O)NR 6A In an embodiment, Z A -SO 2 NR6A In an embodiment, Z A is -(CH 2 In one embodiment, Z A is -(CH 2 ) 2 In an embodiment, Z A is —O—. In an embodiment, Z A is -NH-. In an embodiment, Z A is -NMe-. In an embodiment, Z A is -NEt-. In an embodiment, Z A is -C(O)-.

[0131] In embodiments, X A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 and one or two optional substituents independently selected from haloalkyl. In an embodiment, X A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In one embodiment, X is one optional substituent selected from haloalkyl. A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0132] In embodiments, X A is one optional substituent that is halo. In embodiments, X A is one optional substituent that is chloro. In an embodiment, X A is one optional substituent that is bromo. In an embodiment, X A is one optional substituent that is iodo. In embodiments, X A is one optional substituent that is fluoro.

[0133] In embodiments, X A is C 1 ~C 3 In one embodiment, X is an alkyl group. A is C 1 ~C 3 In one embodiment, X is an optional substituent that is alkoxy. A is C 1~C 3 One optional substituent is haloalkyl.

[0134] In embodiments, X A is one optional substituent selected from fluoro, methyl, ethyl or propyl.

[0135] In embodiments, X A are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0136] In embodiments, X A is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0137] In embodiments, X A is one optional substituent selected from fluoro, methyl and ethyl.

[0138] In embodiments, X A In an embodiment, X A is fluoro.

[0139] In an embodiment, Het A represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is optionally substituted with 1 to 3 groups independently selected from alkyl. A represents a heteroaromatic bicyclic group of 5 to 9 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is optionally substituted with 1 to 3 groups independently selected from alkyl. A represents a heteroaromatic bicyclic group of 5 to 9 atoms containing at least one nitrogen atom as a ring member, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and optionally substituted with 1 to 3 groups independently selected from alkyl.

[0140] In an embodiment, Het A is indole. In an embodiment, Het A is an optionally substituted indole. In an embodiment, Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with 1 to 3 groups independently selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with one group selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is an indole optionally substituted with two groups independently selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and indole optionally substituted with three groups independently selected from alkyl.

[0141] In an embodiment, Het A is indole optionally substituted with one group selected from fluoro, methyl, methoxy and ethyl. In embodiments, Het A is indole optionally substituted with two groups independently selected from fluoro, methyl, methoxy, and ethyl. In embodiments, Het A is an indole optionally substituted with three groups independently selected from fluoro, methyl, methoxy, and ethyl.

[0142] In an embodiment, Het A represents a heteroaromatic monocyclic group of 5 to 9 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is optionally substituted with 1 to 3 groups independently selected from alkyl. A represents a heteroaromatic monocyclic group of 5 atoms containing, as a ring member, at least one heteroatom selected from N, O and S, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is optionally substituted with 1 to 3 groups independently selected from alkyl. A represents a heteroaromatic monocyclic group of 5 atoms containing at least one nitrogen atom as a ring member, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is optionally substituted with 1 to 3 groups independently selected from alkyl. A represents a heteroaromatic monocyclic group of 5 atoms containing two nitrogen atoms as ring members, and Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and optionally substituted with 1 to 3 groups independently selected from alkyl.

[0143] In an embodiment, Het A is pyrazole. In an embodiment, Het A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is a pyrazole optionally substituted with 1 to 3 groups independently selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, Het is a pyrazole optionally substituted with one group selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In one embodiment, Het is a pyrazole optionally substituted with two groups independently selected from alkyl. A Ha, Halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and pyrazole optionally substituted with three groups independently selected from alkyl.

[0144] In an embodiment, Het A is pyrazole optionally substituted with one group selected from fluoro, methyl, methoxy and ethyl. In an embodiment, Het A is pyrazole optionally substituted with two groups independently selected from fluoro, methyl, methoxy, and ethyl. A is pyrazole optionally substituted with three groups independently selected from fluoro, methyl, methoxy, and ethyl.

[0145] In an embodiment, Het A is pyrazole optionally substituted with two groups independently selected from methyl and ethyl. In embodiments, Het A is a pyrazole optionally substituted with two methyl groups.

[0146] In an embodiment, ring A is a 5-6 membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5- to 6-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one or two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5- to 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one or two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and a 5-6 membered non-aromatic heterocyclic ring as defined above, optionally substituted with one or two groups independently selected from alkyl.

[0147] In an embodiment, ring A is a 5-6 membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5- to 6-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one or two groups selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5- to 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one or more groups selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkyl.

[0148] In an embodiment, ring A is a 5-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5-membered heterocyclic ring as described above, optionally substituted with one group selected from alkyl, halo, C ... 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkyl.

[0149] In an embodiment, ring A is a 6-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 6-membered heterocyclic ring as described above, optionally substituted with one group selected from alkyl, halo, C ... 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as ring members, one or two heteroatoms selected from N and O, and is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkyl.

[0150] In an embodiment, ring A is a 5-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as a ring member, one heteroatom selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as a ring member, one heteroatom selected from N and O, and is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 5-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as a ring member, one heteroatom selected from N and O, and is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkyl.

[0151] In an embodiment, ring A is a 6-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing, as a ring member, one heteroatom selected from N and O, and is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 6-membered heterocyclic ring as described above, optionally substituted with one group selected from alkyl, halo, C ... 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is a 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing, as a ring member, one heteroatom selected from N and O, and is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and alkyl.

[0152] In an embodiment, ring A is a 5-6 membered heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 5-6 membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 5-6 membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members.

[0153] In an embodiment, ring A is a 5-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 5-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 5-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members.

[0154] In an embodiment, ring A is a 6-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 6-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members. In an embodiment, ring A is a 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one or two heteroatoms selected from N and O as ring members.

[0155] In an embodiment, ring A is a 5-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member. In an embodiment, ring A is a 5-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member. In an embodiment, ring A is a 5-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member.

[0156] In an embodiment, ring A is a 6-membered heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member. In an embodiment, ring A is a 6-membered aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member. In an embodiment, ring A is a 6-membered non-aromatic heterocyclic ring fused to the pyrimidine in formula (II) and containing one heteroatom selected from N and O as a ring member.

[0157] In an embodiment, Ring A is selected from pyrrole, furan, tetrahydrofuran, and tetrahydropyran. In an embodiment, Ring A is selected from pyrrole and furan. In an embodiment, Ring A is pyrrole. In an embodiment, Ring A is furan. In an embodiment, Ring A is tetrahydrofuran. In an embodiment, Ring A is tetrahydropyran.

[0158] In embodiments, ring A is halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is selected from the group consisting of pyrrole, furan, tetrahydrofuran, and tetrahydropyran, optionally substituted with one or two groups independently selected from alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is selected from the group consisting of pyrrole, furan, tetrahydrofuran, and tetrahydropyran, optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and pyrrole, furan, tetrahydrofuran, or tetrahydropyran, optionally substituted with two groups independently selected from alkyl.

[0159] In an embodiment, ring A is pyrrole, furan, tetrahydrofuran, or tetrahydropyran, optionally substituted with one or two groups independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy. In an embodiment, ring A is pyrrole, furan, tetrahydrofuran, or tetrahydropyran, optionally substituted with one group independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy. In an embodiment, ring A is pyrrole, furan, tetrahydrofuran, or tetrahydropyran, optionally substituted with two groups independently selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy.

[0160] In embodiments, Ring A is pyrrole optionally substituted with one group selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy. In embodiments, Ring A is pyrrole optionally substituted with methyl. In embodiments, Ring A is pyrrole optionally substituted with ethyl. In embodiments, Ring A is pyrrole optionally substituted with fluoro. In embodiments, Ring A is pyrrole optionally substituted with chloro. In embodiments, Ring A is pyrrole optionally substituted with methoxy. In embodiments, Ring A is pyrrole optionally substituted with ethoxy.

[0161] In embodiments, ring A is absent and the pyrimidine is selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is absent and the pyrimidine is optionally substituted with one or two groups independently selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 In an embodiment, ring A is absent and the pyrimidine is optionally substituted with one group selected from halo, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl and C 1 ~C 3 and optionally substituted with two groups independently selected from alkyl.

[0162] In embodiments, Ring A is absent and the pyrimidine is optionally substituted with halo. In embodiments, Ring A is absent and the pyrimidine is C 1 ~C 3 In an embodiment, ring A is absent and the pyrimidine is optionally substituted with C 1 ~C 3 In an embodiment, ring A is absent and the pyrimidine is optionally substituted with haloalkyl. 1 ~C 3 Optionally substituted with alkyl. In an embodiment, Ring A is absent and the pyrimidine is unsubstituted.

[0163] In embodiments, Ring A is absent and the pyrimidine is optionally substituted with one group selected from fluoro, chloro, bromo, and iodo. In embodiments, Ring A is absent and the pyrimidine is optionally substituted with one group selected from methoxy, ethoxy, and propoxy. In embodiments, Ring A is absent and the pyrimidine is -CF3 , -CHF 2 , -CH 2 F, -CCl 3 , -CHCl 2 and -CH 2 In an embodiment, ring A is absent and the pyrimidine is optionally substituted with one group selected from methyl, ethyl, and propyl.

[0164] In embodiments, Ring A is absent and the pyrimidine is substituted with fluoro. In embodiments, Ring A is absent and the pyrimidine is substituted with methoxy. In embodiments, Ring A is absent and the pyrimidine is -CF 3 In an embodiment, ring A is absent and the pyrimidine is substituted with methyl.

[0165] In embodiments, the compound of formula (IIA):

change

[0166] In embodiments, R 13A is independently selected from H, methyl, ethyl, propyl, and isopropyl. 13A is H. In an embodiment, R 13A is methyl. In embodiments, R 13A is ethyl. In embodiments, R 13A is propyl. In embodiments, R 13A is isopropyl.

[0167] In an embodiment, Y A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1~C 3 and one or two optional substituents independently selected from haloalkyl. In embodiments, Y A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl. In an embodiment, Y A Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0168] In an embodiment, Y A is one optional substituent that is halo. In embodiments, Y A is one optional substituent that is chloro. In embodiments, Y A is one optional substituent that is bromo. A is one optional substituent that is iodo. In embodiments, Y A is one optional substituent that is fluoro.

[0169] In an embodiment, Y A is C 1 ~C 3 In one embodiment, Y is one optional substituent that is alkyl. A is C 1 ~C 3 In one embodiment, Y is an alkoxy group. A is C 1 ~C 3 One optional substituent is haloalkyl.

[0170] In an embodiment, Y A is one optional substituent that is methyl, ethyl, propyl, methoxy, ethoxy, propoxy, chloro, bromo, fluoro, or iodo. A is one optional substituent that is methyl. In embodiments, Y A is one optional substituent that is ethyl. In embodiments, Y A is one optional substituent that is methoxy. In embodiments, Y A is one optional substituent which is ethoxy.

[0171] In an embodiment, Y A are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0172] In an embodiment, Y A are two optional substituents independently selected from chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.

[0173] In an embodiment, Y A does not exist.

[0174] In an embodiment, a compound of formula (III):

change

[0175] In embodiments, X B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 and one or two optional substituents independently selected from haloalkyl. In an embodiment, X B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In one embodiment, X is one optional substituent selected from haloalkyl. B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0176] In embodiments, X B is one optional substituent that is halo. In embodiments, X B is one optional substituent that is chloro. In an embodiment, X B is one optional substituent that is bromo. In an embodiment, X B is one optional substituent that is iodo. In an embodiment, X B is one optional substituent that is fluoro.

[0177] In embodiments, X B is C 1 ~C 3 In one embodiment, X is an alkyl group. B is C 1 ~C 3 In one embodiment, X is an optional substituent that is alkoxy. B is C 1 ~C 3 One optional substituent is haloalkyl.

[0178] In embodiments, X B is one optional substituent which is methyl, ethyl or propyl.

[0179] In embodiments, X B are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0180] In embodiments, X B is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0181] In embodiments, X B is one substituent selected from methoxy and fluoro.

[0182] In embodiments, X B does not exist.

[0183] In an embodiment, Y B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl. In an embodiment, Y B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl. In an embodiment, Y B Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0184] In an embodiment, Y B is one optional substituent that is halo. In embodiments, Y B is one optional substituent that is chloro. In embodiments, Y B is one optional substituent that is bromo. B is one optional substituent that is iodo. In embodiments, Y B is one optional substituent that is fluoro.

[0185] In an embodiment, Y B is C 1 ~C 3 In one embodiment, Y is an alkyl group. B is C 1 ~C 3 In one embodiment, Y is an alkoxy group. B is C 1 ~C 3 One optional substituent is haloalkyl.

[0186] In an embodiment, Y B is one optional substituent which is methyl, ethyl or propyl.

[0187] In an embodiment, Y B are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0188] In an embodiment, Y B is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0189] In an embodiment, Y B does not exist.

[0190] In an embodiment, Z 3B O and NR 3B In an embodiment, Z 3B is O. In an embodiment, Z 3B is NR 3B is.

[0191] In an embodiment, Z 3B is NH. In an embodiment, Z 3B is NCH 3 In an embodiment, Z 3B is NCH 2 CH 3 In an embodiment, Z 3B is NCH 2 CH 2 CH 3 In an embodiment, Z 3B is NCH(CH 3 ) 2 is.

[0192] In an embodiment, Z 2B is N. In an embodiment, Z 2B is CR 2B is.

[0193] In an embodiment, Z 1B is N. In an embodiment, Z 1B is C.

[0194] In embodiments, Ring B is a pyrrole or furan fused to a pyrimidine. In embodiments, Ring B is a pyrrole fused to a pyrimidine. In embodiments, Ring B is a furan fused to a pyrimidine.

[0195] In an embodiment,

change

change

[0196] In an embodiment,

change

change

[0197] In an embodiment,

change

change

change

change

change

change

[0198] In an embodiment,

change

change

[0199] In an embodiment,

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[0200] In an embodiment,

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[0201] In an embodiment,

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[0202] In an embodiment,

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[0203] In an embodiment,

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[0204] In an embodiment,

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[0205] In embodiments, R 1B is H and C 1 ~C 3 In embodiments, R 1B is H. In an embodiment, R 1B is methyl. In embodiments, R 1B is ethyl. In embodiments, R 1B is propyl. In embodiments, R 1B is isopropyl.

[0206] In embodiments, R 2B H, halo, C 1 ~C 3 Alkyl and C 1 ~C 3 In an embodiment, R 2B is H. In an embodiment, R 2B is halo. In embodiments, R 2B is C 1 ~C 3 In embodiments, R 2B is C 1 ~C 3 It is haloalkyl.

[0207] In embodiments, R 2B is H, fluoro, bromo, chloro, iodo, methyl, ethyl, propyl, isopropyl and C 1 ~C 3 In an embodiment, R 2B is fluoro. In embodiments, R 2B is chloro. In embodiments, R 2B is iodo. In embodiments, R 2B is bromo. In embodiments, R2B is methyl. In embodiments, R 2B is ethyl. In embodiments, R 2B is propyl. In embodiments, R 2B is isopropyl. In embodiments, R 2B is C 1 ~C 3 It is haloalkyl.

[0208] In embodiments, R 3B is H and C 1 ~C 3 In embodiments, R 3B is H. In an embodiment, R 3B is methyl. In embodiments, R 3B is ethyl. In embodiments, R 3B is propyl. In embodiments, R 3B is isopropyl.

[0209] In embodiments, R 7B is H and C 1 ~C 3 In embodiments, R 7B is selected from H, methyl, ethyl, propyl, and isopropyl. 7B is H. In an embodiment, R 7B is methyl. In embodiments, R 7B is ethyl. In embodiments, R 7B is propyl. In embodiments, R 7B is isopropyl.

[0210] In embodiments, R 8B is H, C 1 ~C 3 Alkyl and -C(O)-R 10B In embodiments, R 8B is H, methyl, ethyl, propyl, isopropyl and -C(O)-R 10B In embodiments, R 8B is H. In an embodiment, R 8B is methyl. In embodiments, R 8B is ethyl. In embodiments, R 8B is propyl. In embodiments, R 8B is isopropyl. In some embodiments, R 8B is -C(O)-R10B In an embodiment, R 8B is —C(O)—H. In embodiments, R 8B is -C(O)-CH 3 In an embodiment, R 8B is -C(O)-CH 2 CH 3 In an embodiment, R 8B is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 8B is -C(O)-CH(CH 3 ) 2 In an embodiment, R 8B is -C(O)-OCH 3 In an embodiment, R 8B is -C(O)-OCH 2 CH 3 In an embodiment, R 8B is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 8B is -C(O)-OCH(CH 3 ) 2 is.

[0211] In embodiments, R 10B is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 10B is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy and C 1 ~C 3 In an embodiment, R 10B is H. In an embodiment, R 10B is methyl. In embodiments, R 10B is ethyl. In embodiments, R 10B is propyl. In embodiments, R 10B is isopropyl. In embodiments, R 10B is methoxy. In embodiments, R 10B is ethoxy. In embodiments, R 10B is propoxy. In embodiments, R 10B is isopropoxy. In embodiments, R 10B is C 1 ~C 3 It is haloalkyl.

[0212] In embodiments, R 4B is H. In an embodiment, R 4B is methyl. In embodiments, R 4B is ethyl. In embodiments, R 4B is propyl. In embodiments, R 4B is isopropyl. In embodiments, R 4B is -C(O)-R 10B In an embodiment, R 4B is —C(O)—H. In embodiments, R 4B is -C(O)-CH 3 In an embodiment, R 4B is -C(O)-CH 2 CH 3 In an embodiment, R 4B is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 4B is -C(O)-CH(CH 3 ) 2 In an embodiment, R 4B is -C(O)-OCH 3 In an embodiment, R 4B is -C(O)-OCH 2 CH 3 In an embodiment, R 4B is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 4B is -C(O)-OCH(CH 3 ) 2 is.

[0213] In embodiments, R 5B is H and C 1 ~C 3 In embodiments, R 5B is H. In an embodiment, R 5B is methyl. In embodiments, R 5B is ethyl. In embodiments, R 5B is propyl. In embodiments, R 5B is isopropyl.

[0214] In embodiments, R 6B is H. In an embodiment, R6B is methyl. In embodiments, R 6B is ethyl. In embodiments, R 6B is propyl. In embodiments, R 6B is isopropyl. In some embodiments, R 6B is -C(O)-R 10B In an embodiment, R 6B is —C(O)—H. In embodiments, R 6B is -C(O)-CH 3 In an embodiment, R 6B is -C(O)-CH 2 CH 3 In an embodiment, R 6B is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 6B is -C(O)-CH(CH 3 ) 2 In an embodiment, R 6B is -C(O)-OCH 3 In an embodiment, R 6B is -C(O)-OCH 2 CH 3 In an embodiment, R 6B is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 6B is -C(O)-OCH(CH 3 ) 2 is.

[0215] In an embodiment, G B is the formula -NR 4B -(CR 1B ) 2~3 -NR 5B R 6B In an embodiment, G B is the formula -NR 4B -(CH 2 ) 2~3 -NR 5B R 6B is a group of R 4B 、R 5B and R 6B are each independently selected from methyl and ethyl. B is -N(CH 3 )-(CH 2 ) 2~3 -N(CH 3 ) 2 In an embodiment, G B is -N(CH 3 )-(CH 2 ) 2 -N(CH 3 ) 2 In an embodiment, G B is -N(CH 3 )-(CH 2 ) 3 -N(CH 3 ) 2 is.

