Amino-substituted heterocycles for treating cancer having an EGFR mutation

Abstract

Amino-substituted heteroaromatic compounds, such as 4-aminoquinazoline, pharma- ceutically acceptable salts of the compounds, and pharmaceutical compositions thereof are disclosed. Methods of treating or preventing cancer using the amino-substituted heteroaromatic compounds, pharma- ceutically acceptable salts of the compounds, and pharmaceutical compositions thereof are also disclosed.

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 174,177, filed April 13, 2021; No. 63 / 239,089, filed August 31, 2021; No. 63 / 242,837, filed September 10, 2021; and No. 63 / 292,605, filed December 22, 2021, the contents of which are incorporated herein by reference.

Background Art

[0002] Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit extracellular signals such as growth signals to cells through kinase activity. RTKs regulate a number of important biological processes including development, growth, and cell homeostasis. Abnormalities in RTK signaling can lead to uncontrolled cell growth, which ultimately results in cancer.

[0003] Human epidermal growth factor receptor (HER) family proteins are RTKs that were first identified and associated with cancer. HER is also known as ErbB, a name derived from the viral homolog v-erb-b2 avian erythroblastic leukemia viral oncogene homolog. The HER family includes the following four members: EGFR / HER1 / ErbB1, HER2 / ErbB2, HER3 / ErbB3, and HER4 / ErbB4. They share a highly related structure that includes an extracellular domain that binds ligands, a single transmembrane domain, and an intracellular kinase domain. Several ligands for EGFR (e.g., EGF and TGF-α) and HER3 / HER4 (e.g., neuregulin) have been identified, but no ligand for HER2 is known. HER receptors form homo- or hetero-dimers when activated, catalyzing downstream signaling via the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and other pathways.

[0004] Dysregulation of EGFR is a feature of many cancers. Cancer cells overactivate EGFR through various mechanisms, including overexpression, missense mutations, insertions, and deletions. EGFR is often overexpressed in many solid tumors, such as non-small cell lung cancer (NSCLC), breast cancer, glioblastoma, prostate cancer, colorectal cancer, head and neck cancer, and many other solid tumors. EGFR variant 3 (EGFR vIII) with large deletions in exons 2-7 is found in approximately 30% of glioblastomas. Various activating mutations in EGFR cause approximately 30% of NSCLC, and higher prevalence is associated with the adenocarcinoma histotype, non-smokers, Asians, and women. These activating mutations are further classified into point mutations (mainly L858R in exon 21), short deletions in exon 19 (mainly E746_A750del), short insertions in exon 20, and other rarer mutations not specified herein. L858R, E746_A750del, and exon 20 insertions account for approximately 35-40%, 40-45%, and 5-10% of all EGFR mutant NSCLC cases, respectively.

[0005] HER2 dysregulation is also a well-established cause of cancer. HER2 overexpression is found in 15-25% of breast cancer cases and is one of the major molecular subtypes of breast cancer and is also found in ovarian cancer, gastric cancer, esophageal cancer, endometrial cancer, and lung cancer. HER2 mutations are found in approximately 2% of NSCLC patients but, unlike EGFR, are mostly limited to exon 20 insertions (mainly A775_G776insYVMA).

[0006] Known agents used to treat oncogenic EGFR or HER2 have significant deficiencies including one or more of the following: toxicity due to wild-type EGFR inhibition, limited activity in the central nervous system (CNS), and insufficient activity against exon 20 insertions and drug-resistant mutations. Since EGFR has important epithelial functions in the adult gastrointestinal tract lining and skin, inhibition of non-mutated EGFR is thought to cause adverse reactions such as diarrhea and rash, which are common safety signals with many existing EGFR inhibitors. Up to 60% of EGFR-mutant NSCLC patients and up to 45% of HER2-mutant NSCLC patients develop brain metastases during the course of the disease. Thus, CNS activity is an important consideration in future therapy development. Among the major types of EGFR and HER2 mutations, exon 20 insertions represent an unmet need as there are no FDA-approved targeted therapies for these indications. For these reasons, there is a need to develop a new generation of inhibitors that spare wild-type EGFR, cross the blood-brain barrier, and exhibit specific activity against exon 20 insertions and / or drug-resistant mutations.

SUMMARY OF THE INVENTION

[0007] In certain embodiments, the present disclosure provides a compound of formula (I):

CHEMICAL

CHEMICAL

CHEMICAL

[0008] In some embodiments of formula (I) (or its sub-formulas), V is N or

Chemical formula

[0009] In one embodiment of formula (I) (or its sub-formula), [Chemical formula] is [Chemical formula] and [Chemical formula] is [Chemical formula] When Y 1 and Y 2 are each independently CR 4 , then R 2 in Y 4 is C 1~5 alkyl, and R 1 in Y 4 is halo, provided that. In one embodiment, R 2 in Y 4 is methyl. In one embodiment, R 1 in Y 4 is fluoro. In one embodiment, R 2 in Y 4is methyl, and Y 1 in which R 4 is fluoro.

[0010] In one embodiment of formula (I) (or a sub-formula thereof),

Chemical formula

[0011] In certain embodiments, the present disclosure relates to formula (II):

Chemical formula

Chemical formula

Chemical formula

[0012] In one embodiment of formula (II) (or a sub-formula thereof),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0013] In certain embodiments, the compound of formula (II) is a compound of formula (III):

Chemical formula

[0014] In certain aspects, the disclosure provides a compound of formula (a-I):

Chemical formula

Chemical formula

Chemical formula

[0015] In some embodiments of formula (a-I) (or its sub-formulas), K is C=O, V is N, or

Chemical formula

Chem.

Chem.

Chem.

[0016] In one embodiment of formula (a-I) (or its sub-formula), K is a bond. In one embodiment of formula (a-I) (or its sub-formula), K is C=O. In one embodiment of formula (a-I) (or its sub-formula), K is SO2.

[0017] In certain embodiments, the disclosure relates to formula (I-i):

Chem.

Chem.

[0018] In certain embodiments, the compound of formula (I-i) is of formula (I-i-a):

Chemical formula

[0019] In certain embodiments, the compound of formula (I-i) is of formula (I-i-a0):

Chemical formula

[0020] In certain embodiments, the compound of formula (I-i) is of formula (I-i-a1):

Chemical formula

[0021] In certain embodiments, the compound of formula (I-i-a1) is of the following formula:

Chemical formula

[0022] In certain embodiments, the compound of formula (I-i-a1) is of the following formula:

Chemical formula

[0023] In certain embodiments, the compound of formula (I-i-a1) is of the following formula:

Chemical formula

[0024] In certain embodiments, the compound of formula (I-i-a1) is of the following formula:

Chemical formula

[0025] In certain embodiments, the compound of formula (I-i-a1) is of formula (I-i-a2):

Chemical formula

[0026] In certain embodiments, the present disclosure provides a pharmaceutical composition suitable for use in a subject in the treatment or prevention of cancer, comprising an effective amount of a compound described herein (e.g., a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or any of their sub-formulas), or any of its pharmaceutically acceptable salts, stereoisomers, or tautomers, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation may be for use in the treatment or prevention of a condition or disease described herein.