[0216] In an embodiment, G B is a 5-6 membered saturated ring containing one or two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10B and optionally substituted with one or two groups independently selected from:

[0217] In an embodiment, G B is a six-membered saturated ring containing one or two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10B In embodiments, G is optionally substituted with one or two groups independently selected from B is a six-membered saturated ring containing one nitrogen atom as a ring member, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10B In embodiments, G is optionally substituted with one or two groups independently selected from B is a six-membered saturated ring containing two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10B and optionally substituted with one or two groups independently selected from:

[0218] In an embodiment, G B is the basis of the following formula

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[0219] In an embodiment, G B is the basis of the following formula

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[0220] In an embodiment, a compound of formula (IV):

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[0221] In embodiments, X C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 and one or two optional substituents independently selected from haloalkyl. In an embodiment, X C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In one embodiment, X is one optional substituent selected from haloalkyl. C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0222] In embodiments, X C is one optional substituent that is halo. In embodiments, X C is one optional substituent that is chloro. In an embodiment, X C is one optional substituent that is bromo. In an embodiment, X C is one optional substituent that is iodo. In an embodiment, X C is one optional substituent that is fluoro.

[0223] In embodiments, X C is C 1 ~C 3 In one embodiment, X is an alkyl group. C is C 1 ~C 3 In one embodiment, X is an optional substituent that is alkoxy. C is C 1 ~C 3 One optional substituent is haloalkyl.

[0224] In embodiments, X C is one optional substituent which is methyl, ethyl or propyl.

[0225] In embodiments, X C are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0226] In embodiments, X C is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0227] In embodiments, X C are two substituents that are fluoro.

[0228] In embodiments, X C does not exist.

[0229] In an embodiment, Y C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl. In an embodiment, Y C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 haloalkyl. In an embodiment, Y C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1~C 3 are two optional substituents independently selected from haloalkyl.

[0230] In an embodiment, Y C is one optional substituent that is halo. In embodiments, Y C is one optional substituent that is chloro. In embodiments, Y C is one optional substituent that is bromo. C is one optional substituent that is iodo. In embodiments, Y C is one optional substituent that is fluoro.

[0231] In an embodiment, Y C is C 1 ~C 3 In one embodiment, Y is an alkyl group. C is C 1 ~C 3 In one embodiment, Y is an alkoxy group. C is C 1 ~C 3 One optional substituent is haloalkyl.

[0232] In an embodiment, Y C is one optional substituent which is methyl, ethyl or propyl.

[0233] In an embodiment, Y C are two optional substituents independently selected from chloro, bromo, iodo, and fluoro.

[0234] In an embodiment, Y C is chloro, bromo, iodo, fluoro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy and C 1 ~C 3 are two optional substituents independently selected from haloalkyl.

[0235] In an embodiment, Y C does not exist.

[0236] In an embodiment, Z 3C O, CH 2 and N.R. 3C In an embodiment, Z 3C is O. In an embodiment, Z 3C is CH 2 In an embodiment, Z 3C is NR 3C is.

[0237] In an embodiment, Z 3C is NH. In an embodiment, Z 3C is NCH 3 In an embodiment, Z 3C is NCH 2 CH 3 In an embodiment, Z 3C is NCH 2 CH 2 CH 3 In an embodiment, Z 3C is NCH(CH 3 ) 2 is.

[0238] In an embodiment, Z 1C and Z 2C is independently selected from N and CH. In embodiments, Z 1C and Z 2C is CH. In an embodiment, Z 1C and Z 2C is N. In an embodiment, Z 1C is CH and Z 2C is N. In an embodiment, Z 1C is N and Z 2C is CH.

[0239] In embodiments, R 2C is H and C 1 ~C 3 In embodiments, R 2C is H. In an embodiment, R 2C is methyl. In embodiments, R 2C is ethyl. In embodiments, R 2C is propyl. In embodiments, R 2C is isopropyl.

[0240] In embodiments, R 1C is H and C 1 ~C 3 In embodiments, R 1C is H. In an embodiment, R 1C is methyl. In embodiments, R1C is ethyl. In embodiments, R 1C is propyl. In embodiments, R 1C is isopropyl.

[0241] In embodiments, R 3C is H and C 1 ~C 3 In embodiments, R 3C is H, methyl, ethyl, propyl, or isopropyl. 3C is H. In an embodiment, R 3C is methyl. In embodiments, R 3C is ethyl. In embodiments, R 3C is propyl. In embodiments, R 3C is isopropyl.

[0242] In embodiments, R 8C is H, C 1 ~C 3 Alkyl and -C(O)-R 10C In embodiments, R 8C is H, methyl, ethyl, propyl, isopropyl and -C(O)-R 10C In embodiments, R 8C is selected from H and methyl.

[0243] In embodiments, R 8C is H. In an embodiment, R 8C is methyl. In embodiments, R 8C is ethyl. In embodiments, R 8C is propyl. In embodiments, R 8C is isopropyl. In embodiments, R 8C is -C(O)-R 10C In an embodiment, R 8C is —C(O)—H. In embodiments, R 8C is -C(O)-CH 3 In an embodiment, R 8C is -C(O)-CH 2 CH 3 In an embodiment, R 8C is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 8C is -C(O)-CH(CH 3) 2 In an embodiment, R 8C is -C(O)-OCH 3 In an embodiment, R 8C is -C(O)-OCH 2 CH 3 In an embodiment, R 8C is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 8C is -C(O)-OCH(CH 3 ) 2 is.

[0244] In embodiments, R 10C is H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R 10C is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy and C 1 ~C 3 In an embodiment, R 10C is H. In an embodiment, R 10C is methyl. In embodiments, R 10C is ethyl. In embodiments, R 10C is propyl. In embodiments, R 10C is isopropyl. In embodiments, R 10C is methoxy. In embodiments, R 10C is ethoxy. In embodiments, R 10C is propoxy. In embodiments, R 10C is isopropoxy. In embodiments, R 10C is C 1 ~C 3 It is haloalkyl.

[0245] In embodiments, R 7C is H, C 1 ~C 4 Alkyl (C 1 ~C 3 and 5-6 membered heterocyclic groups containing, as ring members, heteroatoms selected from N, O and S (halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 optionally substituted with one or two groups independently selected from haloalkyl.

[0246] In embodiments, R 7C is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methyl (C 1 ~C 3 optionally substituted with alkoxy), ethyl (C 1 ~C 3 optionally substituted with alkoxy), propyl (C 1 ~C 3 optionally substituted with alkoxy), butyl (C 1 ~C 3 and 5-6 membered heterocyclic groups containing, as ring members, heteroatoms selected from N, O and S (halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 optionally substituted with one or two groups independently selected from haloalkyl.

[0247] In embodiments, R 7C is substituted by methoxy C 2 ~C 4 In embodiments, R 7C is methoxybutyl. In embodiments, R 7C is ethoxybutyl. In embodiments, R 7C is methoxypropyl. In embodiments, R 7C is ethoxypropyl. In embodiments, R 7C is a 5-6 membered heterocyclic group containing, as ring members, heteroatoms selected from N, O, and S. In an embodiment, R 7C is a 6-membered heterocyclic group containing, as ring members, heteroatoms selected from N, O, and S. In embodiments, R 7C is a 6-membered heterocyclic group containing one O as a ring member. In an embodiment, R 7C is a 6-membered heterocyclic group containing one N as a ring member. In an embodiment, R 7C is a 6-membered heterocyclic group containing two N as ring members.

[0248] In embodiments, R 7C is piperazine. In embodiments, R 7C is piperidine. In embodiments, R 7C is tetrahydropyran. In embodiments, R 7C is tetrahydrofuran. In embodiments, R 7C is tetrahydropyran or tetrahydrofuran.

[0249] In embodiments, R 7C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In an embodiment, R is a piperazine substituted with one or two groups independently selected from haloalkyl. 7C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C1 ~C 3 In one embodiment, R is a piperidine substituted with one or two groups independently selected from haloalkyl. 7C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 In one embodiment, R is a tetrahydropyran substituted with one or two groups independently selected from haloalkyl. 7C Ha, Halo, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy and C 1 ~C 3 and tetrahydrofuran substituted with one or two groups independently selected from haloalkyl.

[0250] In an embodiment, G C is -NR 4C -(CR 2C ) 2~3 -NR 5C R 6C In an embodiment, R 4C is H, C 1 ~C 3 Alkyl and -C(O)-R 10C In embodiments, R 4C is H, methyl, ethyl, propyl, isopropyl and -C(O)-R 10C is selected from.

[0251] In embodiments, R 4C is H. In an embodiment, R 4C is methyl. In embodiments, R 4C is ethyl. In embodiments, R 4C is propyl. In embodiments, R 4C is isopropyl. In embodiments, R 4C is -C(O)-R 10C In an embodiment, R 4C is —C(O)—H. In embodiments, R 4C is -C(O)-CH 3 In an embodiment, R 4C is -C(O)-CH 2 CH 3 In an embodiment, R 4C is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 4C is -C(O)-CH(CH 3 ) 2 In an embodiment, R 4C is -C(O)-OCH 3 In an embodiment, R 4C is -C(O)-OCH 2 CH 3 In an embodiment, R 4C is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 4C is -C(O)-OCH(CH 3 ) 2 is.

[0252] In embodiments, R 5C is H and C 1 ~C 3 In embodiments, R 5C is H. In an embodiment, R 5C is methyl. In embodiments, R 5C is ethyl. In embodiments, R 5C is propyl. In embodiments, R 5C is isopropyl.

[0253] In embodiments, R 6C is H. In an embodiment, R 6C is methyl. In embodiments, R 6C is ethyl. In embodiments, R 6C is propyl. In embodiments, R 6C is isopropyl. In embodiments, R 6C is -C(O)-R 10C In an embodiment, R 6C is —C(O)—H. In embodiments, R 6C is -C(O)-CH 3 In an embodiment, R 6C is -C(O)-CH 2 CH 3 In an embodiment, R 6C is -C(O)-CH 2 CH 2 CH 3 In an embodiment, R 6C is -C(O)-CH(CH 3 ) 2 In an embodiment, R6C is -C(O)-OCH 3 In an embodiment, R 6C is -C(O)-OCH 2 CH 3 In an embodiment, R 6C is -C(O)-OCH 2 CH 2 CH 3 In an embodiment, R 6C is -C(O)-OCH(CH 3 ) 2 is.

[0254] In an embodiment, G C is the formula -NR 4C -(CR 2C ) 2~3 -NR 5C R 6C In an embodiment, G C is the formula -NR 4C -(CH 2 ) 2~3 -NR 5C R 6C is a group of R 4C 、R 5C and R 6C are each independently selected from methyl and ethyl. C is -N(CH 3 )-(CH 2 ) 2~3 -N(CH 3 ) 2 In an embodiment, G C is -N(CH 3 )-(CH 2 ) 2 -N(CH 3 ) 2 In an embodiment, G C is -N(CH 3 )-(CH 2 ) 3 -N(CH 3 ) 2 is.

[0255] In an embodiment, GC is a 5-6 membered saturated ring containing one or two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10C and optionally substituted with one or two groups independently selected from:

[0256] In an embodiment, G C is a six-membered saturated ring containing one or two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10C In embodiments, G is optionally substituted with one or two groups independently selected from C is a six-membered saturated ring containing one nitrogen atom as a ring member, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10C In embodiments, G is optionally substituted with one or two groups independently selected from C is a six-membered saturated ring containing two nitrogen atoms as ring members, which is 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl and -C(O)-R 10C and optionally substituted with one or two groups independently selected from:

[0257] In an embodiment, G C is the basis of the following formula

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[0258] Similarly, disclosed are enantiomers, mixtures of enantiomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variations thereof of any of the compounds described herein. Pharmaceutical Compositions, Combinations and Other Related Uses

[0259] In yet another aspect, the disclosure provides pharmaceutical compositions comprising the compounds described above in admixture with at least one pharmaceutically acceptable carrier or excipient.

[0260] The compounds described above can be used for any suitable purpose, for example, the compounds can be used in therapy and / or testing.

[0261] In yet another aspect, the present disclosure provides methods of treating and / or preventing a proliferative disorder, cancer, or tumor.

[0262] In yet another aspect, the disclosure provides the use of the above compound for the manufacture of a medicament.

[0263] In yet another aspect, the present disclosure provides a combination for treating and / or preventing a proliferative disorder in a subject, comprising an effective amount of the compound described above, or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing a proliferative disorder, cancer, or tumor.

[0264] In yet another aspect, the present disclosure provides a method for modulating an immune response. In yet another aspect, the present disclosure provides a method for treating and / or preventing a neurodegenerative disease. In yet another aspect, the present disclosure provides a method for treating pain in a cancer patient.

[0265] In yet another aspect, the present disclosure provides a method of inhibiting the activity of a cancer-associated tyrosine kinase, such as EGFR kinase, FLT3 kinase, VEGFR, NTRK, RET, ALK, ROS / ROS1, DYRK1 and CK2 kinase, in a subject or cell, comprising contacting the tyrosine kinase with a compound of the present disclosure, i.e., any compound of Formulas (I)-(IV) or any of the compounds in Table 1.

[0266] The method can be used for any suitable purpose, hi some embodiments, the method can be used to treat a proliferative disorder, cancer, or tumor.

[0267] In some embodiments, any of the compounds selected from the group consisting of the compounds in Table 1 can be used in the compositions, combinations, and methods of the disclosure. formulation

[0268] Any suitable formulation of the compounds described herein can be prepared. Generally, see Remington's Pharmaceutical Sciences, (2000) Hoover, JE editor, 20th edition, Lippincott Williams and Wilkins Publishing Company, Easton, Pa., pages 780-857. Formulations are selected to suit the appropriate administration route. If the compound is sufficiently basic or acidic to form a stable non-toxic acid or base salt, it may be appropriate to administer the compound as a salt. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate. Pharmaceutically acceptable salts are obtained using standard procedures well known in the art, for example, with a sufficiently basic compound, such as an amine, and a suitable acid which provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids are also made.

[0269] When the contemplated compounds are administered in a pharmacological composition, it is contemplated that the compounds can be formulated in a mixture with pharmaceutically acceptable additives and / or carriers. For example, the contemplated compounds can be administered orally as a neutral compound or as a pharmaceutically acceptable salt, or intravenously with a saline solution. Conventional buffers such as phosphate, bicarbonate, or citrate can be used for this purpose. Of course, those skilled in the art can modify the formulation within the scope of the teachings of this specification to provide various formulations for specific administration routes. In particular, the contemplated compounds may be modified to make them more soluble in water or other vehicles, which can be easily achieved, for example, by minor modifications (salt formulation, esterification, etc.) that are well within the ordinary skill of the art. It is also well within the ordinary skill of the art to modify the administration route and dosage regimen of a particular compound to manage the pharmacokinetics of the compound to maximize the beneficial effect in patients.

[0270] Compounds according to any of Formulas I-IV described herein are generally soluble in organic solvents such as chloroform, dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, glycerol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. In one embodiment, the present disclosure provides a formulation prepared by combining a compound of any of Formulas I-IV with a pharmaceutically acceptable carrier. In one aspect, the formulation may be prepared using a method comprising: a) dissolving the compound described in a water-soluble organic solvent, a non-ionic solvent, a water-soluble lipid, a cyclodextrin, a vitamin such as tocopherol, a fatty acid, a fatty acid ester, a phospholipid, or a combination thereof to obtain a solution; and b) adding saline or a buffer containing 1-10% carbohydrate solution. In one example, the carbohydrate comprises dextrose. The pharmaceutical compositions obtained using this method are stable and useful for veterinary and clinical applications.

[0271] Illustrative examples of water-soluble organic solvents for use in the present method include, but are not limited to, polyethylene glycol (PEG), alcohol, acetonitrile, N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, or combinations thereof. Examples of alcohols include, but are not limited to, methanol, ethanol, isopropanol, glycerol, or propylene glycol.

[0272] Illustrative examples of water-soluble nonionic surfactants for use in the present methods include, but are not limited to, CREMOPHOR® EL, polyethylene glycol-modified CREMOPHOR® (polyoxyethylene glycerol triricinoleate 35), hydrogenated CREMOPHOR® RH40, hydrogenated CREMOPHOR® RH60, PEG-succinate, polysorbate 20, polysorbate 80, SOLUTOL® HS (polyethylene glycol 660 12-hydroxystearate), sorbitan monooleate, poloxamer, LABRAFIL® (ethoxylated persic oil), LABRASOL® (capryl-caproyl macrogol-8-glyceride), GELUCIRE® (glycerol esters), SOFTIGEN® (PEG 6 caprylic acid glyceride), glycerin, glycol-polysorbate, or combinations thereof.

[0273] Illustrative examples of water-soluble lipids for use in the present methods include, but are not limited to, vegetable oils, triglycerides, plant oils, or combinations thereof. Examples of lipid oils include, but are not limited to, castor oil, polyoxyl castor oil, corn oil, olive oil, cottonseed oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, triglycerides of coconut oil, palm seed oil and its hydrogenated forms, or combinations thereof.

[0274] Illustrative examples of fatty acids and fatty acid esters for use in the present methods include, but are not limited to, oleic acid, monoglycerides, diglycerides, mono- or di-fatty acid esters of PEG, or combinations thereof.

[0275] Illustrative examples of cyclodextrins for use in the present methods include, but are not limited to, alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or sulfobutylether-beta-cyclodextrin.

[0276] Illustrative examples of phospholipids for use in the present methods include, but are not limited to, soybean phosphatidylcholine or distearoylphosphatidylglycerol, and hydrogenated versions thereof or combinations thereof.

[0277] Those skilled in the art can modify the formulation within the scope of the teachings of this specification to obtain a number of formulations for specific administration routes.In particular, the compounds may be modified to make them more soluble in water or other vehicles.It is also well within the ordinary skill of those in the art to modify the administration route and dosage regimen of a specific compound to manage the pharmacokinetics of the compound to maximize the beneficial effect in patients. Drug combinations

[0278] The method of the embodiments includes administering an effective amount of at least one exemplary compound of the present disclosure, optionally in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful in treating a proliferative disorder, cancer, or tumor from which the subject is suffering. Optionally, the compound may be administered in combination with one or more additional therapeutic agents, particularly therapeutic agents known to be useful in treating a neurodegenerative disease.

[0279] The additional active ingredient may be administered in a separate pharmaceutical composition from at least one exemplary compound of the present disclosure, or may be included in a single pharmaceutical composition with at least one exemplary compound of the present disclosure. The additional active ingredient may be administered simultaneously with, before, or after the administration of at least one exemplary compound of the present disclosure.

[0280] In yet another aspect, the present disclosure provides a combination for treating and / or preventing a cell proliferation disorder in a subject, comprising an effective amount of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any of the subformulas described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing a cell proliferation disorder, such as cancer or a tumor, in a subject, preferably a subject diagnosed with a need for treatment of such a disorder. Second therapeutic agents suitable for use in combination with the compounds of the present disclosure include small molecule and antibody therapeutic agents useful for treating the same conditions treated by a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a subformula thereof. Chemotherapeutic agents for use in such combinations include 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, irinotecan, regorafenib, trifluridine, tipiracil, drugs that target VEGF (such as bevacizumab, ziv-aflibercept or ramucirumab), or drugs that target EGFR (such as cetuximab or panitumumab).

[0281] In one embodiment, the combination of the present disclosure includes a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or any subformula thereof, in combination with an immuno-oncology therapeutic agent, such as a PD-1 or PD-L1 inhibitor, or other known checkpoint inhibitor that helps the body's own immune system recognize and fight cancer cells. Checkpoint inhibitors assist the subject's immune system in recognizing and attacking abnormal cells, such as cancerous cells, and can significantly enhance the efficacy of chemotherapy, such as the compounds disclosed herein. Suitable checkpoint inhibitors include biologics and small molecule therapeutic agents. Examples of these include ipilimumab, nivolumab, atezolizumab, avelumab, pembrolizumab, tislelizumab, and durvalumab.

[0282] In yet another aspect, the present disclosure provides a combination for treating and / or preventing a neurodegenerative disease in a subject, comprising an effective amount of Formula (I), Formula (II), Formula (III) or Formula (IV), or any of the subformulas described herein, or a pharmaceutically acceptable salt thereof, and an effective amount of a second prophylactic or therapeutic agent for treating and / or preventing a neurodegenerative disease in a subject, preferably a subject diagnosed with such a disorder, in need of such treatment. Methods of Using Exemplary Compounds and Pharmaceutical Compositions Thereof

[0283] The present disclosure also provides pharmaceutical compositions for treating and / or preventing a proliferative disorder, cancer, or tumor, comprising any compound according to any of Formulas I-IV, or any of the compounds of the Examples herein, particularly compounds corresponding to the compound identification numbers in Table 1.

[0284] The present disclosure further provides pharmaceutical compositions for treating and / or preventing neurodegenerative diseases, such as, for example, Alzheimer's disease or Parkinson's disease, comprising any compound according to any of Formulas I-IV, or any of the compounds of the Examples herein, particularly compounds corresponding to the compound identification numbers in Table 1.

[0285] The present disclosure further provides pharmaceutical compositions for modulating immune responses and for pain relief in cancer patients, comprising any compound according to any of Formulas I-IV, or any of the compounds of the Examples herein, particularly compounds corresponding to the compound identification numbers in Table 1.

[0286] To practice the methods of the disclosure, compounds having Formulas I-IV and pharmaceutical compositions thereof may be administered orally, parenterally, by inhalation, topically, rectally, nasally, bucally, vaginally, via an implanted reservoir, or other drug administration methods. The term "parenteral," as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0287] According to the techniques known in the art, suitable dispersing or wetting agents and suspending agents can be used to prepare sterile injectable compositions, such as sterile aqueous or oily injections or suspensions.Sterile injectable preparations can also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents.Among the acceptable vehicles and solvents that can be used are mannitol, water, Ringer's solution and isotonic sodium chloride solution.Suitable carriers and other components of pharmaceutical compositions are usually sterilized.

[0288] In addition, sterile, fixed oils (e.g., synthetic monoglycerides or diglycerides) are commonly used as solvents or suspending media. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethylcellulose or similar dispersants. Various emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0289] Compositions for oral administration may be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase together with an emulsifying or suspending agent. If necessary, certain sweeteners, flavorings, or colorings can be added. Nasal aerosol or inhalation compositions can be prepared according to techniques well known in the field of pharmaceutical formulation, and can be prepared as solutions, for example, in saline, using suitable preservatives (e.g., benzyl alcohol), absorption enhancers to enhance bioavailability, and / or other solubilizers or dispersants known in the art.

[0290] Furthermore, any of the compounds according to Formulas I-IV or the compounds of the Examples herein may be administered alone or in combination with other therapeutic agents for treating various proliferative disorders, cancers or tumors, such as anti-cancer agents, or agents for treating neurodegenerative diseases. Combination therapy according to the present disclosure includes the administration of at least one exemplary compound of the present disclosure and at least one other pharmaceutically active ingredient. The active ingredient(s) and pharmaceutically active agent(s) may be administered individually or together. The amounts of the active ingredient(s) and pharmaceutically active agent(s), as well as the relative timing of administration, are selected to achieve the desired combined therapeutic effect.

[0291] The chemotherapeutic agents for use in such pharmaceutical combinations and combination therapy include 5-fluorouracil, leucovorin, oxaliplatin, capecitabine, irinotecan, regorafenib, trifluridine, tipiracil, VEGF targeting drugs (such as bevacizumab, ziv-aflibercept or ramucirumab), or EGFR targeting drugs (such as cetuximab or panitumumab).The checkpoint inhibitors suitable for use in such pharmaceutical combinations and combination therapy include biological agents and small molecule therapeutic agents.Examples of these include ipilimumab, nivolumab, atezolizumab, avelumab, pembrolizumab, tislelizumab and durvalumab. [Example]

[0292] The compounds of the present disclosure can be synthesized using known methods and starting materials in light of the reaction schemes and examples herein. Synthesis of aryl chlorides / intermediates Scheme 1 [ka] Intermediate 4a: 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2) [ka]

[0293] To a mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 1 (10.5 g, 55.9 mmol), 4-tosyl chloride (12.4 g, 65.0 mmol), and tetrabutylammonium bromide (0.5 g, 1.6 mmol) in dichloromethane (120 ml) was added NaOH (20% aqueous, 60 ml) at room temperature. The reaction mixture was stirred for 0.5 h. The dichloromethane layer was separated and washed with water, then with Na 2 SO 4 The mixture was dried at 0°C and filtered. The filtrate was concentrated to approximately 30 mL. Heptane (50 mL) was then added. The resulting mixture was stirred at 0°C for 2 hours and then filtered. The filter cake was washed with a solution of dichloromethane and heptane (1 / 3, v / v) and dried to give the title compound 2 (16.5 g, 90.6% yield based on the recovery of the mother liquor) as a white solid. 2-Chloro-4-(1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4a) [ka]

[0294] To a mixture of 2 (3.48 g, 10.17 mmol) in PhCl (50 mL) was added AlCl (1.76 g, 13.22 mmol). The mixture was stirred at room temperature for 0.5 h, and then indole 3a (1.67 g, 14.24 mmol) was added. The mixture was stirred at 85 °C for 12 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic phase was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give 4a (2.2 g, 51.16% yield) as a brown solid. MS-ESI (M+H) + :423.0。 Intermediates 4b and 5b: 2-chloro-4-(1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4b) [ka]

[0295] A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (15.60 g, 45.6 mmol) in chlorobenzene (150 ml) was added to the solution of AlCl at room temperature. 3 (7.15 g, 53.6 mmol) was added and the mixture was stirred for a while. 1-Methylindole 3b (6.95 g, 53.0 mmol) was then added dropwise and the mixture was heated to 80° C. for 19 h. The reaction was cooled in an ice bath and quenched by the addition of concentrated HCl (20 mL) and water (40 mL). After stirring for 30 min, the mixture was filtered and the resulting solid was collected. This solid was then added to saturated NaCl solution for 30 min. 2 CO 3 The solid was stirred in refluxing ethyl acetate (35 ml) and collected by filtration. After drying for 1 hour, the solid was stirred in refluxing ethyl acetate (35 ml) for 30 minutes. The mixture was allowed to cool to 0°C, at which point heptane (20 ml) was added. The mixture was stirred for an additional 30 minutes and then filtered. The filter cake was dried to give the title compound 4b (15.0 g, 75.3% yield) as a pale yellow solid. 2-Chloro-4-(1-methyl-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (5b) [ka]

[0296] To a solution of 2-chloro-4-(1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 4b (10.10 g, 23.1 mmol) in methanol (120 mL) was added NaOH (20.20 g, 50.5 mmol). The reaction was stirred for 1 hour and then cooled to 15 °C. A precipitate was observed in the reaction, and then the methanol (approximately 20 mL) was partially evaporated in vacuo. The mixture was then cooled to 0 °C, at which point ice water (100 mL) was added. The resulting mixture was stirred for 2 hours and filtered. The filter cake was washed three times with water and dried to give the title compound 5b (4.5 g, 68.8% yield) as a pale yellow solid. Intermediates 4c and 5c: 2-chloro-4-(4-fluoro-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4c)

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[0297] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.45 g, 0.01 mol) in chlorobenzene (50 ml) was added AlCl at room temperature. 3 (1.92 g, 0.014 mol) was added. The resulting solution was stirred for 30 min, and then a solution of 4-fluoro-1H-indole 3c (1.81 g, 13.4 mmol) in chlorobenzene (5 ml) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80° C. for 4 h. The reaction mixture was then allowed to cool and quenched with water (20 ml) and HCl (1 M, 30 ml). The mixture was stirred for an additional 0.5 h and then filtered to give the title compound 4c, which was used in the next step without further purification. 2-Chloro-4-(4-fluoro-1H-indol-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (5c)

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[0298] To the above solution of 4c in methanol was added another portion of NaOH (6.1 g, 0.15 mol). The mixture was then stirred at 45° C. for 0.5 h. The reaction mixture was then allowed to cool and quenched with water (100 ml). The mixture was stirred for 0.5 h and then filtered. The filter cake was washed with water and then stirred in ethyl acetate (20 ml) overnight. The resulting mixture was filtered, and the filter cake was dried in vacuo to give the title compound 5c (0.9 g, 31.5% overall for two steps). Intermediate 4d: 2-chloro-4-(4-fluoro-1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4d)

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[0299] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (1.3301 g, 3.89 mmol) in chlorobenzene (20 ml) was added AlCl at room temperature. 3 (630.5 mg, 4.72 mmol) was added. The resulting solution was stirred for a while, and then 4-fluoro-1-methyl-1H-indole 3d (1.0833 g, 7.26 mmol) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80° C. for 21 hours. The reaction mixture was then allowed to cool and poured into water (150 ml). The mixture was stirred for another hour and then filtered to give the title compound 4d (0.22 g). The filtrate was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol=10 / 1) to give a further amount of 4d as a gray solid (730 mg, total 950 mg, 53.7% yield). Intermediate 4f: 2-chloro-4-(5-fluoro-1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4f)

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[0300] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.43 g, 0.01 mol) in toluene (50 ml) was added AlCl at room temperature. 3 (1.75 g, 0.013 mol) was added. The resulting solution was stirred for 30 minutes, and then a solution of 5-fluoro-1-methyl-1H-indole 3f (2.3 g, 0.15 mol) in toluene (5 ml) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was then allowed to cool and quenched with water (10 ml) and HCl (1 M, 30 ml). The mixture was stirred for an additional 0.5 hours and then filtered. The filter cake was dried in vacuo to give the title compound 4f (4.0 g, 58.7% yield). Intermediate 4h: 2-chloro-4-(6-fluoro-1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4h)

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[0301] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.43 g, 0.01 mol) in chlorobenzene (50 ml) was added AlCl at room temperature. 3 (1.75 g, 0.013 mol) was added. The resulting solution was stirred for 30 minutes, and then a solution of 6-fluoro-1-methyl-1H-indole 3h (2.3 g, 0.15 mol) in chlorobenzene (5 ml) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 85° C. for 4 hours. The reaction mixture was then allowed to cool and quenched with water (10 ml) and HCl (1 M, 30 ml). The mixture was stirred for an additional 0.5 hours and then filtered. The filter cake was dried in vacuo to give the title compound 4h (3.5 g, 76.9% yield). Intermediate 4l: 2-chloro-4-(5,6-difluoro-1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4i)

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[0302] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.41 g, 0.01 mol) in chlorobenzene (50 ml) was added AlCl at room temperature. 3 (1.75 g, 0.013 mol) was added. The resulting solution was stirred for 30 minutes, and then a solution of 5,6-difluoro-1-methyl-1H-indole 3l (2.05 g, 0.15 mol) in chlorobenzene (5 ml) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80°C for 4 hours. The reaction mixture was then allowed to cool and quenched with water (20 ml) and HCl (1 M, 30 ml). The mixture was stirred for an additional 0.5 hours and then filtered. The filter cake was dried in vacuo to give the title compound 4l (3.8 g, 80.51% yield). Intermediate 4m: 2-chloro-4-(5-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4m)

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[0303] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.45 g, 10 mmol) in chlorobenzene (50 ml) was added AlCl at room temperature. 3 (1.73 g, 12.97 mmol) was added. The resulting solution was stirred for 30 minutes, and then 5-methyl-1H-indole 3m (1.51 g, 11.46 mmol) was added dropwise to the reaction solution at room temperature. The resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was then allowed to cool and quenched with water (20 ml) and HCl (1 M, 10 ml). The mixture was stirred for an additional 0.5 hours and then filtered. The filter cake was stirred in water (50 ml) for 0.5 hours. After filtration, the filter cake was stirred in ethyl acetate (20 ml) overnight. The solid was then collected by filtration and dried in vacuo to give the title product 4m (2.1 g, 48.06% yield). Intermediate 4n: 2-chloro-4-(1,5-dimethyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4n)

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[0304] To a stirred solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 2 (3.45 g, 0.01 mol) in toluene (50 ml) was added AlCl at room temperature. 3 (1.75 g, 0.013 mol) was added. The resulting solution was stirred for 30 minutes, and then a solution of 1,5-dimethyl-1H-indole 3n (2.3 g, 0.15 mol) in toluene (5 ml) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was then allowed to cool and quenched with water (10 ml) and HCl (1 M, 30 ml). The mixture was stirred for an additional 0.5 hours and then filtered. The filter cake was dried in vacuo to give the title compound 4n (4.2 g, 44.3% yield). Intermediate 4u: 2-chloro-4-(1-ethyl-5-fluoro-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (4u)

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[0305] A solution of 2 (1.01 g, 2.95 mmol) in PhCl (20 mL) was added to AlCl 3 (597 mg, 4.48 mmol) was added and then stirred at 20° C. for 0.5 h. To the reaction was added a solution of 1-ethyl-5-fluoro-1H-indole 3u (806 mg, 4.94 mmol) in PhCl (5 mL). The reaction mixture was stirred at 80° C. for 16 h. The reaction was cooled to room temperature, quenched with HCl (4 N, 15 mL), and then stirred for 1 h. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL) and dried under reduced pressure to give 4u (1.01 g, 73.0% yield) as a white solid. Scheme 2

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[0306] A solution of 4a (1 g, 2.36 mmol) and DIPEA (0.915 g, 7.98 mmol) in dichloromethane (50 mL) was added with Boc 2 0 (0.619 g, 2.84 mmol) was added. The mixture was stirred at 20 °C for 8 h. The mixture was concentrated and purified by flash column chromatography (dichloromethane / methanol = 100 / 1 to 10 / 1) to give 4v (0.8 g, 64.69% yield) as a white solid. MS-ESI (M+H) + :523.1。 Scheme 3

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[0307] The synthesis of 7 was similar to that of 2. Using 6 (2.05 g, 10.0 mmol), 4-tosyl chloride (2.21 g, 11.6 mmol), NaOH (20% aqueous, 12 ml), and tetrabutylammonium bromide (0.02 g, 0.062 mmol), 7 (3.2 g, 88.9% yield) was obtained as a white solid. 2-chloro-5-fluoro-4-(1-methyl-1H-indol-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (8)

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[0308] The synthesis of 8 was similar to that of 4b. This reaction was repeated a total of three times by using 7 (2.13 g, 10.0 mmol). All of the crude materials were combined and purified by flash column chromatography to give 8 as a gray solid (2.5 g, 92.9% yield). Scheme 4

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[0309] 2 (1.85 g, 5.5 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 9 (1.21 g, 5.5 mmol), Pd(dppf)Cl in N,N-dimethylacetamide (25 mL). 2 (0.19 g, 0.25 mmol) and Na 2 CO 3 (2M, aqueous, 10 ml, 20 mmol) was added to N 2 The mixture was stirred at 80°C for 3 hours under reduced pressure. After cooling to room temperature, the reaction mixture was filtered through Celite®, and the filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water, and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography (eluted with ethyl acetate) to give the title compound 10 (1.2 g, 54.0% yield) as a white solid. Scheme 5

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[0310] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine 1 (200.3 g, 1.06 mol) in THF (2.3 L) was slowly added NaH (80%, 35.4 g, 1.17 mol) while maintaining the temperature between −5 and −10 °C. The mixture was stirred for an additional 15 min until hydrogen evolution ceased. Next, within 30 min, a solution of POMCl (189.6 g, 1.2 mol) in THF (0.7 L) was added to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 3–4 h. When HPLC showed that 1 was consumed, the reaction mixture was filtered through Celite® and washed with ethyl acetate (0.5 L). The entire filtrate was combined and concentrated under vacuum. The residue was then diluted with ethyl acetate (2.5–3 L) and washed with water (1 L × 2) and brine (1 L). The ethyl acetate layer was separated and dried under vacuum to give crude 11 as a yellow solid, which was used directly in the next step. (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (12)

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[0311] To a mixture of pyrimidine 11 (320 g, 1.06 mol) and 3-nitrophenol (146 g, 1.04 mol) in DMF (2.5 L) was added K 2 CO 3 (290 g, 2.1 mol) was added. The reaction mixture was stirred at room temperature for 5-6 h. When HPLC showed that 2 was consumed, K 2 CO 3 The residue was filtered through Celite® and washed with ethyl acetate (0.5 L). The filtrate was diluted with ethyl acetate (3 L) and water (2 L). The ethyl acetate layer was separated and washed successively with water (1 L x 3), brine (1 L x 3), and water (1 L x 1). If necessary, the extraction of the aqueous phase was repeated. The organic layer was dried in vacuo to give crude product 12 (342 g, 80% yield), which was then purified by crystallization in a petroleum ether / ethyl acetate system (petroleum ether / ethyl acetate = 25 / 3, v / v; 5.6 ml per 1 g of crude product 12). LC-MS: m / z 405.2 [M+H] + 。 1 H NMR (500 MHz, CDCl 3 ): δ ppm 8.17-8.14 (m, 1H), 8.14-8.13 (m, 1H), 7.63-7.62 (m, 2H), 7.37 (d, J = 3.7 Hz, 1H), 6.62 (d, J = 3.7 Hz, 1H), 6.18 (s, 2H), 1.17 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ): δ ppm 178.4, 161.6, 154.6, 152.7, 152.5, 149.1, 130.3, 128.6, 128.2, 120.8, 117.4, 104.8, 100.3, 65.9, 39.0, 27.0 (*3). (4-(3-aminophenoxy)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (13)

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[0312] Ethanol (25 mL) and H 2 A solution of (2-chloro-4-(3-nitrophenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate 12 (2.3 g, 5.68 mmol) in 2H₂O (5 mL) was treated with iron powder (1.6 g, 28.65 mmol) and NH 4 Cl (2.0 g, 38.53 mmol) was added. The mixture was stirred at 90° C. for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 The organic phase was concentrated under reduced pressure to give crude product 13 (2.0 g, 93.9% yield) as a gray solid, which was used in the next step without further purification. (2-chloro-4-(3-(2,2,2-trifluoroacetamido)phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (14)

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[0313] 13 (1.69 g, 4.51 mmol) and Et 3 A solution of N (3.64 g, 36.00 mmol) in dichloromethane (15 mL) was stirred at 0° C. for 10 min. Then, trifluoroacetic anhydride (1.65 g, 7.86 mmol) was added dropwise, and the mixture was stirred at 40° C. for an additional 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and H 2 Wash with NaCl (20 mL x 2). 2 SO 4 After concentration, the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=7 / 1) to give product 14 (1.56 g, 73.5% yield) as an off-white solid. (2-chloro-4-(3-(2,2,2-trifluoro-N-methylacetamido)phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (15)

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[0314] A solution of 14 (1.55 g, 3.29 mmol) in DMF (12 mL) was 2 CO 3 (0.88 g, 6.38 mmol) was added. The mixture was stirred at room temperature for 10 minutes, and then MeI (0.65 g, 4.58 mmol) was added. The mixture was stirred at 45° C. for 2.5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL). The organic phase was 2 Wash with 20 mL of NaCl. 2 SO 4 After concentration, the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=10 / 1) to give product 15 (1.45 g, 90.8% yield) as an off-white solid. Scheme 6:

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[0315] A solution of 3a (1.00 g, 8.54 mmol) in 1,2-dichloroethane (5 mL) was stirred at 0° C. for 10 min. MeMgBr was then added dropwise, followed by a solution of 2,4-dichloro-5-fluoropyrimidine 16 (1.62 g, 9.70 mmol) in 1,2-dichloroethane (15 mL). The mixture was stirred at room temperature overnight. The reaction was then HCl 2 The reaction mixture was quenched with O (10 mL) and filtered off. The filter cake was dried in an air-circulating oven at 40° C. for 2.5 h to give product 17a (0.6 g, 28.38% yield) as a brown solid. Intermediate 17b: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole (17b)