[0027] Aspects of the present disclosure are methods of treating cancer, which include administering to a mammal (e.g., a human subject) in need of treating cancer an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or any of the embodiments thereof disclosed herein) or a pharmaceutical composition provided herein. In certain embodiments, provided herein is a method of treating HER2-related cancer, which includes administering to a mammal (e.g., a human subject) in need of treating HER2-related cancer an effective amount of a compound disclosed herein (e.g., a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or any of the embodiments thereof disclosed herein) or a pharmaceutical composition provided herein. In certain embodiments, the human subject is in need of such treatment. In certain embodiments, the human subject has been identified or diagnosed as having HER2-related cancer. In certain embodiments, HER2-related cancer is associated with deregulation of the HER2 gene, HER2 kinase, or the expression or activity or level of either of them. In certain embodiments, HER2-related cancer is associated with HER2 overexpression, and / or HER2 amplification, and / or HER2 mutation(s). In certain embodiments, the cancer is a solid tumor. In certain embodiments, HER2-related cancers include, but are not limited to, non-small cell lung cancer, breast cancer, ovarian cancer, brain cancer, biliary tract cancer, cervical cancer, gastric cancer, esophageal cancer, endometrial cancer, glioblastoma, prostate cancer, skin cancer, esophageal tumor, colorectal cancer, bladder cancer, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, prostate cancer, and head and neck cancer. In some embodiments, the HER2-related cancer is non-small cell lung cancer. In some embodiments, the HER2-related cancer is breast cancer. In certain embodiments, the HER2-related cancer is brain cancer. In certain embodiments, the HER2 exon 20 mutation is one or more selected from YVMA insertion, VC insertion, and GSP insertion.In certain embodiments, the HER2 exon 20 mutation is one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, G778_S779insCPG, G780_P781dupGSP, Y772_A775dup, G778_P780dup, E770_A771insGIRD, G778_S779insLPS, M774_A775insAYVM, G778_S779insLPG, G778dup, G776delinsVC, M774delinsWLV, A775_G776insSVMA, and A775_G776insI. In certain embodiments, the HER2 exon 20 mutation is one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, G778_S779insCPG, and G780_P781dupGSP. In certain embodiments, the HER2 exon 20 mutation is one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, and G778_S779insCPG.

[0028] In some embodiments, a method of treating or preventing cancer may include administering a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), (III), or a sub-formula thereof, in combination with a second therapeutic agent (e.g., an immunomodulatory agent or a platinum analog). BRIEF DESCRIPTION OF THE DRAWINGS

[0029]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

BEST MODE FOR CARRYING OUT THE INVENTION

[0030] Definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide one of ordinary skill in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings given to them below, unless otherwise specified.

[0031] In some embodiments, chemical structures are disclosed along with their corresponding chemical names. In the event of a conflict, the meaning of the chemical structure, rather than the chemical name, shall control.

[0032] As used in this disclosure, terms such as "comprises," "comprising," "containing," and "has" may have the meanings given to them in the United States Patent Laws and may mean "includes," "including," etc. "Consisting essentially of" or "consists essentially" likewise have the meanings given in the United States Patent Laws, and the term is open-ended and permits the presence of elements other than those recited, so long as the presence of such other elements does not substantially change the basic or novel characteristics of the recited elements, except for prior art embodiments.

[0033] As used herein, the term "or" is understood to be inclusive unless specifically stated otherwise or otherwise apparent from the context. As used herein, the terms "a", "an", and "the" are understood to be singular or plural unless specifically stated otherwise or otherwise apparent from the context.

[0034] The term "acyl" is understood in the art and refers to a group represented by the general formula: hydrocarbyl C(O)-, preferably alkyl C(O)-.

[0035] The term "acylamino" is understood in the art and refers to an amino group substituted with an acyl group and can be represented, for example, by the formula: hydrocarbyl C(O)NH-.

[0036] The term "acyloxy" is understood in the art and refers to a group represented by the general formula: hydrocarbyl C(O)O-, preferably alkyl C(O)O-.

[0037] The term "alkoxy" refers to an alkyl group to which oxygen is attached, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0038] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and can be represented by the general formula: alkyl-O-alkyl.

[0039] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to encompass both "unsubstituted alkenyl" and "substituted alkenyl", the latter referring to an alkenyl moiety having substituents in place of one or more hydrogens on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons that are or are not included in one or more double bonds. Further, such substituents include all those intended for an alkyl group as described below, except where stability is inhibited. For example, substitution of an alkenyl group by one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is intended.

[0040] An "alkyl" group or "alkane" is a straight or branched chain non-aromatic hydrocarbon that is fully saturated. Usually, a straight or branched chain alkyl group has from 1 to about 20, preferably from 1 to about 10 carbon atoms, unless otherwise defined. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. A C1-C6 straight or branched chain alkyl group is also referred to as a "lower alkyl" group.

[0041] Furthermore, as used throughout this specification, examples, and the claims, the term "alkyl" (or "lower alkyl") is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having a substituent in place of one or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, can include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that a substituted moiety on a hydrocarbon chain can itself be substituted if appropriate. For example, substituents for substituted alkyl can include amino, azide, imino, amide, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamide, sulfamoyl, and sulfonate), and silyl groups, in both substituted and unsubstituted forms, as well as ether, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), -CF3, -CN, etc. Exemplary substituted alkyls are described below. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, etc.

[0042] The term "C x~y ", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is intended to include a group containing x to y carbons in the chain. For example, the term "C x~y"Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing a straight-chain alkyl or branched-chain alkyl group with x to y carbons in the chain, such as haloalkyl groups like trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents hydrogen when the group is in a terminal position and a bond when it is internal. The term "C 2~y Alkenyl" and "C 2~y Alkynyl" are similar in length and possible substitutions to the above alkyl, but refer to a substituted or unsubstituted unsaturated aliphatic group containing at least one double bond or triple bond, respectively.

[0043] As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

[0044] As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group and can be represented by the general formula: alkylS-.