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[0316] To a solution of 3b (2.08 g, 15.86 mmol) in chlorobenzene (50 mL) was added AlCl 3 (2.21 g, 16.57 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (2.72 g, 16.29 mmol) were added. The mixture was stirred at 70° C. for 5 hours. The mixture was heated under H 2 The mixture was quenched with 20 mL of O and filtered off. The filter cake was washed with ethyl acetate (30 mL × 2) and dried in an air-circulating oven at 40 °C overnight to give product 17b (2.78 g, 67.0% yield) as a light brown solid. Intermediate 17d: 3-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-methyl-1H-indole (17d)

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[0317] The synthesis of 17d was similar to that of 17b. The reaction of 3d (1.12 g, 7.51 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.04 g, 6.23 mmol) gave the product 17d (0.76 g, 43.43% yield) as a brown solid. Intermediate 17f: 3-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-methyl-1H-indole (17f)

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[0318] The synthesis of 17f was similar to that of 17b. The reaction of 3f (1.12 g, 7.51 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.01 g, 6.05 mmol) gave the product 17f (0.98 g, 57.87% yield) as a gray solid. Intermediate 17g: 3-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluoro-1H-indole (17g)

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[0319] The synthesis of 17g was similar to that of 17b. The reaction of 3g (1.02 g, 7.55 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.33 g, 7.97 mmol) gave the product 17g (0.87 g, 43.39% yield) as a light brown solid. Intermediate 17h: 3-(2-chloro-5-fluoropyrimidin-4-yl)-6-fluoro-1-methyl-1H-indole (17h)

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[0320] The synthesis of 17h was similar to that of 17b. The reaction of 3h (1.12 g, 7.51 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.02 g, 6.11 mmol) gave the product 17h (0.97 g, 56.82% yield) as a light brown solid. Intermediate 17l: 3-(2-chloro-5-fluoropyrimidin-4-yl)-5,6-difluoro-1-methyl-1H-indole (17l)

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[0321] The synthesis of 17l was similar to that of 17b. The reaction of 3l (1.20 g, 7.18 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.20 g, 7.18 mmol) gave the product 17l (1.31 g, 61.30% yield) as an off-white solid. Intermediate 17m: 3-(2-chloro-5-fluoropyrimidin-4-yl)-5-methyl-1H-indole (17m)

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[0322] The synthesis of 17m was similar to that of 17b. The reaction of 3m (1.00 g, 7.62 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.30 g, 7.79 mmol) gave the product 17m (0.78 g, 39.10% yield) as a gray solid. Intermediate 17n: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1,5-dimethyl-1H-indole (17n)

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[0323] The synthesis of 17n was similar to that of 17b. The reaction of 3n (1.11 g, 7.64 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.08 g, 6.47 mmol) gave the product 17n (0.75 g, 41.99% yield) as a gray solid. Intermediate 17p: 3-(2-chloro-5-fluoropyrimidin-4-yl)-5-methoxy-1-methyl-1H-indole (17p)

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[0324] The synthesis of 17p was similar to that of 17b. The reaction of 3p (1.22 g, 7.57 mmol) and 2,4-dichloro-5-fluoropyrimidine 16 (1.26 g, 7.55 mmol) gave the product 17p (0.73 g, 33.07% yield) as a gray solid. Scheme 7

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[0325] A solution of 18 (5.35 g, 30 mmol) in PhCl (30 mL) was added to AlCl within 5 min at 20 °C. 3 (5.01 g, 38 mmol) was added and stirred for 0.5 h. Then, a solution of 3a (3.5 g, 30 mmol) in PhCl (30 mL) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 4 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic phase was concentrated and purified by flash column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to give the title compound 19a (1.8 g, 23% yield) as a brown solid. MS-ESI (M+H) + :260.3、262.4。 Intermediate 19b: 3-(2-chloro-5-methoxypyrimidin-4-yl)-1-methyl-1H-indole (19b)

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[0326] A solution of 18 (3.55 g, 20 mmol) in PhCl (20 mL) was added to AlCl within 5 min at 20 °C. 3 (2.70 g, 20 mmol) was added and then stirred at 20 °C for 0.5 h. To the reaction mixture was added a solution of 3b (2.63 g, 20 mmol) in PhCl (15 mL). The reaction mixture was stirred at 80 °C for 4 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic phase was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound 19b (4.10 g, 75% yield) as a pink solid. MS-ESI (M+H) + :308.2、310.3。 Intermediate 19d: 3-(2-chloro-5-methoxypyrimidin-4-yl)-4-fluoro-1-methyl-1H-indole (19d)

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[0327] A solution of 18 (607.0 mg, 3.39 mmol) in chlorobenzene (10 ml) was added to AlCl at room temperature. 3 (504.2 mg, 3.78 mmol) was added. The resulting solution was stirred for a while, and then 4-fluoro-1-methyl-1H-indole 3d (0.6 g, 4.02 mmol) was added dropwise to the reaction mixture at room temperature. The resulting mixture was heated at 80° C. for 18 hours. The reaction mixture was then allowed to cool and poured into ice water. The mixture was stirred for an additional 2 hours, and then ethyl acetate was added. The mixture was filtered to give the title compound 19d (489 mg). The filtrate was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol=10 / 1) to give an additional amount of 4d as a gray solid (420 mg, total 909 mg, 91.9% yield). Intermediate 19i: 3-(2-chloro-5-methoxypyrimidin-4-yl)-7-fluoro-1H-indole (19i)

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[0328] 18 (400 mg, 2.24 mmol) and AlCl in chlorobenzene (20 mL) 3 A mixture of 3i (300 mg, 2.24 mmol) was stirred at room temperature for 30 min, then 3i (300 mg, 2.0 mmol) was added. The mixture was stirred at 80° C. for 3 h. The reaction was cooled to room temperature and H 2 The mixture was quenched with 200 mL of HCl (10 mL). The solid was collected by filtration and 2 Washing by stirring in 200 (5 mL) and ethyl acetate (5 mL) afforded 19i as a pale yellow solid (400 mg, approx. 72% yield). Intermediate 19j: 3-(2-chloro-5-methoxypyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole (19j)

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[0329] 18 (2.5 g, 14 mmol) and AlCl in chlorobenzene (100 mL) 3 A mixture of 3j (2 g, 15 mmol) was stirred at room temperature for 30 min, then 3j (2.2 g, 14.8 mmol) was added. The mixture was stirred at 80° C. for 3 h. The reaction was cooled to 0° C. 2 O (6 mL) and HCl (1N, 3 mL) were added sequentially. The solid was collected by filtration and 2 Washing by stirring in 200 (10 mL) and ethyl acetate (10 mL) gave 19j as a purple solid (1.8 g, ∼44% yield). MS-ESI (M+H) + :292.5、294.6。 Intermediate 19q: 3-(2-chloro-5-methoxypyrimidin-4-yl)-7-methyl-1H-indole (19q)

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[0330] A solution of 3q (0.50 g, 3.81 mmol) in chlorobenzene (10 mL) was added to AlCl 3 (0.50 g, 3.75 mmol) and 2,4-dichloro-5-methoxypyrimidine 18 (0.68 g, 3.81 mmol) were added. The reaction mixture was stirred at 40° C. for 5 h, then H 2 The resulting mixture was stirred at room temperature for 10 minutes, and the precipitate was filtered off. The filter cake was washed with dichloromethane (5 mL × 2) and dried in an air-circulating oven at 40 °C for 1.5 hours to give product 19q (1.02 g, 97.76% yield) as a gray solid. Intermediate 19r: 3-(2-chloro-5-methoxypyrimidin-4-yl)-1,7-dimethyl-1H-indole (19r)

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[0331] The synthesis of 19r was similar to that of 19q by using 3r (1.50 g, 10.33 mmol) and 2,4-dichloro-5-methoxypyrimidine 18 (1.36 g, 7.60 mmol), and the product 19r (2.62 g, 119.87% yield) was obtained as a yellow solid. Intermediate 19s: 3-(2-chloro-5-methoxypyrimidin-4-yl)-7-methoxy-1H-indole (19s)

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[0332] 2,4-Dichloro-5-methoxypyrimidine 18 (976 mg, 5.45 mmol) and AlCl in dichloromethane (30 mL) 3 A mixture of (718 mg, 5.45 mmol) was stirred at room temperature for 30 minutes, and then 7-methoxy-1-methyl-1H-indole 3s (897 mg, 5.56 mmol) was added. The mixture was stirred at 40° C. for 5 hours. The reaction was cooled to room temperature. 2 O (10 mL) was then added. The solid was collected by filtration and 2 Washing by stirring in O (5 mL) and ethyl acetate (5 mL) gave 19s as a black solid (1.2 g, approx. 76% yield). Scheme 8

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[0333] 2,4-Dichloro-5-methoxypyrimidine 18 (1.0 g, 5.6 mmol), 1,3-dimethyl-1H-pyrazole-4-boronic acid pinacol ester 9 (1.22 g, 5.5 mmol), Pd(dppf)Cl in N,N-dimethylacetamide (20 mL). 2 (0.2 g, 0.27 mmol) and Na 2 CO 3 (2M, aqueous, 10 ml, 20 mmol) was added to N 2 The mixture was stirred at 80°C for 1 hour under reduced pressure. After cooling to room temperature, the reaction mixture was filtered through Celite®, and the filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water, and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography (eluted with ethyl acetate) to give the title compound 20 (0.8 g, 61.0% yield) as a white solid. Scheme 9:

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[0334] A solution of 3b (1.01 g, 7.70 mmol) in chlorobenzene (15 mL) was added with AlCl 3 (0.92 g, 6.90 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.52 g, 7.01 mmol) were added. The mixture was stirred at 80° C. for 2 hours. The mixture was heated at 80° C. for 2 hours. 2 The mixture was quenched with 20 mL of HCl and filtered off. The filter cake was washed with ethyl acetate (20 mL × 2) and dried in an air-circulating oven at 40 °C overnight to give product 22b (0.79 g, 35.9% yield) as a brown solid. Intermediate 22a: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indole (22a)

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[0335] The synthesis of 22a was similar to that of 22b by using 3a (1.02 g, 8.71 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.56 g, 7.19 mmol), and the product 22a (1.33 g, 62.09% yield) was obtained as a gray solid. Intermediate 22c: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-4-fluoro-1H-indole (22c)

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[0336] The synthesis of 22c was similar to that of 22b by using 3c (2.02 g, 14.95 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (2.94 g, 13.55 mmol), and the product 22c (0.67 g, 15.67% yield) was obtained as a gray solid. Intermediate 22d: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-4-fluoro-1-methyl-1H-indole (22d)

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[0337] The synthesis of 22d was similar to that of 22b by using 3d (1.11 g, 7.44 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.30 g, 5.99 mmol), and the product 22d (0.36 g, 18.20% yield) was obtained as a dark brown solid. Intermediate 22e: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole (22e)

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[0338] The synthesis of 22e was similar to that of 22b by using 3e (2.01 g, 14.87 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (2.95 g, 13.60 mmol), and the product 22e (2.42 g, 56.18% yield) was obtained as a gray solid. Intermediate 22f: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1-methyl-1H-indole (22f)

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[0339] The synthesis of 22f was similar to that of 22b by using 3f (1.01 g, 6.77 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.21 g, 5.58 mmol), and the product 22f (0.78 g, 42.28% yield) was obtained as a gray solid. Intermediate 22g: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1H-indole (22g)

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[0340] The synthesis of 22g was similar to that of 22b by using 3g (2.10 g, 15.54 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (3.37 g, 15.54 mmol), to give the product 22g (1.60 g, 32.62% yield) as a gray solid. Intermediate 22h: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-fluoro-1-methyl-1H-indole (22h)

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[0341] The synthesis of 22h was similar to that of 22b by using 3h (1.02 g, 6.84 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.21 g, 5.58 mmol), to give product 22h (0.53 g, 28.92% yield) as a light brown solid. Intermediate 22i: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-fluoro-1H-indole (22i)

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[0342] The synthesis of 22i was similar to that of 22b by using 3i (5.00 g, 37.00 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (7.99 g, 36.82 mmol), to give the product 22i (6.23 g, 53.34% yield) as a purple solid. Intermediate 22j: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-fluoro-1-methyl-1H-indole (22j)

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[0343] The synthesis of 22j was similar to that of 22b by using 3j (2.21 g, 14.82 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (3.24 g, 14.93 mmol), and the product 22j (1.42 g, 29.07% yield) was obtained as a light brown solid. Intermediate 22l: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5,6-difluoro-1-methyl-1H-indole (22l)

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[0344] The synthesis of 22l was similar to that of 22b by using 3l (0.60 g, 3.59 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (0.79 g, 3.64 mmol), and the product 22l (0.38 g, 30.45% yield) was obtained as a brown solid. Intermediate 22n: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1,5-dimethyl-1H-indole (22n)

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[0345] The synthesis of 22n was similar to that of 22b by using 3n (0.90 g, 6.20 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.01 g, 4.65 mmol), and the product 22n (0.39 g, 25.69% yield) was obtained as a brown solid. Intermediate 22p: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-methoxy-1-methyl-1H-indole (22p)

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[0346] The synthesis of 22p was similar to that of 22b by using 3p (1.12 g, 6.95 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (1.22 g, 5.62 mmol), and the product 22p (0.24 g, 12.43% yield) was obtained as a brown solid. Intermediate 22q: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1H-indole (22q)

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[0347] The synthesis of 22q was similar to that of 22b by using 3q (2.01 g, 15.32 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (3.32 g, 15.32 mmol), and the product 22q (3.00 g, 62.81% yield) was obtained as a gray solid. Intermediate 22r: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-methyl-1-methyl-1H-indole (22r)

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[0348] The synthesis of 22r was similar to that of 22b by using 3r (5.53 g, 38.09 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine 21 (8.26 g, 38.09 mmol), and the product 22r (7.44 g, 59.98% yield) was obtained as a red-purple solid. Intermediate 22s: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-methoxy-1H-indole (22s)

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[0349] The synthesis of 22s was similar to that of 22b by using 3s (1.97 g, 13.39 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.94 g, 13.55 mmol), and the product 22s (2.00 g, 45.60% yield) was obtained as a brown solid. Intermediate 22t: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-7-methoxy-1-methyl-1H-indole (22t)

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[0350] The synthesis of 22t was similar to that of 22b by using 3t (2.19 g, 13.59 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.96 g, 13.64 mmol), and the product 22t (1.86 g, 40.07% yield) was obtained as a brown solid. Intermediate 22u: 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-ethyl-5-fluoro-1H-indole

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[0351] The synthesis of 22u was similar to that of 22b by using 3u (675 mg, 4.14 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (703 mg, 3.24 mmol), to give the product 22u (601 mg, 53.9% yield) as a red solid. Scheme 10

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[0352] A solution of indole (12.8 g, 109 mmol) in THF (150 mL) was added to CH at 0°C for 10 min. 3 MgBr (3.0 M in 2-methyltetrahydrofuran, 36.5 mL, 109 mmol) was added dropwise. The solution was then stirred at 0° C. for 0.5 h. 23 (10.0 g, 54.5 mmol) was then added, resulting in a yellow solution. The ice bath was removed, and the solution was then stirred at room temperature for 1 h, resulting in a red solution. The mixture was heated to 60° C. and then stirred at 60° C. for 1.5 h. The mixture was then cooled to room temperature and saturated aqueous NH 4 Cl (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 3). The organic layer was extracted with Na 2 SO 4 The residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1 to 5:1 to 1:100) to give 24a (11 g, 76.4% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.74 (s, 1H), 8.72 (d, J = 3.2 Hz, 1H), 8.52 (dd, J = 6.6, 2.5 Hz, 1H), 7.55 (dd, J = 6.4, 2.2 Hz, 1H), 7.30 - 7.23 (m, 2H). Intermediate 24b: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (24b)

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[0353] Compound 23 (1.0 g, 5.4 mmol) and AlCl in PhCl (10 mL) 3 A mixture of (1.45 g, 10.9 mmol) was stirred at room temperature for 30 min, then 1-methyl-1H-indole 3b (1.07 g, 8.18 mmol) was added. The mixture was stirred at 80° C. overnight. The reaction was cooled to 0° C. 2 0 (3 mL) and HCl (1N, 1.5 mL) were subsequently added. The solid was collected by filtration. The crude product was 2 Slurrying with 2H2O (5 mL) and ethyl acetate (5 mL) gave 24b as a yellow solid (1.46 g, 96.7% yield). MS-ESI (M+H) + :277.9。 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 7.6 Hz, 1H), 8.42 (d, J = 7.6 Hz, 2H), 7.38 (s, 3H), 3.91 (s, 3H). Intermediate 24i: 3-(2,5-dichloropyrimidin-4-yl)-7-fluoro-1H-indole (24i)

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[0354] A solution of 23 (1.02 g, 5.56 mmol) in PhCl (50 mL) was added to AlCl at 20 °C. 3 (1.52 g, 11.40 mmol) was added to the reaction. The reaction was then stirred at 20° C. for 0.5 h. To the reaction was added a solution of 3j (1.05 g, 6.41 mmol) in PhCl (5 mL). The reaction was stirred at 80° C. for 3 h. The reaction was then cooled to room temperature and quenched with aqueous 4 N HCl (30 mL). The mixture was extracted with dichloromethane. The organic layer was washed with water, saturated NaHCO 3 3 , washed with brine, Na 2 SO 4 The organic layer was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to give 24j (1.19 g, 73.7% yield) as a yellow solid. MS-ESI (M+H) + :224.0。 Intermediate 24q: 3-(2,5-dichloropyrimidin-4-yl)-7-methyl-1H-indole (24q)

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[0355] A solution of 23 (2.06 g, 11.23 mmol) in PhCl (50 mL) was added in several portions to AlCl 3 (2.24 g, 16.80 mmol) was added and the reaction was stirred at 20 °C for 0.5 h. Then, a solution of 3q (1.73 g, 13.19 mmol) in PhCl (5 mL) was added. The resulting mixture was stirred at 80 °C for 5 h. The reaction was cooled to room temperature and quenched with aqueous 4 N HCl (15 mL). The mixture was diluted with dichloromethane (100 mL), filtered through silica gel, and concentrated to give the crude product. The crude was slurried with ethyl acetate (20 mL) to give 24q (1.81 g, 57.9% yield) as a gray solid. Intermediate 24r: 3-(2,5-dichloropyrimidin-4-yl)-1,7-dimethyl-1H-indole (24r)

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[0356] A solution of 23 (3.56 g, 19.41 mmol) in PhCl (100 mL) was added in several portions to AlCl 3 (3.81 g, 28.57 mmol) was added and the reaction was stirred at 20 °C for 0.5 h. Then, a solution of 3r (3.34 g, 23.00 mmol) in PhCl (5 mL) was added. The resulting mixture was stirred at 80 °C for 3 h. The reaction was cooled to room temperature and quenched with aqueous 4 N HCl (90 mL). The mixture was diluted with dichloromethane (100 mL), filtered through silica gel, and concentrated to give the crude product. The crude was slurried with ethyl acetate (20 mL) to give 24r (5.01 g, 89.9% yield) as a white solid. Intermediate 24s: 3-(2,5-dichloropyrimidin-4-yl)-7-methoxy-1H-indole (24s)

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[0357] A solution of 2,4,5-trichloropyrimidine 23 (2.71 g, 14.8 mmol) in PhCl (30 mL) was treated with AlCl at 20 °C within 3 min. 3(2.56 g, 19.2 mmol) was added and then stirred at 20° C. for 0.5 h. To the reaction mixture was added a solution of 7-methoxy-1H-indole 3s (2.22 g, 15.1 mmol) in PhCl (20 mL). The resulting mixture was stirred at 80° C. for 3 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic phase was concentrated and purified by flash column chromatography (dichloromethane / methanol = 100 / 1 to 30 / 1) to give the title compound 24s (2.1 g, 48% yield) as a brown solid. MS-ESI (M+H) + :294.2 / 296.3。 Intermediate 24t: 3-(2,5-dichloropyrimidin-4-yl)-7-methoxy-1-methyl-1H-indole (24t)

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[0358] A solution of 2,4,5-trichloropyrimidine 23 (3.67 g, 20 mmol) in PhCl (30 mL) was added to AlCl within 5 min at 20 °C. 3 (2.68 g, 20 mmol) was added and then stirred at 20° C. for 0.5 h. To the reaction mixture was added a solution of 7-methoxy-1-methyl-1H-indole 3t (3.26 g, 20 mmol) in PhCl (20 mL). The resulting mixture was stirred at 80° C. for 3 h. The mixture was quenched with water and extracted with dichloromethane. The combined organic phase was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound 24t (4.5 g, 75% yield) as a pink solid. MS-ESI (M+H) + :308.2 / 310.3。 Scheme 11

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[0359] To a solution of 24a (5.0 g, 18.9 mmol) in THF (100 mL) was added Boc 2 O (4.96 g, 22.7 mmol), Et 3 N (3.2 mL, 22.7 mmol), DMAP (232 mg, 1.89 mmol) were added. The mixture was stirred overnight at room temperature under Ar. The mixture was poured into water (200 mL) and extracted with dichloromethane (300×3 mL). The organic layer was purified by NaCl distillation. 2 SO 4 The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 10 / 1 to 1 / 5) to give 24v (5.0 g, 72.5% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (s, 1H), 8.61 (s, 1H), 8.56 - 8.53 (m, 1H), 8.20 (dd, J = 6.8, 2.1 Hz, 1H), 7.46 - 7.38 (m, 2H), 1.73 (s, 9H). Scheme 12:

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[0360] To a mixture of NaH (5.45 g, 136.17 mmol) in anhydrous THF (100 mL) was added 25 (10 g, 90.78 mmol) in portions at 0 °C. The mixture was stirred under Ar at 0 °C for 0.5 h. The mixture was then added with CH 3 O at 0 °C under Ar. 3 I (8.48 mL, 136.17 mmol) was added dropwise. The mixture was stirred under Ar at 25° C. for 16 h. The mixture was then saturated with NH 4 After quenching with Cl (50 mL), the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL) and 2 SO 4 After drying at 40°C, filtration and concentration in vacuo, 26 (6 g, 53.22% yield) was obtained as a yellow oil, which was used in the next step without further purification. MS-ESI (M+H + ):125.4。 1 H NMR (400 MHz, CDCl 3 ) δ 6.92 (d, J = 0.7 Hz, 1H), 6.76 (d, J = 0.9 Hz, 1H), 3.59 (s, 3H), 3.03 - 2.98 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H). 5-Bromo-2-isopropyl-1-methyl-1H-imidazole (27)

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[0361] To a mixture of 26 (1.5 g, 12.08 mmol) in dichloromethane (15 mL) under Ar at 0° C., NBS (1.61 mL, 9.06 mmol) in MeCN (20 mL) was added dropwise. The mixture was stirred under Ar at 0° C. for 1 h. The mixture was then added to aqueous NaCl. 2 S 2 O 5 The mixture was quenched with 10 mL of ethyl acetate (10%) and extracted with ethyl acetate (30 mL x 3). The organic phase was concentrated in vacuo, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1 to 2 / 1) to give 27 (1.64 g, 66.86% yield) as a yellow solid. MS-ESI (M+H + +2):204.9。 1 H NMR (400 MHz, CDCl 3 ) δ 6.91 (s, 1H), 3.53 (s, 3H), 2.99 (dt, J = 13.7, 6.8 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H). 2,5-Dichloro-4-(2-isopropyl-1-methyl-1H-imidazol-5-yl)pyrimidine (28)

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[0362] To a mixture of 27 (400 mg, 1.97 mmol) in THF (5 mL) was added isopropylmagnesium chloride (3.03 mL, 3.94 mmol, 1.3 M in THF) at 0° C. under Ar. The mixture was stirred at 0° C. under Ar for 1 h. The mixture was transferred to a solution of 2,4,5-trichloropyrimidine 23 (0.45 mL, 3.94 mmol) in THF (5 mL) stirred at 0° C. under Ar. The resulting mixture was stirred at 25° C. under Ar for 16 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl (10 mL) and extracted with ethyl acetate (20 mL x 3). 2 SO 4 The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 28 (125 mg, 23.41% yield) as a yellow solid. MS-ESI (M+H) + :271.2。 1 H NMR (400 MHz, CDCl 3 ) δ 7.68 (s, 1H), 7.43 (s, 1H), 4.00 (s, 3H), 3.11 (dt, J = 13.6, 6.8 Hz, 1H), 1.37 (d, J = 6.8 Hz, 6H). Scheme 13

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[0363] A solution of 29 (2.0 g, 10.58 mmol) in 1,2-dimethoxyethane (25 mL) was prepared by the addition of 1-methyl-1H-indole 3b (2.8 g, 21.16 mmol), FeCl 3 (3.5 g, 21.16 mmol) was added. The mixture was stirred under Ar at 60° C. for 16 h. After the mixture was cooled to room temperature, ethanol (25 mL) and H 2 The mixture was diluted with 2H2O (75 mL) and stirred for 2 h. The solid was collected by filtration and the filter cake was washed with water (100 mL). The solid was dried under vacuum to give 30 (3.5 g, 81% yield). MS-ESI (M+H) + :284.1。 1 H NMR (400 MHz, CDCl 3 ) δ 8.82 -8.80 (m, 1H), 8.34 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.42-7.40 (m, 3H), 7.01 (s, 1H), 3.95 (s, 3H). Scheme 14

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[0364] In a cooled, oven-dried 500 ml three-neck round-bottom flask, add N 2 Bottom, AlCl 3 (6.1 g, 45.74 mmol) was added. 2 Cl 2 (130 mL) and 2,6-lutidine (4.9 g, 45.74 mmol) was added. 3 (1.0 M in dichloromethane, 46 mL, 45.74 mmol) was added. After 30 min, a homogeneous yellow solution was obtained, to which 1-methyl-1H-indole 3b (5.0 g, 38.12 mmol) was added. The reaction was stirred for 2.5 h, then N 2 A solution of pinacol 31 (9.9 g, 83.86 mmol) in triethylamine (85 mL, 610 mmol) in an oven-dried 100 mL round-bottom flask cooled under N was added, taking care to avoid any significant increase in the reaction temperature. 2 The flask was transferred via cannula under positive pressure. 2 Cl 2 After washing with 20 mL of pentane (20 mL × 2), the volatiles were removed under vacuum. The resulting beige solid was suspended in petroleum ether (800 mL), and the solid was removed by filtration and washed with additional pentane (100 mL × 5). The extracts were combined and the volatiles were removed in vacuo to give the crude product. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give 32 (8.2 g, 83.7% yield) as a pale yellow solid. 1 H NMR (400 MHz, CD 3 OD) δ 7.91 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.23-7.19 (m, 1H), 7.13-7.09 (m, 1H), 3.85 (s, 3H), 1.39 (s, 12H). 2,4-Dichloro-5,6-dimethoxypyrimidine (34a)

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[0365] To a solution of 2,4,6-trichloro-5-methoxypyrimidine 33 (1.0 g, 4.68 mmol) in methanol (20 mL) was added MeONa (265 mg, 4.92 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in 100 mL of ethyl acetate, and the mixture was stirred at room temperature for 30 min. After filtration, the filtrate was concentrated to give 34a (915 mg, 93.45% yield). 1 H NMR (400 MHz, DMSO-d6) δ 4.02 (s, 3H), 3.83 (s, 3H). 3-(2-chloro-5,6-dimethoxypyrimidin-4-yl)-1-methyl-1H-indole (35a)

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[0366] A solution of 34a (910 mg, 4.38 mmol) and 32 (675 mg, 2.63 mmol) in 1,4-dioxane / water (20 mL, 4:1) was treated with PdCl 2 (dppf) (96 mg, 0.13 mmol) and K 2 CO 3 (1.2 g, 8.75 mmol) was added. The mixture was stirred under Ar at 110° C. overnight. After the mixture was cooled to room temperature, it was diluted with ethyl acetate and the organic phase was washed with water. The organic phase was diluted with Na 2 SO 4 The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 30 / 1) to give 35a as a green solid (260 mg, 19% yield). MS-ESI (M+H) + :304.1。 1 H NMR (400 MHz, CDCl 3 ) δ 8.57 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.33-7.28 (m, 2H), 4.21 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H). Intermediate 35b: 2,6-dichloro-5-methoxypyrimidin-4-amine (34b)

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[0367] To a solution of 33 (3 g, 14 mmol) in DMSO (12 mL) was added ammonium hydroxide (25%, 1.6 mL, 21 mmol). The mixture was stirred at room temperature for 30 min. The mixture was poured into water (80 mL) to give a suspension. The suspension was filtered, and the solid was washed with water to give a white solid. The solid was dried under vacuum to give 34b (2.5 g, 91.5% yield). MS-ESI (M+H) + :194.1。 2-Chloro-5-methoxy-6-(1-methyl-1H-indol-3-yl)pyrimidin-4-amine (35b)

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[0368] 1,2-Dimethoxyethane (15 mL) and H 2 A solution of 34b (500 mg, 2.58 mmol) in 0 (5 mL) was diluted with 32 (928 mg, 3.61 mmol), CsF (548 mg, 3.61 mmol) and Pd(dppf). 2 Cl 2 (181 mg, 0.258 mmol) was added. The mixture was stirred under Ar at 100° C. for 16 h. After concentration, the residue was purified by reversed-phase column (0.5% NH 4 Purification by OH / MeCN (0-40-60%) gave 35b (630 mg) as a green solid. MS-ESI (M+H) + :289.0。 Scheme 15:

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[0369] To a solution of 36 (6.2 g, 62 mmol) and dimethyl carbonate 37 (13.95 g, 155 mmol) in THF (150 mL) was added NaH (6.2 g, 155 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 min and then at room temperature for 30 min. Then, the mixture was heated under reduced pressure with N 2 The mixture was stirred at 40°C overnight under reduced pressure. The mixture was cooled to 0°C, and 250 mL of 1.0 M HCl and 300 mL of ethyl acetate were added. The two phases were separated. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40°C, filtered, and concentrated. The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 40 / 1 to 10 / 1) to give 38 as a colorless oil (3.1 g, 31% yield). 2-(Methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-ol (40)

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[0370] 38 (3.3 g, 11.77 mmol) of H 2 In a solution of NaO (100 mL), 2 CO 3 (2.5 g, 23.54 mmol), 39 (3.1 g, 19.6 mmol) were added. The mixture was stirred overnight at room temperature in the dark. The mixture was filtered, and the filter cake was washed with water (200 mL) and dried under vacuum to give 40 as a white solid (1.7 g, 43.75% yield). MS-ESI (M+H) + :199.1。 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 4.32 (s, 2H), 3.83 (t, J = 5.6 Hz, 2H), 2.56 (t, J = 5.6 Hz, 2H), 2.47 (s, 3H). 7,8-Dihydro-5H-pyrano[4,3-d]pyrimidine-2,4-diol (41)

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[0371] 40 (900 mg, 4.545 mmol) of H 2 To a solution of 41 in 10 mL of HCl (1.0 mL, 4.545 mmol), AcOH (1.6 mL, 27.27 mmol) were added. The mixture was stirred under Ar at 100 °C overnight. After cooling to room temperature, the mixture was filtered and the solid was dried under vacuum to give 41 (600 mg, 78.5% yield). MS-ESI (M+H) + :169.1。 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.86 (s, 1H), 4.19 (s, 2H), 3.77 (t, J = 5.6 Hz, 2H), 2.39 (t, J = 5.6 Hz, 2H). 2,4-Dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (42)

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[0372] 41 (600 mg, 3.57 mmol) of POCl 3 (5 mL) solution was added DIPEA (1.2 mL, 7.14 mmol). The mixture was stirred under Ar at 80° C. overnight. The mixture was concentrated to give a residue. The residue was washed with saturated NaHCO 3 with the addition of ice. 3 The mixture was neutralized to pH 7 with NaCl, and the resulting mixture was extracted with ethyl acetate (100 mL x 3). 2 SO 4 The crude product was purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 42 (620 mg, 84.7% yield). MS-ESI (M+H) + :240.0。 1 H NMR (400 MHz, DMSO-d6) δ 4.66 (t, J = 8.8 Hz, 2H), 3.98-3.97 (m, 2H), 2.92-2.91 (m, 2H). 2-Chloro-4-(1-methyl-1H-indol-3-yl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (43)

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[0373] A solution of 42 (520 mg, 2.536 mmol) in PhCl (15 mL) was added to AlCl 3 (677 mg, 5.073 mmol) was added. The mixture was stirred at room temperature for 2 h, and then 1-methyl-1H-indole 3b (500 mg, 3.8 mmol) was added. The resulting mixture was stirred at 80 °C under Ar for 16 h. After cooling to room temperature, the mixture was diluted with ethanol (15 mL) and H 2 The mixture was diluted with 2H2O (45 mL) and stirred at room temperature for 2 h. The solid was collected by filtration, and the filter cake was washed with water (100 mL) and dried under vacuum to give 43 (565 mg, 74.3% yield). MS-ESI (M+H) + :300.1。 1 H NMR (400 MHz, CDCl 3 ) δ 8.60-8.56 (m, 1H), 7.40-7.33 (m, 3H), 7.28 (s, 1H), 4.85 (s, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.00 (t, J = 6.0 Hz, 2H). Scheme 16

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[0374] To a solution of triethylethane-1,1,2-tricarboxylate 44 (100 g, 406.08 mmol) in absolute ethanol (800 mL) was added sodium ethoxide (27.63 g, 406.08 mmol) and urea 45 (24.39 g, 406.08 mmol). The mixture was stirred at reflux overnight. After cooling to room temperature, the mixture was evaporated to dryness. The residue was diluted with water and acidified with dilute hydrochloric acid (2N). The mixture was evaporated to dryness to give the desired product 46 (100 g, crude) as a pale yellow solid. MS-ESI (M+H) + :215.0。 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.01 (s, 2H), 3.95 (q, J = 7.2 Hz, 2H), 3.00 (s, 2H), 1.25 - 1.15 (m, 3H) Ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (47)

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[0375] POCl 3 To a mixture of 46 (100 g, 33.3 mmol) in 4H (800 mL), DIEA (160 mL) was added dropwise. The mixture was stirred at 100 °C for 2 h. Most of the POCl 3 The solvent was removed under reduced pressure, and the residue was made basic with aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 0-20%) to give the desired product 47 (22 g, 17.48% yield) as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.30 - 4.16 (m, 2H), 3.94 (s, 2H), 1.33 - 1.24 (m, 3H).MS-ESI(M+H) + 269.0。 2-(2,4,6-trichloropyrimidin-5-yl)ethan-1-ol (48)

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[0376] To a mixture of 47 (5.0 g, 18.55 mmol) in THF (50 mL) was added DIBAL-H (37.1 mL, 1 M). The mixture was stirred at 0 °C for 12 h. The mixture was then diluted with saturated NH 4 The mixture was quenched with Cl solution, the aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. Purification by flash column chromatography (50 min, ethyl acetate / petroleum ether = 0 to 50%) afforded the desired product 48 (2.75 g, 65.16% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.69 (s, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H). 2,4-Dichloro-5,6-dihydrofuro[2,3-d]pyrimidine (49)

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[0377] To a solution of 48 (5.0 g, 21.98 mmol) in 1,4-dioxane (750 mL) was added DIEA (11.49 mL). The mixture was stirred at 100 °C for 12 h. The mixture was concentrated and purified by flash column chromatography (30 min, ethyl acetate / petroleum ether = 0 to 40%) to give the desired product 49 (2.0 g, 47.63% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.83 (t, J = 8.8 Hz, 2H), 3.32 (t, J = 8.8 Hz, 2H);MS-ESI(M+H) + :191.1。 2-Chloro-4-(1-methyl-1H-indol-3-yl)-5,6-dihydrofuro[2,3-d]pyrimidine (50)

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[0378] DME (20 mL) and H 2 A solution of 49 (2.0 g, 10.47 mmol) and 32 (2.69 g, 10.47 mmol) in 2 mL of HO was diluted with CsF (4.77 g, 31.41 mmol) and Pd(PPh 3 ) 2 Cl 2 (670.07 mg, 1.05 mmol) was added. The mixture was heated in a microwave oven under N 2 The mixture was stirred at 100°C under atmospheric pressure for 12 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (dichloromethane / methanol = 100 / 1 to 20 / 1) to give the desired product 50 (0.7 g, 23.40% yield) as a yellow solid. MS-ESI (M+H) + :286.1 I. Synthesis of Arylamines / Intermediates Scheme 17

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[0379] To a solution of piperazine 52 (8.1 g, 94.04 mmol) in 1,4-dioxane (150 mL) was added 4-fluoro-2-methoxy-1-nitrobenzene 51a (13.0 g, 75.97 mmol). The mixture was stirred at 100 °C for 4 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL) and purified by H 2 Wash with NaCl (50 mL x 2). 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=15 / 1) to give the desired product 53a (10.5 g, 47.1% yield) as a yellow solid. 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone (54a)

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[0380] 53a (9.5 g, 40.04 mmol) and Et 3 A solution of N (10.50 g, 103.76 mmol) in dichloromethane (50 mL) was stirred at 0° C. for 10 min. Then, acetyl chloride (6.80 g, 86.63 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was diluted with saturated NaHCO 3 (5 mL) and diluted with dichloromethane (100 mL). 2 Wash with 2 mL of NaCl. 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=12 / 1) to give crude product 54a (12.6 g) as a yellow solid, which was used in the next step without further purification. 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (55a)

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[0381] To a solution of 54a (12.6 g, 45.11 mmol) in ethanol (100 mL) was added 5% Pd / C (1.84 g, w%=15%) and hydrazine hydrate (80%, 50 mL). The mixture was stirred at 50° C. for 3 h. The mixture was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL). The organic phase was purified by H 2 Wash with 2 mL of NaCl. 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=15 / 1) to give product 55a (8.3 g, 83.2% overall yield for two steps) as an off-white solid. Intermediate 55b: 1-(2-fluoro-4-nitrophenyl)piperazine (53b)

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[0382] The synthesis of 53b was similar to that of 53a. Using piperazine (10.21 g, 118.53 mmol) and 1,2-difluoro-4-nitrobenzene (13.47 g, 84.67 mmol), 53b was obtained as a yellow oil (14.0 g, 52.4% yield). 1-(4-(2-fluoro-4-nitrophenyl)piperazin-1-yl)ethanone (54b)

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[0383] The synthesis of 54b was similar to that of 54a. Using 53b (14.0 g, 62.16 mmol) and acetyl chloride (7.81 g, 99.49 mmol), 54b was obtained as a yellow solid (15.6 g, 93.9% yield). 1-(4-(4-amino-2-fluorophenyl)piperazin-1-yl)ethanone (55b)

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[0384] The synthesis of 55b was similar to that of 55a. Using 54b (15.12 g, 56.57 mmol), 55b was obtained as a pale yellow solid (13.1 g, 97.6% yield). Scheme 18