[0045] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter referring to an alkynyl moiety having a substituent in place of hydrogen on one or more carbons of the alkynyl group. Such substituents can be present on one or more carbons that are or are not included in one or more triple bonds. Further, such substituents include all those intended for alkyl groups as described above, except when stability is inhibited. For example, substitution of an alkynyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is intended.

[0046] As used herein, the term "amide" refers to the group:

Chemical formula

[0047] The terms "amine" and "amino" are understood in the art and include both unsubstituted and substituted amines, as well as their salts, for example,

Chem.

[0048] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0049] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared by two adjacent rings and at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0050] The term "carbamate" is understood in the art and refers to the group:

Chem.

[0051] As used herein, the terms "carbocyclic" and "carbocyclic ring" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocyclic ring encompasses both aromatic carbocyclic rings and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings encompass both cycloalkane rings in which all carbon atoms are saturated and cycloalkene rings containing at least one double bond.

[0052] The term "carbocyclic ring" encompasses monocyclic rings of 5 to 7 members and bicyclic rings of 8 to 12 members. Each ring of a bicyclic carbocyclic ring may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Carbocyclic rings encompass bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused carbocyclic ring" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with the other ring. Each ring of a fused carbocyclic ring may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic as long as the valences permit. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. A "carbocyclic ring" may be substituted at any one or more positions where a hydrogen atom can be present.

[0053] A "cycloalkyl" group is a cyclic hydrocarbon that is completely saturated. Examples of "cycloalkyl" include monocyclic rings and bicyclic rings. Generally, a monocyclic cycloalkyl group has 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl includes bicyclic molecules in which one, two, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from a saturated ring, an unsaturated ring, and an aromatic ring. A "cycloalkenyl" group is a cyclic hydrocarbon that contains one or more double bonds.

[0054] As used herein, the term "carbocyclic alkyl" refers to an alkyl group substituted with a carbocyclic group.

[0055] The term "carbonate" is understood in the art and refers to the group: -OCO2-R 34 wherein 34 R represents a hydrocarbyl group.

[0056] As used herein, the term "carboxy" refers to the group represented by the formula: -CO2H.

[0057] As used herein, the term "ester" refers to the group: -C(O)OR 35 wherein 35 R represents a hydrocarbyl group.

[0058] As used herein, the term "ether" refers to a hydrocarbyl group linked through oxygen to another hydrocarbyl group. Thus, an ether substituent of a hydrocarbyl group can be hydrocarbyl-O-. The ether can be symmetric or asymmetric. Examples of ethers include, but are not limited to, heterocyclic-O-heterocyclic and aryl-O-heterocyclic. Ethers include "alkoxyalkyl" groups which can be represented by the general formula: alkyl-O-alkyl.

[0059] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0060] As used herein, the terms "hetaralkyl" and "heteroaralkyl" refer to an alkyl group substituted with a heteroaryl group. As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom in which no two heteroatoms are adjacent.

[0061] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, in which the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are shared between two adjacent rings and at least one of the rings is heterocyclic aromatic and the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine.

[0062] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0063] The terms "heterocyclyl", "heterocyclic", and "heterocyclic ring" refer to a substituted or unsubstituted non-aromatic ring structure having a ring structure with at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring. The terms "heterocyclyl" and "heterocyclic ring" also include polycyclic ring systems having two or more cyclic rings in which one or more carbons are shared by two adjacent rings and at least one of the rings is heterocyclic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl, such as bicyclic systems (e.g., fused or spiro bicyclic heterocyclyl). The terms "heterocyclyl" and "heterocyclic ring" also include substituted or unsubstituted partially unsaturated non-aromatic ring structures. In some embodiments, heterocyclyl is a 3- to 10-membered monocyclic or bicyclic ring system having at least one double bond. In some embodiments, heterocyclyl is a 3- to 10-membered monocyclic or bicyclic ring system having only one double bond. In some embodiments, heterocyclyl is a 6-membered heterocyclyl ring having at least one double bond. In some embodiments, heterocyclyl is a 6-membered heterocyclyl ring having only one double bond. Examples of heterocyclyl groups include piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, tetrahydrofuran, 1,4-diazabicyclo[2.2.2]octane (DABCO), tetrahydroquinoline, and the like.

[0064] As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclic group.

[0065] As used herein, the term "hydrocarbyl" refers to a group that is bonded through a carbon atom having no =O or =S substituent, usually has at least one carbon-hydrogen bond and mainly a carbon skeleton, and may optionally contain heteroatoms. Thus, for the purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl, while substituents such as acetyl (having an =O substituent on the linked carbon atom) and ethoxy (linked through oxygen rather than carbon) are not considered hydrocarbyl. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocyclic, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

[0066] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0067] When used with a chemical moiety, such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, the term "lower" is intended to encompass groups having 10 or fewer, preferably 6 or fewer, non-hydrogen atoms in the substituent. "Lower alkyl" refers to an alkyl group containing, for example, 10 or fewer, preferably 6 or fewer, carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, for example, in the description of hydroxyalkyl and aralkyl (wherein, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0068] The terms "polysicyclic", "polycyclic", and "polycyclic ring" refer to two or more rings where two or more atoms are shared between two adjacent rings, e.g., two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) where the rings are "fused rings". Each ring of the polycyclic ring can be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10 atoms, preferably 5 to 7 atoms, in the ring.

[0069] The term "silyl" refers to a silicon moiety to which three hydrocarbyl moieties are attached.

[0070] The term "substituted" refers to a moiety having a substituent in place of one or more hydrogens on one or more carbons of a backbone. "Substitution" or "substituted with" is understood to mean that such substitution is in accordance with the allowed valences of the substituted atoms and substituents, and includes the implicit condition that the substitution results in a stable compound, i.e., a compound that does not undergo transformation, such as by rearrangement, cyclization, elimination, etc., spontaneously. As used herein, the term "substituted" is intended to encompass all allowed substituents of an organic compound. In a broad aspect, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Allowed substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of this disclosure, a heteroatom such as nitrogen can have a hydrogen substituent satisfying the valence of the heteroatom and / or any allowed substituent of an organic compound described herein. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted where appropriate. Unless otherwise specifically stated as "unsubstituted", references herein to chemical moieties are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0071] The term "sulfate" is understood in the art and refers to the group: -OSO3H, or a pharmaceutically acceptable salt thereof.

[0072] The term "sulfonamide" is understood in the art and has the general formula:

Chem.

[0073] The term "sulfoxide" is understood in the art and refers to the group: -S(O)-R 38 wherein R 38 represents hydrocarbyl.