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[0385] A solution of tert-butyl piperazine-1-carboxylate (3.37 g, 18.12 mmol), 51a (3.10 g, 18.12 mmol), and N,N-diisopropylethylamine (6.31 mL, 36.2 mmol) in DMSO (11 mL) was incubated in a sealed tube at 95 °C for 20 h. Upon cooling, the reaction mixture crystallized into a yellow solid. This was diluted with 150 mL of ethyl acetate, 20 mL of water, 20 mL of NaHCO 3 , and the resulting mixture was stirred for 20 h. 3 The organic solution was washed successively with MgSO 4 and brine (20 mL). 4 After drying at rt and concentration, 57 (5.0 g, 82% yield) was obtained as a yellow crystalline solid. (MS-ESI) (M+H) + :338.0。 1 H NMR (400 MHz, CDCl 3 ) δ 8.00 (dd, J = 9.3, 3.2 Hz, 1H), 6.41 (d, J = 9.3 Hz, 1H), 6.31 (s, 1H), 3.95 (d, J = 1.6 Hz, 3H), 3.63-3.58 (m, 4H), 3.42-3.37 (m, 4H), 1.49 (s, 9H). tert-Butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (58)

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[0386] Pd / C (10%, 1.4 g, 1.34 mmol) and 57 (3.0 g, 8.9 mmol) were treated with methanol (30 mL) and stirred under an atmosphere of hydrogen (balloon) for 23 h. The reaction mixture was filtered, and the resulting purple solution was then concentrated in vacuo to give 58 (2.9 g, 9.2 mmol) as a yellow solid, which was used directly in the next step without further purification. (MS-ESI) (M+H) + :m / z307.9 Scheme 19:

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[0387] 1,4-dioxane (125 mL) and H 2 To a solution of 59 (5 g, 26.71 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 60 (10.9 g, 53.3 mmol) in 2H2O (5 mL) was added Pd(dppf)Cl 2 (980 mg, 1.3 mmol) and K 2 CO 3 (7.37 g, 53.3 mmol) was added. The mixture was stirred at 110 °C for 16 h. The mixture was concentrated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1 to 1 / 1) to give 61 (3 g, 48.89% yield) as a white solid. MS-ESI (M+H) + :231.0。 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 8.69 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 7.6, 4.9 Hz, 1H), 7.24 - 7.20 (m, 2H), 4.05 (s, 3H). 2-Methoxy-4-(piperidin-3-yl)aniline (62)

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[0388] To a mixture of 61 (1 g, 4.34 mmol) in methanol (20 mL), PtO 2 (99 mg, 0.43 mmol) and concentrated HCl (2 mL, 24 mmol) were added. 2 The mixture was stirred at 25° C. for 16 h under reduced pressure. The mixture was filtered and concentrated to give 62 (1 g, approximately 100% yield) as a yellow oil, which was used in the next step without further purification. MS-ESI (M+H) + :207.1。 tert-Butyl 3-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (63)

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[0389] A mixture of 62 (1 g, 8.73 mmol) in methanol (20 mL) and dichloromethane (20 mL) was treated with Et 3 N (1.21 mL, 0.43 mmol) and Boc 2 0 (952 mg, 4.36 mmol) was added. The mixture was stirred under Ar at 0 °C for 2 h. 2 The mixture was quenched with 2H2O (1 mL) and concentrated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 63 (535 mg, 40.02% yield) as a yellow oil. MS-ESI (M+H) + :307.3。 Scheme 20:

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[0390] 3-Nitroaniline 64 (10.12 g, 73.27 mmol) in dichloromethane (100 mL), Et 3 A mixture of N (10.11 g, 100.10 mmol) was stirred at 0° C. for 30 min. Then, propionyl chloride (7.78 g, 85.06 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was diluted with saturated NaHCO 3 (30 mL) and diluted with dichloromethane (100 mL). The organic phase was2 Wash with 2 mL of NaCl. 2 SO 4 The organic phase was concentrated under reduced pressure to give crude product 65a (12.62 g, 88.7% yield) as a gray solid, which was used in the next step without further purification. N-(3-aminophenyl)propionamide (66a)

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[0391] To a solution of 65a (12.0 g, 61.80 mmol) in ethanol (40 mL), 5% Pd / C (1.25 g, w%=10%) and hydrazine hydrate (80%, 50 mL) were added. The mixture was stirred at 60° C. for 6 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 The organic phase was concentrated to give the desired product 66a (8.21 g, 83.2% yield) as a reddish-brown oil. Intermediate 66b: N-(3-nitrophenyl)acrylamide (65b)

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[0392] A reactor (250 mL) was charged with 64 (27 g, 0.2 mol), N,N-diisopropylethylamine (50 g, 0.4 mol), and tetrahydrofuran (120 mL). The reactor was then cooled in an ice bath. The internal temperature of the reactor was lowered to -3 °C, and acryloyl chloride (27 g, 0.3 mol) dissolved in tetrahydrofuran (20 mL) was added dropwise over 1 h. The reaction mixture was stirred for 0.5 h. Aqueous NaOH (1 M, 100 mL) was added dropwise to the reaction mixture. The reaction mixture was then stirred for 0.5 h. The tetrahydrofuran layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were concentrated. The crude product 65b was dissolved in ethyl acetate (500 mL) and then washed with water (100 mL × 3). The ethyl acetate solution was slowly evaporated under vacuum. Crude 65b was heated to reflux with 100 ml of ethyl acetate to dissolve it. Then, 150 ml of petroleum ether was added dropwise to the solution. The solution was cooled to room temperature, and product 65b (32.9 g, 85.6% yield) precipitated. N-(3-aminophenyl)acrylamide (66b)

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[0393] Compound 65b (28.8 g, 150 mmol) was dissolved in tetrahydrofuran (200 mL). Next, the flask was charged with water (80 mL), NH 4 Cl (32.1 g, 600 mmol) and iron powder (42 g, 750 mmol) were added. The reaction solution was heated to reflux for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product 3 was dissolved in ethyl acetate (400 ml) and added with aqueous NaHCO 3 The pH was adjusted with HCl, and then washed with water (100 ml × 3). The ethyl acetate solution was slowly evaporated under vacuum to give crude 66b, which was then purified by flash column chromatography to give product 66b (16.5 g, 67.6% yield). Scheme 21

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[0394] 1,2-Difluoro-4-nitrobenzene 51b (2.95 g, 18.54 mmol) in dioxane (10 mL), N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine 67 (2.05 g, 20.06 mmol) and Et 3 A mixture of N (3.20 g, 31.69 mmol) was stirred at 100° C. for 3 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL) and 2 Wash with NaCl (40 mL x 2). 2 SO4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give product 68b (3.6 g, 74.4% yield) as a yellow oil. N 1 -(2-(dimethylamino)ethyl)-2-fluoro-N 1 -Methylbenzene-1,4-diamine (69b)

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[0395] A mixture of 68b (3.5 g, 14.51 mmol) and 5% Pd / C (0.68 g, W%=19%) in dichloromethane (10 mL) was heated at 77°C for 1 hour. 2 The mixture was stirred overnight at 0° C. under reduced pressure. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude product 69b (2.0 g, 65.4% yield) as a brown oil, which was used in the next step without further purification. Intermediate 69c:N 1 ,N 1 ,N 2 -trimethyl-N 2 -(4-Nitrophenyl)ethane-1,2-diamine (68c)

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[0396] 1-Fluoro-4-nitrobenzene 51c (3.96 g, 28.07 mmol) in dioxane (20 mL), N 1 ,N 1 ,N 2 -trimethylethane-1,2-diamine 67 (3.05 g, 29.85 mmol) and Et 3 A mixture of N (5.5 g, 54.4 mmol) was stirred at 90° C. for 7.5 hours. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and 2 Wash with NaCl (40 mL x 2). 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give product 68c (5.50 g, 82.5% yield) as a yellow oil. N 1 -(2-(dimethylamino)ethyl)-N 1 -Methylbenzene-1,4-diamine (69c)

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[0397] A mixture of 68c (5.50 g, 24.63 mmol) and 5% Pd / C (0.54 g, w%=9.8%) in methanol (50 mL) was stirred at room temperature for 4.5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude product 69c (4.30 g, 90.3% yield) as a brown oil, which was used in the next step without further purification. Scheme 22

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[0398] A solution of 68b (5.0 g, 20.75 mmol) in TFA (50 mL) was stirred at 0 °C for 10 min. 3 (4.2 g, 41.49 mmol) was added and the mixture was stirred at 0° C. for an additional 1.5 h. The reaction mixture was diluted with dichloromethane and the solvent was evaporated in vacuo. The residue was then diluted with dichloromethane and filtered. The organic phase was concentrated to give crude product 70, which was used directly in the next step without further purification. N 1 -(2-(dimethylamino)ethyl)-6-fluoro-N 1 -Methyl-4-nitrobenzene-1,2-diamine (71)

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[0399] To a solution of 70 (1.19 g, 4.15 mmol) in acetic acid (15 mL) was added iron powder (930 mg, 8.6 mmol). The mixture was stirred at room temperature overnight. After concentration, the residue was purified by flash column chromatography (dichloromethane to dichloromethane / methanol = 50 / 1) to give 71 as a yellow solid (700 mg, 66% yield). MS-ESI (M+H) + :257.1。 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.20 (s, 2H), 3.28 (br, 4H), 2.75 (s, 6H), 2.60 (s, 3H). N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluoro-5-nitrophenyl)acetamide (72)

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[0400] 71 (0.7 g, 2.7 mmol) of Ac 2 The mixture was concentrated in vacuo and the residue was extracted with Et 2 The solid was collected by filtration and dried under vacuum to give 72 as a yellow solid (440 mg, 54%). MS-ESI (M+H) + :299.1。 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.99 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 3.35-3.32 (m, 4H), 2.80 (s, 6H), 2.70 (s, 3H), 2.25 (s, 3H). N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)-3-fluorophenyl)acetamide (73)

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[0401] To a solution of 72 (1.0 g, 3.3 mmol) in tetrahydrofuran / ethyl acetate (20 mL) (1:1), Pd / C (120 mg) was added. The mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 1.5 h. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give 73 as a light brown solid (840 mg, 93% yield). MS-ESI (M+H) + :269.1。 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.41 (s 1H), 6.04 (d, J = 9.6 Hz, 1H), 5.36 (s, 2H), 3.14 (br, 4H), 2.78 (s, 6H), 2.55 (s, 3H), 2.14 (s, 3H). Scheme 23

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[0402] To a solution of 2-fluorothioanisole 74 (2.8 g, 19.7 mmol) in dichloromethane (20 ml) was added 3-chloroperoxybenzoic acid (10.3 g, 59.7 mmol) in small portions at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with aqueous NaCl. 2 SO 3 The mixture was quenched with dichloromethane and the organic layer was extracted with aqueous saturated NaHCO 3 and concentrated in vacuo to give the title compound 75 (4.0 g), which was used directly in the next step without further purification. 1-Fluoro-2-(methylsulfonyl)-4-nitrobenzene (76)

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[0403] 1-Fluoro-2-(methylsulfonyl)benzene 75 (2.0 g, 11.5 mmol) and concentrated H 2 SO 4 (15 ml) of the mixture was cooled in an ice-salt bath and stirred for 10 minutes. To this mixture was added KNO while maintaining the temperature below 20°C. 3 (3.2 g, 31.7 mmol) was added in small portions. The mixture was stirred for 0.5 h and then poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, and concentrated in vacuo to give a yellow solid. This solid was then stirred in ethyl acetate (5 mL) and petroleum ether (5 mL) for 1 h and then filtered. The filter cake was collected and dried to give the title compound 76 (1.8 g, 83.4% yield over two steps) as a yellow solid. N 1 ,N 1 ,N 2 -trimethyl-N 2 -(2-(methylsulfonyl)-4-nitrophenyl)ethane-1,2-diamine (77)

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[0404] A mixture of 1-fluoro-2-(methylsulfonyl)-4-nitrobenzene 76 (1.0 g, 4.6 mmol), N,N,N'-trimethylethylenediamine 67 (0.93 g, 9.1 mmol), and N,N-diisopropylethylamine (1.47 g, 11.4 mmol) in N,N-dimethylacetamide (10 ml) was heated at reflux for 2.5 h and then cooled to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, and then purified by filtration. 2 SO 4 Drying at rt, filtration and concentration in vacuo afforded the title compound 77 (1.50 g) as an oil, which was used directly in the next step without further purification. N 1 -(2-(dimethylamino)ethyl)-N 1 -Methyl-2-(methylsulfonyl)benzene-1,4-diamine (78)

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[0405] N in tetrahydrofuran (20 ml) 1 ,N 1 ,N 2 -trimethyl-N 2 A mixture of -(2-(methylsulfonyl)-4-nitrophenyl)ethane-1,2-diamine 77 (1.50 g, 5.0 mmol) and Pd / C (10% on activated carbon, 0.143 g, 0.13 mmol) was hydrogenated using a hydrogen balloon at room temperature for 2 hours. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated in vacuo to give the title compound 78 (1.5 g) as an oil, which was used directly in the next step without further purification. Scheme 24:

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[0406] 2-Fluoro-5-nitroaniline 79 (7.99 g, 51.18 mmol) in DMAC (20 mL), N 1 ,N 1 ,N 2 A mixture of N,N-trimethylethane-1,2-diamine 67 (7.63 g, 74.67 mmol) and N,N-diisopropylethylamine (8.01 g, 61.98 mmol) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was 2 The mixture was diluted with 200 mL of ethyl acetate (50 mL) and extracted with ethyl acetate (70 mL x 3). The combined organic phase was diluted with 200 mL of ethyl acetate (50 mL) and extracted with ethyl acetate (70 mL x 3). 2 Wash with 20 mL of NaCl (50 mL x 3). 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give product 80 (10.6 g, 86.9% yield) as a yellow oil. N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitrophenyl)acetamide (81a)

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[0407] 80 (10.01 g, 42.01 mmol) and Et 3 A solution of N (8.45 g, 83.51 mmol) in dichloromethane (50 mL) was stirred at 0° C. for 25 min. Then, acetyl chloride (5.12 g, 65.22 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was diluted with saturated NaHCO 3 (30 mL) and diluted with ethyl acetate (100 mL). The organic phase was 2 The residue was dried in an air-circulating oven at 45° C. to give product 81a (8.68 g, 73.7% yield) as a pale yellow solid. N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide (82a)

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[0408] To a solution of 81a (2.12 g, 7.56 mmol) in methanol (20 mL) was added 5% Pd / C (0.25 g, w%=12%) and hydrazine hydrate (80%, 15 mL). The mixture was stirred at 60° C. for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The organic phase was 2 Wash with 20 mL of NaCl (30 mL x 3). 2 SO 4 The organic phase was concentrated to give product 82a (1.80 g, 95.1% yield) as an off-white solid. Intermediate 82b: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitrophenyl)-2,2,2-trifluoroacetamide (81b)

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[0409] To a solution of compound 80 (3.7 g, 15.54 mmol) in dichloromethane (60 ml) was added triethylamine (3.1 g, 30.69 mmol). The reaction mixture was cooled in an ice-salt bath. Anhydrous 2,2,2-trifluoroacetic acid (3.92 g, 18.67 mmol) was then added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour, and then acetic acid (0.4 ml) was added. The reaction mixture was stirred for 0.5 hours, washed with water (50 ml x 3), and then concentrated under reduced pressure to give the title compound 81b (3.9 g, 75.1% yield). MS-ESI (M+H) + :335.2。 N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-2,2,2-trifluoroacetamide (82b)

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[0410] Compound 81b (3.9 g, 11.67 mmol) was mixed with 5% Pd / C (0.2 g, 0.09 mmol) in methanol (50 ml). The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography (dichloromethane / methanol = 10 / 1) to give the title compound 82b (1.4 g, 39.3% yield). MS-ESI (M+H) +:305.4。 Intermediate 82c: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-nitrophenyl)propionamide (81c)

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[0411] 80 (5.00 g, 20.98 mmol) and Et 3 A solution of N (4.22 g, 41.78 mmol) in dichloromethane (20 mL) was stirred at 0° C. for 15 min. Then, propionyl chloride (3.05 g, 32.96 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 2.5 h. The reaction mixture was diluted with saturated NaHCO 3 (40 mL) and diluted with dichloromethane (40 mL). The organic phase was 2 The residue was dried in an air circulating oven at 45° C. to give product 81c (4.70 g, 76.10% yield) as a black oil. N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)propionamide (82c)

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[0412] To a solution of 81c (4.70 g, 15.97 mmol) in methanol (15 mL) was added 5% Pd / C (0.47 g, w%=10%) and hydrazine hydrate (80%, 40 mL). The mixture was stirred at 55° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). The organic phase was 2 Wash with 25 mL of NaCl. 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give product 82c (1.82 g, yield 43.12%) as a pale yellow oil. Scheme 25

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[0413] 2-Fluoro-5-nitro-aniline 79 (1.041 g, 6.7 mmol) was dissolved in methanol (50 ml), and 33% aqueous formaldehyde solution (5 ml, 57.1 mmol) was added at 0 °C. 3 After addition of CN (2.165 g, 35.1 mmol) and acetic acid (7.5 ml), the reaction mixture was stirred at room temperature for 22 hours. 2 The mixture was quenched with 20 mL of HCl and the pH was adjusted to 8-9 with 4 g of NaOH. The resulting mixture was extracted with 100 mL of dichloromethane. The organic phase was separated and concentrated under reduced pressure to give crude title compound 83a (1.2 g, 98% yield) as a yellow oil, which was used directly in the next step without further purification. N 1 -(2-(dimethylamino)ethyl)-N 1 ,N 2 ,N 2 -Trimethyl-4-nitrobenzene-1,2-diamine (84a)

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[0414] 83a (182.6 mg, 0.99 mmol) in DMSO (1 mL), N 1 ,N 1 ,N 2 A mixture of 67 (305.2 mg, 2.99 mmol) and 1,2-trimethylethanediamine 68 (305.2 mg, 2.99 mmol) was stirred at 120° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and 2 The mixture was washed with O. The organic phase was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / methanol=15 / 1) to give product 84a (0.23 g, 87.1% yield) as a deep red oil. N 1 -(2-(dimethylamino)ethyl)-N 1 ,N 2 ,N 2 -Trimethylbenzene-1,2,4-triamine (85a)

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[0415] A solution of 84a (0.25 g, 0.94 mmol) and 5% Pd / C (105.3 mg, 0.05 mmol) in methanol (10 mL) was hydrogenated at room temperature for 6.5 hours using a hydrogen balloon. After completion of the reaction, the reaction mixture was filtered through Celite®. The filtrate was concentrated to give crude compound 85a (0.15 g, 91% yield) as a dark oil, which was used directly in the next step without further purification. Intermediate 85b: 2-Fluoro-N-methyl-5-nitroaniline (83b)

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[0416] 2-Fluoro-5-nitro-aniline 79 (1.5947 g, 10.2 mmol) was dissolved in methanol (30 ml), and 33% aqueous formaldehyde solution (1.5 ml, 17.1 mmol) was added at 0 °C. NaBH 3 After addition of CN (1.2004 g, 19.4 mmol) and acetic acid (1 ml), the reaction mixture was stirred at room temperature for 19 hours. 2 The reaction mixture was quenched with 0 (10 mL) and the pH was adjusted to 8-9 with NaOH (0.5 g). The desired product 83b precipitated from the solution as a yellow solid and was obtained by filtration (1.2 g, 69.0% yield). N 1 -(2-(dimethylamino)ethyl)-N 1 ,N 2 -Dimethyl-4-nitrobenzene-1,2-diamine (84b)

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[0417] The synthesis of 84b was carried out using 83b (1.558 g, 9.15 mmol) and N 1 ,N 1 ,N 2 The synthesis of 84a was similar to that of 84b, except that 67 (3.0565 g, 29.9 mmol) was used. The crude product 84b (2.378 g) was used directly in the next step without further purification. N 1 -(2-(dimethylamino)ethyl)-N 1 ,N 2 -Dimethylbenzene-1,2,4-triamine (85b)

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[0418] The synthesis of 85b was similar to that of 85a by using 84b (2.378 g, 9.4 mmol) and 5% Pd / C (0.993 g, 0.47 mmol). The crude product 85b (2.0 g, 95.2% yield) was used directly in the next step without further purification. Intermediate 85c: 2-Fluoro-5-nitro-N-(2,2,2-trifluoro-1-methoxyethyl)aniline (87)

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[0419] Trifluoroacetaldehyde methyl hemiacetal 86 (412 mg, 3.2 mmol), primary aniline 79 (156.3 mg, 1.0 mmol), and p-toluenesulfonic acid monohydrate (26.2 mg, 0.14 mmol) were dissolved in methanol (5 mL). The reaction mixture was stirred at reflux for 24 h. After cooling to room temperature, the contents of the flask were concentrated to remove methanol, followed by addition of ethyl acetate and aqueous NaHCO. 3 The mixture was diluted with hexane. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash column chromatography (eluted with petroleum ether / ethyl acetate=15 / 1) to give product 87 (220 mg, yield 82.0%) as a yellow solid. 2-Fluoro-5-nitro-N-(2,2,2-trifluoroethyl)aniline (83c)

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[0420] Compound 87 (220 mg, 0.82 mmol) and NaBH 4 (108.6 mg, 2.9 mmol) was dissolved in methanol (5 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to remove methanol and then diluted with H 2 The mixture was quenched with O. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were concentrated under reduced pressure to give crude product 83c (170 mg, 87% yield) without further purification. N 1 -(2-(dimethylamino)ethyl)-N 1 -methyl-4-nitro-N 2 -(2,2,2-trifluoroethyl)benzene-1,2-diamine (84c)

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[0421] The synthesis of 84c was carried out using 83c (170 mg, 0.71 mmol) and N 1 ,N 1 ,N 2 The synthesis of 84a was similar to that of 84b by using -trimethylethane-1,2-diamine 67 (228.7 mg, 2.23 mmol). The crude product 84c (330 mg) was used directly in the next step without further purification. N 1 -(2-(dimethylamino)ethyl)-N 1 -methyl-N 2 -(2,2,2-trifluoroethyl)benzene-1,2,4-triamine (85c)

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[0422] The synthesis of 85c was similar to that of 85a by using 84c (330 mg, 1.0 mmol) and 5% Pd / C (117 mg, 0.05 mmol). The crude product 85c (250 mg) was used directly in the next step without further purification. Scheme 26:

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[0423] CH 3 A mixture of 1,2-difluoro-4-nitrobenzene 51b (1.66 g, 10.4 mmol), N'-ethyl-N,N-dimethylethylenediamine 88 (1.28 g, 11.0 mmol) in CN (20 ml) was heated at 80 °C for 18 h. Additional N'-ethyl-N,N-dimethylethylenediamine (0.3 g, 1.9 mmol) and N,N-diisopropylethylamine (1 ml, 6.1 mmol) were then added to the reaction, and the mixture was stirred at 80 °C for an additional 4 h. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was separated and washed with saturated aqueous NaHCO 3 . 3 The crude was purified by flash column chromatography (eluted with ethanol) to give the title compound 89 (1.5 g, 56.4% yield) as a brown oil. N 1 -(2-(dimethylamino)ethyl)-N 1 -Ethyl-2-fluorobenzene-1,4-diamine (90)

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[0424] N in methanol (10 ml) 1 -ethyl-N 1 -(2-fluoro-4-nitrophenyl)-N 2 ,N 2 A mixture of 1,2-dimethylethane-1,2-diamine 89 (0.3 g, 1.2 mmol), Pd / C (5% on activated carbon, 0.06 g, 0.03 mmol), and hydrazine hydrate (80%, 1 mL, 16 mmol) was heated at 80° C. for 2.5 h. After cooling to room temperature, the reaction mixture was filtered through Celite®, and the filtrate was concentrated to remove methanol. The residue was extracted with ethyl acetate. The organic layer was separated, washed with water, and concentrated with NaCl. 2 SO 4 The mixture was dried at rt, filtered and concentrated to dryness. The crude 90 (0.22 g, 83.0% yield) was used directly in the next step without further purification. Scheme 27:

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[0425] A solution of 89 (10.0 g, 39.2 mmol) in TFA (100 mL) was stirred at 0 °C for 10 min. 3 (7.9 g, 78.4 mmol) was added and the mixture was stirred at 0 °C for an additional 1.5 h. The reaction mixture was diluted with dichloromethane (100 mL) and concentrated. The residue was purified by flash column chromatography (dichloromethane to dichloromethane / methanol = 50 / 1) to give 91 as a TFA salt as a yellow solid (7.0 g, 43% yield). MS-ESI (M+H) + :301.2。 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.51-8.48 (m, 1H), 3.52-3.49 (m, 2H), 3.27-3.20 (m, 4H), 2.70 (s, 6H), 1.04 (t, J = 7.6 Hz, 7.6 Hz, 3H). N 1 -(2-(dimethylamino)ethyl)-N 1 -Ethyl-6-fluoro-4-nitrobenzene-1,2-diamine (92)

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[0426] To a solution of 91 (7.0 g, 23.3 mmol) in acetic acid (150 mL) was added iron powder (2.61 g, 46.7 mmol). The mixture was stirred at room temperature overnight. After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol = 100 / 1 to 15 / 1) to give 92 as a yellow solid (4.0 g, 63.5% yield). MS-ESI (M+H) + :271.2。 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (s, 1H), 7.18 (d, J = 7.2 Hz, 1H), 6.16 (s, 2H), 3.26 (br, 2H), 3.02-2.99 (m, 4H), 2.61 (s, 6H), 0.93 (t, J = 7.6 Hz, 3H). N-(2-((2-(dimethylamino)ethyl)(ethyl)amino)-3-fluoro-5-nitrophenyl)acetamide (93)

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[0427] 92 (4.0 g, 14.8 mmol) of Ac 2 The mixture was concentrated in vacuo to remove acetic anhydride, and the residue was extracted with Et 2 The solid was collected by filtration and dried under vacuum to give 93 as a yellow solid (3.8 g, 82% yield). MS-ESI (M+H) + :313.1。 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.01 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 3.44-3.42 (m, 2H), 3.10-3.68 (m, 4H), 3.08 (s, 6H), 2.24 (s, 3H), 0.89 (t, J = 7.6 Hz, 3H). N-(5-amino-2-((2-(dimethylamino)ethyl)(ethyl)amino)-3-fluorophenyl)acetamide (94)

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[0428] To a solution of 93 (624 mg, 2.0 mmol) in tetrahydrofuran / ethyl acetate (20 mL) (1:1), Pd / C (70 mg) was added. The mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 1.5 h. The catalyst was filtered off, and the filtrate was concentrated in vacuo to give 94 as a light brown solid (507 mg, 90% yield). MS-ESI (M+H) + :283.1。 1 H NMR (400 MHz, CD 3 OD) δ 7.15 (s, 1H), 6.27-6.22 (m, 1H), 3.35 (br, 2H), 3.09-3.00 (m, 4H), 2.78 (s, 6H), 2.18 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H). Scheme 28:

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[0429] 2-Fluoro-5-nitroaniline 79 (3.00 g, 19.22 mmol) in DMAC (16 mL), N 1 -ethyl-N 2 ,N 2 A mixture of N,N-dimethylethane-1,2-diamine 88 (4.61 g, 39.67 mmol) and N,N-diisopropylethylamine (3.62 g, 28.01 mmol) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was 2 The mixture was diluted with 200 mL of HCl (35 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phase was diluted with HCl (35 mL) and extracted with dichloromethane (50 mL x 2). 2 The residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give the product 95 (1.01 g, 20.83% yield) as a yellow oil. N 1 -(2-(dimethylamino)ethyl)-N1 -ethyl-N 2 -Methyl-4-nitrobenzene-1,2-diamine (96a)

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[0430] Compound 95 (0.97 g, 3.84 mmol) was dissolved in methanol (15 ml), and 33% aqueous formaldehyde solution (0.4 ml, 4.56 mmol) was added at 0 °C. 3 After addition of CN (0.996 g, 15.9 mmol) and acetic acid (0.5 ml), the reaction mixture was stirred at room temperature for 19.5 hours. 2 The mixture was quenched with 2H2O (1 mL), and the pH was adjusted to 8-9 with NaOH (0.3 g). The resulting mixture was extracted with dichloromethane. The organic layer was separated and concentrated to dryness. The residue was purified by flash column chromatography (methanol / dichloromethane = 1 / 20) to give the title compound 96a (0.54 g, 52.7% yield) as a yellow oil. N 1 -(2-(dimethylamino)ethyl)-N 1 -ethyl-N 2 -Methylbenzene-1,2,4-triamine (97a)

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[0431] The synthesis of 97a was similar to that of 85a by using 96a (0.54 g, 2.0 mmol) and 5% Pd / C (0.21 g, 0.1 mmol). The crude product 97a (0.36 g, 75.1% yield) was used directly in the next step without further purification. Intermediate 97b: N-(2-((2-(dimethylamino)ethyl)(ethyl)amino)-5-nitrophenyl)propionamide (96b)

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[0432] 95 (1.00 g, 3.96 mmol) and Et 3 A solution of N (0.86 g, 8.51 mmol) in dichloromethane (15 mL) was stirred at 0° C. for 18 min. Then, propionyl chloride (0.72 g, 7.78 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was diluted with saturated NaHCO 3 (10 mL) and diluted with dichloromethane (40 mL). 2 The residue was dried in an air circulating oven at 45° C. to give product 96b (1.01 g, 82.64% yield) as a pale yellow oil. N-(5-amino-2-((2-(dimethylamino)ethyl)(ethyl)amino)phenyl)propionamide (97b)

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[0433] To a solution of 96b (1.00 g, 3.24 mmol) in methanol (10 mL) was added 5% Pd / C (0.1 g, w%=10%) and hydrazine hydrate (80%, 14 mL). The mixture was stirred at 55° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (40 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 After concentration, the residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give product 97b (0.68 g, yield 75.32%) as a pale yellow oil. Intermediate 97c: N-(2-fluoro-5-nitrophenyl)acetamide (98)

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[0434] 2-Fluoro-5-nitroaniline 79 (3.04 g, 19.47 mmol) and Et 3 A solution of N (3.92 g, 38.81 mmol) in dichloromethane (60 mL) was stirred at 0° C. for 15 min. Then, acetyl chloride (3.04 g, 38.73 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. The reaction mixture was diluted with saturated NaHCO 3 (20 mL) and diluted with dichloromethane (100 mL). The organic phase was 2 After concentration, the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=10 / 1) to give the product 98 (2.67 g, 82.64% yield) as a yellow solid. N-(2-((2-(dimethylamino)ethyl)(ethyl)amino)-5-nitrophenyl)acetamide (96c)

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[0435] 98 (2.50 g, 12.62 mmol) in DMAC (40 mL), N 1 -ethyl-N 2 ,N 2 A mixture of N,N-dimethylethane-1,2-diamine 88 (2.81 g, 24.18 mmol) and N,N-diisopropylethylamine (3.02 g, 23.37 mmol) was stirred at 100° C. overnight. After cooling to room temperature, the mixture was 2 The mixture was diluted with 200 mL of ethyl acetate (50 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was diluted with 200 mL of ethyl acetate (50 mL x 3). 2 The residue was purified by flash column chromatography (dichloromethane / methanol=20 / 1) to give the product 96c (2.6 g, 70.01% yield) as a yellow oil. N-(5-amino-2-((2-(dimethylamino)ethyl)(ethyl)amino)phenyl)acetamide (97c)

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[0436] To a solution of 96c (2.50 g, 8.49 mmol) in methanol (25 mL), 5% Pd / C (0.28 g, w%=11%) and hydrazine hydrate (80%, 20 mL) were added. The mixture was stirred at 60° C. for 2.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 mL). The organic phase was 2 Wash with 20 mL of NaCl (30 mL x 3). 2 SO 4 After concentration, the residue was dried in an air circulating oven at 45° C. to give product 97c (1.86 g, 82.84% yield) as a pale yellow oil. Scheme 29:

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[0437] To a solution of 99 (2.065 g, 10.1 mmol) in acetic acid (10 mL) was added iron powder (2.769 g, 155.1 mmol). The mixture was stirred at 0° C. for 8 hours, and then dichloromethane (30 mL) was added. The resulting mixture was filtered through Celite®, and the filter cake was washed with dichloromethane and methanol. The filtrate was concentrated in vacuo to give crude compound 100 as a brown oil (3.18 g) without further purification. N 1 -(2-(dimethylamino)ethyl)-5-fluoro-N 1 -Methyl-2-nitrobenzene-1,4-diamine (101a)

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[0438] Compound 100 (1.351 g, 7.8 mmol) and triethylamine (10 mL) in CH 3 To a solution of CN (30 mL) was added N,N,N'-trimethylethylenediamine 67 (1.045 g, 10.2 mmol). The reaction mixture was stirred at 50 °C for 40 h. The solvent was then removed in vacuo, and the residue was purified by flash column chromatography (dichloromethane / methanol = 50 / 1) to give product 101a (597 mg, 30% yield) as a red oil. Intermediate 101b:N 1 -(2-(dimethylamino)ethyl)-N 1 -Ethyl-5-fluoro-2-nitrobenzene-1,4-diamine (101b)

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[0439] The synthesis of 101b was carried out using compound 100 (1.084 g, 6.2 mmol) and N 1 -ethyl-N 2 ,N 2 The synthesis of 101a was similar to that of 101a by using -dimethylethane-1,2-diamine 88 (1.529 g, 13.2 mmol) to give the title compound 101b (648 mg, 38.6% yield) as a red oil. Scheme 30:

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[0440] CH 3 2-Fluoro-5-nitroaniline 79 (5.09 g, 32.60 mmol) in CN (40 mL), N 1 ,N 1 A mixture of N,N-dimethylethane-1,2-diamine 102 (5.67 g, 64.32 mmol) and N,N-diisopropylethylamine (6.00 g, 46.15 mmol) was stirred at 70 °C overnight. The mixture was cooled to 40 °C and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) and HCl 2 Wash with NaCl (50 mL x 2). 2 SO 4 After concentration, the residue was purified by flash column chromatography (petroleum ether / ethyl acetate=2 / 1) to give product 103 (3.80 g, 52.0% yield) as a reddish-brown solid. N-(2-acetamido-4-nitrophenyl)-N-(2-(dimethylamino)ethyl)acetamide (104)

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[0441] 103 (3.80 g, 16.94 mmol) and Et 3 A solution of N (8.55 g, 86.36 mmol) in dichloromethane (80 mL) was stirred at 0° C. for 20 min. Then, acetyl chloride (5.32 g, 67.78 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 2.5 h. The reaction mixture was diluted with saturated NaHCO 3 (40 mL) and diluted with dichloromethane (150 mL). 2 O (40 mL×2) and then concentrated to give the product 104 (4.30 g, 82.30% yield) as a yellow solid. N-(2-acetamido-4-aminophenyl)-N-(2-(dimethylamino)ethyl)acetamide (105)

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[0442] To a solution of 104 (4.00 g, 12.97 mmol) in methanol (50 mL) was added 5% Pd / C (0.41 g, w%=10.2%) and hydrazine hydrate (80%, 40 mL). The mixture was stirred at 50° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 The organic phase was concentrated to give the product 105 (3.20 g, 88.62% yield) as an off-white solid. Scheme 31:

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[0443] 98 (2.50 g, 12.62 mmol) in DMAC (20 mL), N 1 ,N 1 A mixture of N,N-dimethylethane-1,2-diamine 102 (2.10 g, 23.82 mmol) and N,N-diisopropylethylamine (3.23 g, 24.99 mmol) was stirred at 100 °C overnight. After cooling to room temperature, the mixture was 2 The mixture was diluted with 200 mL of HCl (40 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was diluted with HCl (40 mL) and extracted with dichloromethane (50 mL x 3). 2 The residue was dried in an air circulating oven at 45° C. to give product 106 (2.70 g, 97.50% yield) as a reddish-brown oil. 1-(2-(dimethylamino)ethyl)-2-methyl-1H-benzo[d]imidazol-5-amine (107)

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[0444] To a solution of 106 (2.51 g, 10.11 mmol) in methanol (10 mL) was added 5% Pd / C (0.29 g, w%=12%) and hydrazine hydrate (80%, 20 mL). The mixture was stirred at 50° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (100 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 After concentration, the residue was dried in an air circulating oven at 45° C. to give product 107 (1.30 g, 58.91% yield) as a red oil. Intermediate 109: N-(2-((2-(dimethylamino)ethyl)amino)-5-nitrophenyl)acetamide (108)

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[0445] A solution of 98 (1.0 g, 5.05 mmol) in 102 (3 mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL) and washed with NaCl (100 mL × 2) to give Na 2 SO 4 After concentration, the crude product 108 was used directly in the next step. MS-ESI (M+H) + :267.1 N-(5-amino-2-((2-(dimethylamino)ethyl)amino)phenyl)acetamide (109)

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[0446] To a solution of 108 (1.30 g, 1.88 mmol) in methanol (10 mL) was added 5% Pd / C (0.14 g, w%=11%) and hydrazine hydrate (80%, 10 mL). The mixture was stirred at 50° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 After concentration, the residue was dried in an air circulating oven at 45° C. to give product 109 (0.67 g, 58.08% yield) as a red oil. Intermediate 111: tert-butyl(2-(N-(tert-butoxycarbonyl)acetamido)-4-nitrophenyl)(2-(dimethylamino)ethyl)carbamate (110)

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[0447] To a solution of 110 (0.75 g, 1.61 mmol) in tetrahydrofuran / ethyl acetate = 1 / 1 (20 mL) was added Pd / C (300 mg). 2 The mixture was stirred under reduced pressure at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated to give the title product 111 as an off-white solid (1.0 g), which was used in the next step without further purification. MS-ESI (M+H) + :437.3 Scheme 32

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[0448] A solution of 2-(dimethylamino)ethanol 112 (8.60 g, 96.48 mmol) in DMF (100 mL) was stirred at 0° C. for 15 min. NaH (2.94 g, 122.51 mmol) was then added in portions, and the mixture was stirred for an additional 0.5 h at 0° C., followed by the addition of 2-fluoro-5-nitroaniline 79 (5.00 g, 32.03 mmol). The mixture was stirred at room temperature for an additional 3.5 h. The reaction mixture was then heated to 50° C. for 15 min. The resulting mixture was then cooled ... 2 The mixture was quenched with 200 mL of ethyl acetate (50 mL) and diluted with ethyl acetate (200 mL). 2 O (40 mL×2) and then concentrated to give the product 113 (8.3 g, 115% yield) as a red-purple oil. N-(2-(2-(dimethylamino)ethoxy)-5-nitrophenyl)acetamide (114)

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[0449] 113 (7.21 g, 32.01 mmol) and Et 3 A solution of N (9.74 g, 96.43 mmol) in dichloromethane (60 mL) was stirred at 0° C. for 25 min. Then, acetyl chloride (3.80 g, 54.78 mmol) was added dropwise and the mixture was stirred at 0° C. for an additional 1.5 h. The reaction mixture was diluted with saturated NaHCO 3 (40 mL) and diluted with dichloromethane (120 mL). The organic phase was 2 O (40 mL×2) and then concentrated to give the product 114 (9.20 g, 107% yield) as a reddish-brown oil. N-(5-amino-2-(2-(dimethylamino)ethoxy)phenyl)acetamide (115)