[0074] The term "sulfonate" is understood in the art and refers to the group: -SO3H or a pharmaceutically acceptable salt thereof.

[0075] The term "sulfone" is understood in the art and refers to the group: -S(O)2-R 39 wherein R 39 represents hydrocarbyl.

[0076] As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

[0077] As used herein, the term "thioester" refers to the group: -C(O)SR 40 or -SC(O)R 40 wherein R 40 represents hydrocarbyl.

[0078] As used herein, the term "thioether" corresponds to an ether in which oxygen is replaced by sulfur.

[0079] The term "urea" is understood in the art and has the general formula: [Chemical formula] can be represented by the formula, where R 41 and R 42 each independently represents hydrogen or hydrocarbyl, such as alkyl, or R41 any occurrence of 42 is grouped together with the atom(s) between R 42 to form a heterocycle having 4 to 8 atoms in the ring structure.

[0080] The term "protecting group" refers to an atomic group that masks, reduces, or blocks the reactivity of a reactive functional group in a molecule when attached to the functional group. Usually, a protecting group can be selectively removed as desired during synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1 - 8, 1971 - 1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert - butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2 - trimethylsilyl - ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9 - fluorenylmethyloxycarbonyl ("FMOC"), nitroveratryloxycarbonyl ("NVOC"), etc. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives, and allyl ethers.

[0081] In certain embodiments, the compounds of the present disclosure can be racemic compounds. In certain embodiments, the compounds of the present disclosure can be enriched in one enantiomer. For example, the compounds of the present disclosure can have an ee of greater than about 30%, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% ee, or more. In certain embodiments, the compounds of the present disclosure can have two or more stereocenters. In certain such embodiments, the compounds of the present disclosure can be enriched in one or more diastereomers. For example, the compounds of the present disclosure can have a de of greater than about 30%, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% de, or more.

[0082] In certain embodiments, the therapeutic formulation can be enriched to provide predominantly one enantiomer of the compound (e.g., of formula (I) or (II) or (III)). A mixture enriched in an enantiomer can contain, for example, at least about 60 mole percent, more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one enantiomer. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question occupies less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% compared to the amount of the other enantiomer in a composition or mixture of compounds. For example, if a composition or mixture of compounds contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it is said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0083] In certain embodiments, the therapeutic formulation can be enriched to provide predominantly one diastereomer of a compound (e.g., of formula (I) or (II) or (III)). The mixture enriched in the diastereomer can contain, for example, at least about 60 mole percent, more preferably at least about 75, about 90, about 95, or even about 99 mole percent of one diastereomer.

[0084] As used herein, the term "stereoisomer" refers to isomeric molecules that have the same molecular constitution and bonds but differ in the three-dimensional spatial arrangement of their atoms. Stereoisomers are isomers that differ in the spatial arrangement of their atoms rather than in the order of their atomic bonds. In some embodiments, "stereoisomer" refers to the various stereoisomeric forms of a compound that contain one or more asymmetric centers or steric hindrances within the structure. In some embodiments, the stereoisomers are enantiomers, mixtures of enantiomers, atropisomers, or tautomers thereof. In some embodiments, the compounds described herein can be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., atropisomers), or in the form of mixtures of stereoisomers that include racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, the stereoisomers include diastereoisomers, enantiomers, mixtures of diastereoisomers, and mixtures of enantiomers. In some embodiments, the compounds provided herein can be atropisomers. In certain embodiments, an atropisomer is a stereoisomer that results from hindrance to rotation around a single bond, where the energy difference due to steric strain or other factors creates a rotational barrier that is high enough to permit isolation of the individual conformational isomers. Stereoisomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and formation and crystallization of chiral salts, or the preferred isomers can be prepared by asymmetric synthesis.See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0085] In some embodiments, a portion of the compound exists as a mixture of tautomers. A “tautomer” is a structural isomer of a moiety or compound that readily interconverts with another structural isomer. For example, a pyrazole ring has two tautomers:

Chemical formula

[0086] The term “mammal” includes human subjects, primates, and commercially important mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds such as commercially important birds including chickens, ducks, geese, turkeys, and / or pigeons. The term “subject” to which administration is intended includes, but is not limited to, humans (i.e., males or females of any age group such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys). In certain embodiments, the mammal is a human subject.

[0087] As used herein, a therapeutic agent that "prevents" a disorder or condition is a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample as compared to an untreated control sample, or delays the onset of, or reduces the severity of, one or more symptoms of the disorder or condition as compared to an untreated control sample.

[0088] The term "treat" includes prophylactic treatment and / or therapeutic treatment. The term "prophylactic or therapeutic" treatment is understood in the art and includes administration of one or more of the compositions of the present disclosure to a subject. When administered prior to the clinical onset of an undesirable condition (e.g., a disease or other undesirable condition of a subject), the treatment is prophylactic (i.e., the treatment prevents the subject from developing the undesirable condition), while when administered after the onset of an undesirable condition, the treatment is therapeutic (i.e., the treatment is intended to attenuate, ameliorate, or stabilize the existing undesirable condition or its side effects).

[0089] The term "prodrug" is intended to include compounds that are converted under physiological conditions to a pharmaceutically active agent of the present disclosure. General methods for making prodrugs include including one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present disclosure. In certain embodiments, in the formulations shown above, some or all of the compounds disclosed herein may be replaced with the corresponding suitable prodrugs, where, for example, the hydroxyl of the parent compound is provided as an ester or carbonate or carboxylic acid.

[0090] As used herein, "effective amount" refers to an amount sufficient to achieve the desired biological effect. As used herein, "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount sufficient to improve at least one sign or symptom of cancer.

[0091] "Response" to a treatment method can include, among other things, a decrease or improvement in adverse symptoms, a decrease in the progression of a disease or its symptoms, an increase in beneficial symptoms or an improvement in clinical outcome, a reduction in side effects, stabilization of a disease, or partial or complete treatment of a disease.

[0092] In certain embodiments, the pharmaceutically acceptable salts of the compound are selected from the group consisting of alkylammonium salts, dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Zn salts. In certain embodiments, the pharmaceutically acceptable salt is a solvate selected from the group consisting of water, methanol, ethanol, and dimethylformamide.

[0093] In certain embodiments, the compound is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient.

[0094] In certain embodiments, the composition is in a form selected from the group consisting of tablets, capsules, granules, lyophiles for reconstitution, powders, solutions, syrups, suppositories, injections, suspensions, infusion fluids, transdermal delivery systems (e.g., creams, gels, ointments), and solutions suitable for topical administration.