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[0450] To a solution of 114 (8.56 g, 32.03 mmol) in methanol (50 mL) was added 5% Pd / C (0.82 g, w%=9.6%) and hydrazine hydrate (80%, 80 mL). The mixture was stirred at 50° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (150 mL). The organic phase was 2 Wash with 2 mL of NaCl. 2 SO 4 The organic phase was concentrated to give product 115 (5.00 g, 65.8% yield) as a black viscous liquid. Scheme 33:

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[0451] 1,2-Difluoro-4-nitrobenzene 51b (3 g, 18.9 mmol), N,N-dimethylpyrrolidin-3-amine 116 (2 g, 17.9 mmol) and K in DMF (30 mL) 2 CO 3 A mixture of (12 g, 94.3 mmol) was stirred at 110 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (100 mL). The aqueous phase was extracted with dichloromethane. The organic phase was washed with brine and MgSO 4 The resulting product 117 (4.0 g, 83.6% yield) was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.85 (m, 2H), 6.77 (t, J = 9.2 Hz, 1H), 3.74 - 3.64 (m, 2H), 3.61 - 3.51 (m, 1H), 3.33 - 3.30 (m, 1H), 2.77 - 2.74 (m, 1H), 2.20 (s, 6H), 2.15 - 2.08 (m, 1H), 1.79 - 1.76 (m, 1H). 1-(2-Fluoro-4,6-dinitrophenyl)-N,N-dimethylpyrrolidin-3-amine (118)

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[0452] 117 (2.5 g, 9.9 mmol) was dissolved in TFA (20 mL), cooled to 0 °C, and then added KNO 3 was added and the mixture was stirred at 0° C. for 1 hour. The mixture was diluted with water and solid NaCO 3 The pH was adjusted to 7 with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine and added MgSO. 4 The resulting product 118 (2.0 g, 67.8% yield) was used in the next step without further purification. m / z (MS-ESI) (M+H) + :299.2。 1-(2-amino-6-fluoro-4-nitrophenyl)-N,N-dimethylpyrrolidin-3-amine (119)

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[0453] A mixture of 118 (2.0 g, 6.7 mmol) and iron powder (1.1 g, 20.1 mmol) in acetic acid (20 mL) was stirred at room temperature for 16 hours. After concentration in vacuo, the residue was triturated with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 119, which was used in the next step without further purification. N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-3-fluoro-5-nitrophenyl)acetamide (120)

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[0454] Ac 2 A mixture of 119 (2.0 g, 7.4 mmol) in 20 mL of HO was stirred at room temperature for 16 h. Excess solvent was removed in vacuo, and the residue was purified by flash column chromatography (methanol / dichloromethane = 50 / 1 to 30 / 1) to give the resulting product 120 (1.2 g, 52.5% yield). m / z (MS-ESI) (M+H) + :311.2。 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.19 (s, 1H), 7.82 (dd, J = 13.4, 2.6 Hz, 1H), 3.58 - 3.42 (m, 4H), 2.45 (s, 6H), 2.24 - 2.16 (m, 1H), 2.12 (s, 3H), 1.97 - 1.84 (m, 2H). N-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)-3-fluorophenyl)acetamide (121)

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[0455] A mixture of 10% Pd / C (425 mg, 0.4 mmol) and 120 (1.2 g, 3.8 mmol) in methanol (30 mL) was stirred under an atmosphere of hydrogen (balloon) at room temperature for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title product 121 (1.06 g, 98% yield) as a purple solid, which was used in the next step without further purification. m / z (MS-ESI) (M+H) + :281.2。 Scheme 34:

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[0456] A mixture of 98 (2 g, 10.1 mmol), N,N-diisopropylethylamine (2.6 g, 20.2 mmol), and N,N-dimethylpyrrolidin-3-amine 116 (1.1 g, 10.1 mmol) in ethanol (30 mL) was stirred at 85 °C for 16 h. After cooling to room temperature, the mixture was concentrated, and the residue was mixed with water (100 ml) and dichloromethane (100 ml). The organic phase was separated, washed with brine (50 ml), and purified with MgSO. 4 The mixture was dried at rt and then concentrated under reduced pressure. The resulting product 122 (3.1 g, 104% yield) was used in the next step without further purification. N-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acetamide (123)

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[0457] A mixture of 122 (3.0 g, 10.3 mmol) and 10% Pd / C (1.1 g, 1.03 mmol) in methanol (30 mL) was stirred under an atmosphere of hydrogen (balloon) for 16 h. The reaction mixture was filtered, and the filtrate was then concentrated in vacuo to give 123 (2.8 g), which was used in the next step without further purification. (MS-ESI) (M+H) + :263.2。 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.18 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.26 (d, J = 6.0 Hz, 1H), 4.77 (s, 2H), 3.03 (dd, J = 16.0, 7.6 Hz, 1H), 2.93 - 2.67 (m, 4H), 2.15 (s, 6H), 2.04-2.02 (m, 2H), 1.83 - 1.70 (m, 1H). Intermediate R-123: (R)-N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrophenyl)acetamide (R-122)

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[0458] 98 (1.8 g, 9.08 mmol), (R)-N,N-dimethylpyrrolidin-3-amine R-116 (1.00 g, 8.76 mmol) and Cs in DMF (40 mL) 2 CO 3 (4.46 g, 13.69 mmol) was stirred at 80° C. for 2 hours. 2 The mixture was quenched with 200 mL of HCl (50 mL) and diluted with ethyl acetate (50 mL). The organic phase was washed with H 2 Washing with 200 mL x 3 and then concentration gave the product R-122 (2.27 g, 85.5% yield) as a yellow solid. (R)-N-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)acetamide (R-123)

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[0459] To a solution of R-122 (2.27 g, 7.77 mmol) in methanol (20 mL) was added 5% Pd / C (0.22 g, w%=9.7%) and hydrazine hydrate (80%, 20 mL). The mixture was stirred at 60° C. overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL). The organic phase was 2 Wash with 20 mL of NaCl. 2 SO 4 The organic phase was concentrated to give the product R-123 (1.50 g, 73.6% yield) as a dark brown oil. Intermediate S-123: (S)—N-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrophenyl)acetamide (S-122)

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[0460] 98 (2.0 g, 10.09 mmol), (S)-N,N-dimethylpyrrolidin-3-amine S-116 (1.22 g, 10.68 mmol) and K in DMF (30 mL) 2 CO 3 (2.82 g, 20.43 mmol) was stirred...

Claims

1. (A) A compound of formula (I): 【Hua 625】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein X represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Y and Y' each independently represent a group selected from H, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and amino; Z is selected from O, NR 6 , C(═O), SO 2 , C(═O)NR 6 , NR 6 C(═O), SO 2 NR 6 and (CH 2 ) 1-2 , or when Z is NR 6 , NR 3 and R 6 together form a fused imidazolyl ring; Het represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, Het is optionally substituted by 1 to 3 groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1-4 alkyl (optionally substituted with one or more groups selected from halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy), C 3-6 cycloalkyl (optionally substituted with one or more groups selected from C 1-3 alkyl, halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy) or -C(=O)-R*, where R* is H, C 1-3 haloalkyl or C 1-4 alkyl (optionally substituted with OH, CN or C 1-3 alkoxy), or Het is optionally substituted indole; R 1 is selected from H and C 1 -C 3 alkyl; R 2 is selected from H and C 1 -C 3 alkyl; R 3 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C(O)—R 11 ; R 11 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 4 is selected from H and C 1 -C 3 alkyl; R 5 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C(O)—R 12 ; R 12 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl; R 6 is selected from H, C 1 -C 3 alkyl and C(O)—R 13 ; R 13 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 7 and R 8 are each independently selected from H and C 1 -C 3 alkyl, or R 7 and R 8 together can represent oxo (═O); R 9 and R 10 are each independently selected from H and C 1 -C 3 alkyl; n is 1 to 4; (B) A compound of formula (II): 【632】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally 5- to 6-membered heterocyclic ring containing, as ring members, 1 or 2 heteroatoms selected from N and O, which is fused to the pyrimidine in formula (II); Ring A can be aromatic or non-aromatic and is optionally substituted with one or two groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl; Alternatively, Ring A is absent and the pyrimidine is optionally substituted with one or two groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl; Het A represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, Het A being optionally substituted with 1 to 3 groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl and C 1 -C 3 alkyl; X A represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 1A is selected from H and C 1 -C 3 alkyl; G A is selected from —NR 2A R 3A , SO 2 R 7A , halo, and C 1 -C 3 haloalkyl; R 2A is selected from H and C 1 -C 3 alkyl; R 3A is selected from H, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1 -C 3 haloalkyl, —SO 2 R 7A and —C(O)—R 11A ; R 11A is selected from H, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Z A is selected from O, NR 6A , C(═O), SO 2 , C(═O)NR 6A , SO 2 NR 6A and (CH 2 ) 1-2 ; R 4A is selected from H and C 1 -C 3 alkyl; R 5A is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, —C(O)—R 12A and —SO 2 R 7A ; R 12A is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 6A is selected from H and C 1 -C 3 alkyl; each R 7A is independently C 1 -C 3 alkyl; (C) A compound of formula (III): 【Chemical Formula 634】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally 5-membered heteroaromatic ring containing N or O as a ring member and is fused to the ring containing Z 2B in formula (III); Ring B is optionally substituted with one or two groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, and —C(O)—R 10B ; Z 1B is N when ring B is absent, and Z 1B is C when ring B is present; Z 2B is N when ring B is present, and Z 2B is CR 2B when ring B is absent; Z 3B is NR 3B or O; G B is a group of the formula -NR 4B -(CR 1B ) 2-3 -NR 5B R 6B or G B is a 5-6 membered saturated ring containing as ring members one or two nitrogen atoms, which is optionally substituted with one or two groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl and -C(O)-R 10B ; X B represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Y B represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 1B is selected from H and C 1 -C 3 alkyl; R 2B is selected from H, halo, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl; R 3B is selected from H and C 1 -C 3 alkyl; R 4B is selected from H, C 1 -C 3 alkyl and —C(O)—R 10B ; R 5B is selected from H and C 1 -C 3 alkyl; R 6B is selected from H, C 1 -C 3 alkyl and —C(O)—R 10B ; R 7B is selected from H and C 1 -C 3 alkyl; R 8B is selected from H, C 1 -C 3 alkyl and —C(O)—R 10B ; each R 10B is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; (D) Compound of formula (IV): 【Hua 637】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein Z 1C and Z 2C are independently selected from N and CH; Z 3C is selected from O, CH 2 and NR 3C ; G C is a group of the formula —NR 4C —(CR 2C ) 2-3 —NR 5C R 6C , or G C is a 5- to 6-membered saturated ring containing as ring members one or two nitrogen atoms, which is optionally substituted with one or two groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl and —C(O)—R 10C ; X C represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Y C represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; R 1C is selected from H and C 1 -C 3 alkyl; R 2C is selected from H and C 1 -C 3 alkyl; R 3C is selected from H and C 1 -C 3 alkyl; R 4C is selected from H, C 1 -C 3 alkyl and —C(O)—R 10C ; R 5C is selected from H and C 1 -C 3 alkyl; R 6C is selected from H, C 1 -C 3 alkyl and —C(O)—R 10C ; R 7C is selected from H, C 1 -C 4 alkyl (optionally substituted with C 1 -C 3 alkoxy) and 5-6 membered heterocyclic groups containing heteroatoms selected from N, O and S as ring members (optionally substituted with 1 or 2 groups independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl); R 8C is selected from H, C 1 -C 3 alkyl and —C(O)—R 10C ; each R 10C is independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; (E) Compound of formula (IC): 【Chemistry 630】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein X represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Y is selected from H, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and amino; Het represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, Het is optionally substituted by 1 to 3 groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1-4 alkyl (optionally substituted with one or more groups selected from halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy), C 3-6 cycloalkyl (optionally substituted with one or more groups selected from C 1-3 alkyl, halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy) or -C(=O)-R*, where R* is H, C 1-3 haloalkyl or C 1-4 alkyl (optionally substituted with OH, CN or C 1-3 alkoxy), or Het is optionally substituted indole; R 1 is selected from H and C 1 -C 3 alkyl; R 2 is selected from H and C 1 -C 3 alkyl; R 3 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C(O)—R 11 ; R 11 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; and (F) A compound of formula (ID): 【Chemistry 631】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein X represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl; Y and Y' each independently represent a group selected from H, halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, and amino; Het represents a heteroaromatic monocyclic or bicyclic group of 5 to 9 atoms containing as a ring member at least one heteroatom selected from N, O and S, Het is optionally substituted by 1 to 3 groups independently selected from halo, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1-4 alkyl (optionally substituted with one or more groups selected from halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy), C 3-6 cycloalkyl (optionally substituted with one or more groups selected from C 1-3 alkyl, halo, OH, CN, C 1-3 alkoxy and C 1-3 haloalkoxy) or -C(=O)-R*, where R* is H, C 1-3 haloalkyl or C 1-4 alkyl (optionally substituted with OH, CN or C 1-3 alkoxy), or Het is optionally substituted indole; R 1 is selected from H and C 1 -C 3 alkyl; R 4 is selected from H and C 1 -C 3 alkyl; R 5 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and —C(O)—R 12 ; R 12 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy and C 1 -C 3 haloalkyl. or a pharmaceutically acceptable salt thereof, selected from:

2. The compound is a compound of formula (I): (a) Y' is H; and / or (b) Y is selected from F, CF 3 , OMe and Cl; and / or (c) Het is 【Hua 627】 wherein each X' represents up to two optional substituents independently selected from halo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy; and each R 14 represents H, C 1-4 alkyl (optionally substituted with one or more groups selected from halo, OH, CN, C 1-3 alkoxy, and C 1-3 haloalkoxy), C 3-6 cycloalkyl (optionally substituted with one or more groups selected from C 1-3 alkyl, halo, OH, CN, C 1-3 alkoxy, and C 1-3 haloalkoxy), or —C(═O)—R*, where R* is H, C 1-3 haloalkyl, or C 1-4 alkyl (optionally substituted with OH, CN, or C 1-3 alkoxy).

2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

3. The compound is a compound of formula (I): (a) Z is NR 6 or O; and / or (b) n is 1; and / or (c) R 7 , R 8 , R 9 and R 10 each represent H; and / or (d) R 1 is H; and / or (e) The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

4. The compound (A) A compound of formula (IA): 【Hua 628】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variation thereof; or a pharmaceutically acceptable salt thereof, wherein each X' represents up to two optional substituents independently selected from halo, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy, and R 14 is selected from H, methyl, ethyl, isopropyl, cyclopropyl, and -C(=O)-R*, where R* is H, C 1-3 haloalkyl, or C 1-4 alkyl (optionally substituted with OH, CN, or C 1-3 alkoxy); or (B) A compound of formula (IB): 【Chemical 629】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , and R 6 are each independently selected from methyl and ethyl.

2. The compound of claim 1 selected from:

5. The compound of claim 1, wherein the compound is a compound of formula (II): (a) R 1A is H; and / or (b) Het A represents optionally substituted indole; and / or (c) Z A is NR 6A ; and / or (d) The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G A is —NR 2A R 3A .

6. A compound of formula (IIA): 【Hua 633】 or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof, wherein R 13A is selected from H and C 1 -C 3 alkyl; Y A represents one or two optional substituents independently selected from halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and C 1 -C 3 haloalkyl.

2. The compound of claim 1, wherein:

7. The compound of claim 1, wherein the compound is a compound of formula (II): (a) the group -Z A (CH 2 ) 2 -NR 4A R 5A represents -NMe-CH 2 CH 2 -NMe 2 or -NEt-CH 2 CH 2 -NMe 2 ; and / or (b) The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrrole and furan.

8. The compound of claim 7, wherein the compound is a compound of formula (III): (a) R 1B is H; and / or (b) R 3B is H; and / or (c) Z 2B is CR 2B ; and / or (d) Ring B is absent; and / or (e) R 7B is H; and / or (f) G B is —NR 4B —(CR 1B ) 2-3 —NR 5B R 6B ; and / or (g) G B is a group of the following formula: 【Chemistry 635】 and R 6B' is selected from H, C 1 -C 3 alkyl and —C(O)—R 10B ; and / or (h) G B is a group of the following formula: 【Hua 636】 or a pharmaceutically acceptable salt thereof; and R 6B' is selected from H, C 1 -C 3 alkyl and -C(O)-R 10B .

9. The compound of claim 8, wherein the compound is a compound of formula (IV): (a) R 1C is H; and / or (b) R 2C is H; and / or (c) X C represents one or two independently selected halo groups; and / or (d) Y C is absent; and / or (e) Z 1C and Z 2C each represent CH or Z 1C and Z 2C each represent N; and / or (f) Z 3C is O, NH or CH 2 ; and / or (g) R 8C is H or methyl; and / or (h) R 7C is a tetrahydrofuran ring, a tetrahydropyran ring, or a C 2 -C 4 alkyl (substituted by methoxy); and / or (i) G C is a group of the following formula: 【Chemical Formula 638】 and R 6C' is selected from H, C 1 -C 3 alkyl and -C(O)-R 10C ; and / or (j) G C is a group of the formula —NR 4C —(CR 2C ) 2-3 —NR 5C R 6C ; and / or (k) The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G C is a group of the formula NR 4C —(CH 2 ) 2-3 —NR 5C R 6C , where R 4C , R 5C and R 6C are each independently selected from methyl and ethyl.

10. [Chemical 701] 【Chemistry 702】 【Chemistry 703】 【Chemistry 704】 【Chemistry 705】 【Chemistry 706】 【Chemistry 707】 【Chemistry 708】 【Chemistry 709】 【Chemistry 710】 【Chemistry 711】 【Chemical 712】 【Chemical 713】 【Chemical 714】 【Chemistry 715】 【Chemical Formula 716】 【Hua717】 【Chemical 718】 【Chemical 719】 【Hua720】 【Hua721】 【Chemical 722】 【Chemical 723】 【Chemical 724】 【Chemical 725】 【Chemical 726】 【Hua727】 【Chemical 728】 【Chemical 729】 【Chemistry 730】 【Hua731】 【Chemical 732】 【Chemical 733】 【Chemical 734】 【Chemical Formula 735】 【Chemical 736】 【Hua737】 【Chemical 738】 【Chemical 739】 【Chemical 740】 【Chemical 741】 【Chemical 742】 【Chemical 743】 【Chemical 744】 【Chemical 745】 【Chemical 746】 【Hua747】 【Chemical 748】 【Chemical 749】 【Chemistry 750】 【Chemistry 751】 【Chemical 752】 【Chemical 753】 【Chemical 754】 【Chemistry 755】 【Chemical 756】 【Chemical 757】 【Chemical 758】 【Chemical 759】 【Hua760】 【Chemical 761】 【Chemical 762】 【Chemical 763】 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable additive.

12. A pharmaceutical combination comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the additional therapeutic agent is suitable for treating the same condition as the compound of formula (I), (II), (III) or (IV).

13. A composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

14. The composition of claim 13, wherein the therapy is for the treatment of cancer, preferably the cancer is selected from acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), thyroid cancer, mast cell tumor (MCT), solid tumors with NTRK gene fusions, leukemia, lymphoma, lung cancer including non-small cell lung cancer, colon and colorectal cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, breast cancer, liver cancer, sarcoma, epidermoid carcinoma, fibrosarcoma, cervical cancer, gastric cancer, skin cancer, head and neck cancer and pancreatic cancer.

15. The composition of claim 13, wherein the therapy is for the treatment of a cancer associated with a kinase selected from FLT3, EGFR, VEGFR, ALK, NTRK, RET, ROS / ROS1, DYRK1 and CK2a kinase, and the cancer is selected from AML, NSCLC, MCT (mast cell tumor), thyroid cancer and solid tumors with NTRK gene fusion.

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