[0095] Compound The present disclosure relates to a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0096] In some embodiments of formula (I), V is N or

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0097] In some aspects, the disclosure is directed to formula (II): [Chemical formula] a compound or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein [Chemical formula] is a 4- to 7-membered heterocyclyl, R 1 is [Chemical formula] and R a1 , R a2 , R a3 , and R a4 are each independently hydrogen, halo, CN, N(R n1 )2, optionally substituted C 1~5 alkyl, optionally substituted -CH2O-C 1~5 alkyl, optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl, optionally substituted -CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl, each R n1 is independently hydrogen or C 1~5 alkyl, R 2 is, in each occurrence, independently optionally substituted C 1~5 alkyl or, in the case of two geminal R 2 occurrences, together form an oxo moiety, or, in the case of two non-geminal R 2 occurrences, together form a C1-C4 (e.g., C1-C2) alkylene bridge, n is 0 or an integer from 1 to 3 (inclusive at both ends) as allowed by the valence, X 2 is -C=, -CH-, or N, U is CR c or N, R cis hydrogen, halo, or optionally substituted C 1~5 alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 alkyl, optionally substituted C 1~5 alkoxy, or the occurrences of R d and R 2 are grouped together with the intervening atoms to form a heterocycle, W is N or CR e , R e is hydrogen, halo (e.g., fluoro), or cyano, R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halo, optionally substituted C 1~5 alkyl, or optionally substituted C 1~5 alkoxy, R 10 is hydrogen, halo, or optionally substituted C 1~5 alkyl, Q 1 , Q 2 , Q 3 , and Q 4 are each independently NR f or CR g , provided that at least one of Q 1 , Q 2 , Q 3 , and Q 4 is CR g , R f is independently at each occurrence hydrogen, optionally substituted C 1~5 alkyl, or absent, R g is independently at each occurrence hydrogen, optionally substituted C 1~5 alkyl, or absent, and provides the compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0098] In some embodiments, the present disclosure provides a compound of formula (I-i):

Chemical formula

Chemical formula

[0099] In certain embodiments, the compound of formula (I-i) is a compound of formula (I-i-a):

Chemical formula

[0100] In certain embodiments, the compound of formula (I-i-a) is a compound of formula (I-i-a1):

Chemical formula

[0101] In certain embodiments, the compound of formula (I-i) is a compound of formula (I-i-a0): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0102] In certain embodiments, the compound of formula (I-i-a1) is the following formula: [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0103] In certain embodiments, the compound of formula (I-i-a1) is the following formula: [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0104] In certain embodiments, the compound of formula (I-i-a1) is the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0105] In certain embodiments, the compound of formula (I-i-a1) is of the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0106] In certain embodiments, the compound of formula (I-i-a1) is of the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0107] In certain embodiments, the compound of formula (I-i-a1) is of the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0108] In certain embodiments, the compound of formula (I-i-a1) is of the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0109] In certain embodiments, the compound of formula (I-i-a1) is of the following formula: [Chemical formula] The compound is, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0110] In certain embodiments, the compound of formula (I-i-a1) is a compound of formula (I-i-a2): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0111] In certain embodiments, the compound of formula (I-i-a1) is a compound of formula (I-i-a3): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0112] In certain embodiments, the compound of formula (I-i-a1) is a compound of formula (I-i-a4): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0113] In certain embodiments, the compound of formula (I-i-a1) is a compound of formula (I-i-a5): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0114] In certain embodiments, the compound of formula (I-i-a1) is a compound of formula (I-i-a6): [Chemical formula] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0115] In certain embodiments, the compound of formula (I-i) is a compound of formula (I-i-b): [Chemical formula] is a compound of formula (I-i), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0116] In certain embodiments, the compound of formula (I-i) is of formula (I-i-c):

Chemical formula

[0117] In one embodiment of any of formulae (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), s is 0 and t is 1 or 2. In one embodiment of any of formulae (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), s is 1 and t is 1 or 2. In one embodiment of any of formulae (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), s is 2 and t is 1 or 2. In one embodiment of any of formulae (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), s is 1 and t is 1. In one embodiment of any of formulae (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), s is 1 and t is 2.

[0118] In one embodiment of any of formula (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), R 11 is optionally substituted C 1~5 alkyl. In one embodiment of any of formula (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), R 11 is methyl. In one embodiment of any of formula (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), R 12 is optionally substituted C 1~5 alkyl. In one embodiment of any of formula (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), R 12 is methyl.

[0119] In certain embodiments, the present disclosure provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0120] In certain embodiments, the disclosure provides a compound of formula (a-I):

Chemical formula

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0121] In a particular embodiment, the present disclosure relates to a compound of formula (a-I):

Chemical formula

Chemical formula

[0122] In one embodiment of formula (a-I) (or its sub-formulas), K is a bond. In one embodiment of formula (a-I) (or its sub-formulas), K is C=O. In one embodiment of formula (a-I) (or its sub-formulas), K is SO2. In one embodiment of formula (a-I) (or its sub-formulas), J is a bond, and X 1 is N, and K is C=O. In other embodiments of formula (a-I) (or its sub-formulas), J is a bond, and X 1 is N, and K is SO2. In other embodiments of formula (a-I) (or its sub-formulas), J is a bond, and X 1 is N, and K is a bond. In other embodiments of formula (a-I) (or its sub-formulas), J is a bond, and X 1 is N, and K is a bond, and R 1 is CN.

[0123] In one embodiment of formula (I), (II), (I-i), or (a-I) (or their sub-formulas),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0124] In certain embodiments, the present disclosure provides a compound of formula (B):

Chemical formula

Chemical formula

Chemical formula

[0125] In certain embodiments, the compound of formula (B) is of formula (B-i):

Chemical formula

[0126] In certain embodiments of formula (B-i) (or its sub-formulas), R 4a is halo and R 4b is optionally substituted C 1~5 alkyl. In certain embodiments of formula (B-i) (or its sub-formulas), R 4a is F or Cl and R 4b is methyl. In certain embodiments of formula (B-i) (or its sub-formulas), R 4b is halo and R 4a is optionally substituted C 1~5 alkyl. In certain embodiments of formula (B-i) (or its sub-formulas), R 4b is F or Cl and R 4a is methyl. In certain embodiments of formula (B-i) (or its sub-formulas), R 4a and R4b Each of them is independently a halo, optionally substituted C 1~5 alkyl, or optionally substituted C 1~5 alkoxy, and R d is a halo, optionally substituted C 1~5 alkyl, or optionally substituted C 1~5 alkoxy, or the occurrences of R d and R 2 are grouped together with the intervening atoms to form a 3- to 6-membered heterocyclic ring. In certain embodiments, R 4a and R 4b each is independently a halo (e.g., F or Cl), optionally substituted C 1~5 alkyl (e.g., methyl), and R d is a halo (e.g., F). In certain embodiments, R 4a and R 4b each is independently a halo (e.g., F or Cl), optionally substituted C 1~5 alkyl (e.g., methyl), and R d is optionally substituted C 1~5 alkoxy. In certain embodiments, R 4a and R 4b each is independently a halo (e.g., F or Cl), optionally substituted C 1~5 alkyl (e.g., methyl), and R d is optionally substituted C 1~5 alkyl or optionally substituted C 1~5 alkoxy, and the occurrences of R 2 are grouped together with the intervening atoms to form a 3- to 6-membered heterocyclic ring.

[0127] In certain aspects, the disclosure relates to a compound of formula (C):

Chemical formula

Chemical formula

Chemical formula

[0128] In certain embodiments, the disclosure is directed to a compound of formula (D):

Chemical formula

Chemical formula

[0129] In certain embodiments, the disclosure relates to formula (E):

Chemical formula

Chemical formula

Chemical formula

[0130] In certain embodiments of any of formula (I), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas,

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0131] In certain embodiments of any of formula (I), (I-i) (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, [Chemical formula] is a 6- to 10-membered aryl. In some embodiments, [Chemical formula] is a 5- to 10-membered heteroaryl. In certain embodiments, [Chemical formula] contains 1 to 3 nitrogen atoms. In certain such embodiments,

Chem.

Chem.

Chem.

Chem.

[0132] In certain embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas,

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

[0133] In any particular embodiment of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0134] In some embodiments, R 5 is, independently at each occurrence, halo, optionally substituted C 1~5 alkyl, or optionally substituted C 1~5 alkoxy. In some embodiments, R 5 is, independently at each occurrence, optionally substituted C 1~5 alkyl.

[0135] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0136] In some embodiments, R 1 is CN, C 1~5 alkyl, C 1~5 haloalkyl, C 2~5 alkenyl, C 2~5 alkynyl, or 3-6 membered heterocyclyl, where the alkyl, alkenyl, alkynyl, or heterocyclyl is optionally substituted with one or more R ais arbitrarily replaced by the appearance of. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R 1 is C 1~5 alkyl, C 1~5 haloalkyl, C 2~5 alkenyl, C 2~5 alkynyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, or heterocyclyl is optionally substituted by one or more occurrences of R a In some embodiments, R 1 is C 2~5 alkenyl or C 2~5 alkynyl, wherein the alkenyl or alkynyl is optionally substituted by one or more occurrences of R a .

[0137] In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R 1 is C a alkyl optionally substituted by one or more occurrences of R 1~5 . In some embodiments, R 1 is C 1~5 alkyl. In some embodiments, R 1 is C 1~5 haloalkyl. In some embodiments, R 1 is C a alkenyl optionally substituted by one or more occurrences of R 2~5 . In some embodiments, R 1 is C a alkenyl optionally substituted by one or more occurrences of R 2~5is alkynyl. In some embodiments, R 1 is ethenyl, ethynyl, methyl, ethyl, or oxiranyl. In some embodiments, R 1 is ethenyl. In some embodiments, R 1 is ethenyl. In some embodiments, R 1 is ethynyl.

[0138] In some embodiments, R a is, in each occurrence independently, halo, CN, N(R n1 )2, optionally substituted C 1~5 alkyl, optionally substituted -O-C 1~5 alkyl, optionally substituted -O-C 1~5 alkylene -O-C 1~5 alkyl, optionally substituted -CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl, and each R n1 is independently hydrogen or C 1~5 alkyl. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R a is C 1~5 alkyl (e.g., methyl or ethyl). In certain embodiments, R a is C 1~5 haloalkyl. In certain embodiments, R a is -O-C 1~5 alkyl (e.g., methoxy). In certain embodiments, R a is halogen (e.g., F or Cl). In certain embodiments, R a is CN. In certain embodiments, R a is N(R n1 )2. In certain embodiments, R a is N(CH3)2.

[0139] In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R 1 is at least one R 1~5 substituted by optionally substituted C a alkyl. In certain such embodiments, R a is optionally substituted by an amine or a heterocyclic ring, and the amine or the heterocyclic ring is optionally substituted by alkyl. In some embodiments, R 1 is at least one R a substituted by dialkylaminomethyl. In a particular embodiment, R 1 is substituted by only one R a which is dialkylaminomethyl. In certain such embodiments, the dialkylaminomethyl is dimethylaminomethyl. In other embodiments, R 1 is at least one R a substituted by fluoro, methyl, morpholinomethyl, or pyrrolidinyl. In a further embodiment, R 1 is not substituted by R a . In one embodiment, R 1 is unsubstituted.

[0140] In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R 1 is alkynyl. In a particular embodiment, R a is optionally substituted alkyl. In certain such embodiments, R a is methyl.

[0141] In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (I-i-a3), (I-i-a4), (I-i-a5), (I-i-a6), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E) (and their sub-formulas), R 1 is ethenyl, ethynyl, methyl, ethyl, or oxiranyl, and is substituted by at least one R a which is CN, F, Cl, -CH3, -CH2OCH3, -CH2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidinyl. In some embodiments, R 1 is ethenyl or ethynyl, and is substituted by at least one R a which is CN, F, Cl, -CH3, -CH2OCH3, -CH2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidinyl. In some embodiments, R 1 is methyl, ethyl, or oxiranyl, and is substituted by at least one R a which is CN, F, Cl, -CH3, -CH2OCH3, -CH2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidinyl.

[0142] In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, J is NR b and X 1 is CH. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R bis hydrogen or methyl. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R b is hydrogen. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, J is a bond, and X 1 is N.

[0143] In some embodiments, R 2 is, independently at each occurrence, optionally substituted C 1~5 alkyl, or the two occurrences of geminal R 2 are combined to form an oxo moiety, or the two occurrences of non-geminal R 2 are combined to form a C1-C4 alkylene bridge. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2 is, independently at each occurrence, C 1~5 alkyl. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2 is, independently at each occurrence, methyl. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2 is, independently at each occurrence, C 1~5 haloalkyl. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2is, independently at each occurrence, CH2F. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2 is, independently at each occurrence, CHF2. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, two geminal Rs 2 occurrences are grouped together to form an oxo moiety. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R 2 is, independently at each occurrence, methyl or CH2F, or two geminal Rs 2 occurrences are grouped together to form an oxo moiety. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, two non-geminal Rs 2 occurrences are grouped together to form a methylene or ethylene bridge. In some embodiments of any of formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, R d and R 2 occurrences, together with the intervening atoms, are grouped together to form a heterocyclic ring.

[0144] In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 0 or an integer from 1 to 2 (including both ends) as permitted by the valence. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 0. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 1. In other embodiments, n is 2.

[0145] In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 1 and R 2 is bonded to the atom adjacent to X 1 (e.g., R 2 is ortho to X of the 6-membered ring A 1 ). In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 1 and R 2 is bonded to the atom adjacent to X 2 (e.g., R 2 is ortho to X of the 6-membered ring A 2 ). The presence of R 2 can result in a chiral center at the atom to which R 2 is bonded. In one embodiment, the compound has the R configuration at the atom to which R 2 is bonded. In one embodiment, the compound has the S configuration at the atom to which R 2 is bonded. In one embodiment, the compound is a racemic mixture at the atom to which R 2 is bonded.

[0146] In some embodiments of any of formula (I), (I-i) (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, n is 1, and R 2 is bonded to the atom adjacent to N-C(=O)-R 1 (e.g., R 2 is ortho to N-C(=O)-R of the 6-membered ring A 1 ). In one embodiment, n is 1, and R 2 is bonded to the atom adjacent to X 2 (e.g., R 2 is ortho to X of the 6-membered ring A 2 ). The presence of R 2 can result in a chiral center at the atom to which R 2 is bonded. In some embodiments of any of formula (I), (I-i) (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, the compound has the R configuration at the atom to which R 2 is bonded. In some embodiments of any of formula (I), (I-i) (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, the compound has the S configuration at the atom to which R 2 is bonded. In some embodiments of any of formula (I), (I-i) (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, the compound is a racemic mixture at the atom to which R 2 is bonded.

[0147] In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, m is 0 or an integer from 1 to 2 (inclusive at both ends) as allowed by the valence. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, m is 0. In some embodiments of any of Formula (I), (I-i), (I-i-a), (I-i-b), (I-i-c), (a-I), (B), (B-i), (C), (D), and (E), and their sub-formulas, m is 1. In other embodiments, m is 2.

[0148] In one embodiment, ring A (including any substituent R 2 is)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0149] In certain embodiments, the compound of formula (II) is of formula (III):

Chemical formula

[0150] In some embodiments, at least one of R 11 and R 12 is optionally substituted C 1~5 alkyl. In certain such embodiments, at least one of R 11 and R 12 is methyl. In some embodiments, R 13 and R 14at least one of which is optionally substituted C 1~5 alkyl. In certain embodiments, R 13 and R 14 at least one of which is methyl. In some embodiments, R d as well as R 13 and R 14 one of which is grouped together with the intervening atoms to form a heterocycle. In a further embodiment, R 11 , R 12 , R 13 , and R 14 are hydrogen.

[0151] In one embodiment, none of R 11 , R 12 , R 13 , and R 14 is hydrogen. In one embodiment, one of R 11 , R 12 , R 13 , and R 14 is hydrogen and the other three of R 11 , R 12 , R 13 , and R 14 are not hydrogen. In one embodiment, two of R 11 , R 12 , R 13 , and R 14 are hydrogen and the other two of R 11 , R 12 , R 13 , and R 14 are not hydrogen.

[0152] In one embodiment, three of R 11 , R 12 , R 13 , and R 14 are hydrogen and the other one of R 11 , R 12 , R 13 , and R 14 is not hydrogen. In one embodiment, R 12 , R 13 , and R 14 are hydrogen and R 11It is not hydrogen. In one embodiment, R 11 , R 13 , and R 14 are hydrogen, and R 12 is not hydrogen. In one embodiment, R 11 , R 12 , and R 14 are hydrogen, and R 13 is not hydrogen. In one embodiment, R 11 , R 12 , and R 13 are hydrogen, and R 14 is not hydrogen. In one embodiment, the non-hydrogen group is optionally substituted alkyl. In one embodiment, the non-hydrogen group is methyl.

[0153] The presence of R 11 , R 12 , R 13 , or R 14 can result in a chiral center at the atom to which R 11 , R 12 , R 13 , or R 14 is attached. In one embodiment, the compound has an R configuration at the atom to which R 11 , R 12 , R 13 , or R 14 is attached. In one embodiment, the compound has an S configuration at the atom to which R 11 , R 12 , R 13 , or R 14 is attached. In one embodiment, the compound is a racemic mixture at the atom to which R 11 , R 12 , R 13 , or R 14 is attached.

[0154] In one embodiment, [Chemical formula] is [Chemical formula] It is. In one embodiment, the ring is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0155] In certain embodiments, the bond between X 2 and the carbon to which R 13 is attached is a double bond. In other embodiments, the bond between X 2 and the carbon to which R 13 is attached is a single bond.

[0156] In some embodiments, R 1 is

Chem.

Chem.

[0157] As used herein, R a1 is, independently, hydrogen, halo, CN, N(R n1 )2, optionally substituted C 1~5 alkyl, optionally substituted -CH2O-C 1~5 alkyl, optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl, optionally substituted -CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl, and each R n1 is, independently, hydrogen or C 1~5 alkyl. In certain such embodiments, R a1 is hydrogen. In certain embodiments, R a1 is CN. In certain embodiments, R a1 is CN. In certain embodiments, R a1 is -CH2O-C 1~5 alkyl. In certain embodiments, R a1 is -CH2OCH3. In certain embodiments, R a1 is optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl. In certain embodiments, R a1 is -CH2O-(CH2) 1~2 -O-C 1~5 alkyl. In certain embodiments, R a1 is -CH2O-(CH2)2-O-CH3. In certain embodiments, R a1 is optionally substituted -CO2-C 1~5 alkyl. In certain embodiments, R a1 is -CO2CH3.

[0158] As used herein, R a2 is, independently, hydrogen, halo, CN, N(R n1 )2, optionally substituted C 1~5Alkyl, optionally substituted -CH2O-C 1~5 Alkyl, optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 Alkyl, optionally substituted -CO2-C 1~5 Alkyl, or optionally substituted 3- to 6-membered heterocyclyl, and each R n1 is, independently, hydrogen or C 1~5 alkyl. In certain such embodiments, R a2 is hydrogen. In some embodiments, R a2 is optionally substituted C 1~5 alkyl or optionally substituted 3- to 6-membered heterocyclyl. In some embodiments, R a2 is methyl, -CH2-N(CH3)2, -CO2CH3, -CH2OCH3, -CH2O(CH2)2CH3, morpholinomethyl, or pyrrolidinyl. In some embodiments, R a2 is optionally substituted C 1~5 alkyl. In certain embodiments, R a2 is optionally substituted by an amine or a 3- to 6-membered heterocycle, and the amine or the heterocycle is optionally substituted by C 1~5 alkyl. In some embodiments, R a2 is dialkylaminomethyl. In certain embodiments, R a2 is dimethylaminomethyl. In other embodiments, R a2 is hydrogen. In certain embodiments, R a2 is CN. In certain embodiments, R a2 is CN. In certain embodiments, R a2 is -CH2O-C 1~5 alkyl. In certain embodiments, R a2 is -CH2OCH3. In certain embodiments, R a2 is optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl. In certain embodiments, R a2 is -CH2O-(CH2) 1~2 -O-C1~5 is alkyl. In certain embodiments, R a2 is -CH2O-(CH2)2-O-CH3. In certain embodiments, R a2 is optionally substituted -CO2-C 1~5 alkyl. In certain embodiments, R a2 is -CO2CH3.

[0159] As used herein, R a3 is independently hydrogen, halo, CN, N(R n1 )2, optionally substituted C 1~5 alkyl, optionally substituted -CH2O-C 1~5 alkyl, optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl, optionally substituted -CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl, and each R n1 is independently hydrogen or C 1~5 alkyl. In certain such embodiments, R a3 is hydrogen. In some embodiments, R a4 is optionally substituted C 1~5 alkyl. In certain such embodiments, R a3 is methyl. In certain such embodiments, R a3 is CN. In certain such embodiments, R a3 is F.

[0160] In some embodiments, R a1 is independently hydrogen or C 1~5 alkyl, and R a2 is independently hydrogen, halo, CN, N(R n1 ) 2 optionally substituted C 1~5 alkyl, optionally substituted -CH2O-C 1~5 alkyl, optionally substituted -CH2O-(CH2) 1~2 -O-C 1~5 alkyl, optionally substituted -CO2-C 1~5Alkyl, or optionally substituted 3- to 6-membered heterocyclyl, each R n1 is, independently, hydrogen or C 1~5 alkyl, and R a3 is, independently, hydrogen, halo, CN, optionally substituted C 1~5 alkyl.

[0161] In some embodiments, R a1 and R a2 are linked to form an alkenyl group.

[0162] In some embodiments, R a1 and R a2 are hydrogen. In some embodiments, R a1 and R a3 and R a3 are hydrogen.

[0163] In certain embodiments, X 2 is -C=. In other embodiments, X 2 is N. In other embodiments, X 2 is -CH-.

[0164] In some embodiments, U is CR c In certain such embodiments, R c is fluoro. In some embodiments, R c is hydrogen. In other embodiments, U is N.

[0165] In certain embodiments, V is CR d In some embodiments, R d is hydrogen, fluoro, methyl, or methoxy. In certain embodiments, R d is methoxy. In certain embodiments, R d is fluoro. In other embodiments, V is N.

[0166] In some embodiments, W is N. In some embodiments, W is CR eThat is. In some embodiments, W is CH or CF.

[0167] In some embodiments, Y 1 and Y 2 is C R4 That is. In some embodiments, Y 1 is C R4 and Y 2 is N.

[0168] In some embodiments, R 4 is, in each occurrence, independently fluoro, chloro, methyl, methoxy, or difluoromethyl.

[0169] In certain embodiments, R 6 and R 7 are each independently hydrogen, halo, optionally substituted alkoxy, or optionally substituted alkyl. In some embodiments, R 6 and R 7 are each independently hydrogen, fluoro, methoxy, or difluoromethyl. In certain embodiments, R 6 and R 7 are hydrogen. In some embodiments, R 8 and R 9 are each independently hydrogen, halo, or optionally substituted alkyl. In certain embodiments, R 8 and R 9 are each independently hydrogen, chloro, or methyl. In some embodiments, R 8 is methyl. In other embodiments, R 9 is hydrogen. In some embodiments, R 10 is hydrogen, fluoro, chloro, methyl, ethyl, or methoxy. In some embodiments, R 10 is hydrogen.

[0170] In one embodiment, none of R 6 , R 7 , R 8 , and R 9 is hydrogen.

[0171] In one embodiment, R 6 , R 7 , R 8 , and R 9 of which one is hydrogen, and R 6 , R 7 , R 8 , and R 9 the other three of which are not hydrogen. In one embodiment, R 7 is hydrogen, and R 6 , R 8 , and R 9 are not hydrogen. In one embodiment, R 9 is hydrogen, and R 6 , R 7 , and R 8 are not hydrogen.

[0172] In one embodiment, R 6 , R 7 , R 8 , and R 9 of which two are hydrogen, and R 6 , R 7 , R 8 , and R 9 the other two of which are not hydrogen. In one embodiment, R 7 and R 9 are hydrogen, and R 6 and R 8 are not hydrogen. In one embodiment, R 6 and R 9 are hydrogen, and R 7 and R 8 are not hydrogen.

[0173] In one embodiment, R 6 , R 7 , R 8 , and R 9 of which three are hydrogen, and R 6 , R 7 , R 8 , and R 9 the other one of which is not hydrogen. In one embodiment, R 6 , R 7 , and R 9 are hydrogen, and R 8is not hydrogen. In one embodiment, R 7 , R 8 , and R 9 are hydrogen, and R 6 is not hydrogen.

[0174] In one embodiment, R 7 and R 9 are hydrogen, and one of R 6 and R 8 is optionally substituted alkyl, and the other of R 6 and R 8 is halo. In one embodiment, R 7 and R 9 are hydrogen, R 6 is optionally substituted alkyl, and R 8 is halo. In one embodiment, R 7 and R 9 are hydrogen, R 8 is optionally substituted alkyl, and R 6 is halo. In one embodiment, the optionally substituted alkyl is methyl. In one embodiment, the halo is fluoro. In one embodiment, R 7 and R 9 are hydrogen, R 8 is methyl, and R 6 is fluoro.

[0175] In some embodiments, Q 1 is CR g , Q 2 is CR g , Q 3 is CR g , and Q 4 is NR f . In other embodiments, Q 1 is NR f , Q 2 is CR g , Q 3 is CR g , and Q 4 is NR f . In further embodiments, Q 1 is CR g , and Q 2 is CRg and Q 3 is NR f and Q 4 is NR f is. In some embodiments, Q 1 is NRf and Q 2 is NR f and Q 3 is CR g and Q 4 is NR f is. In still other embodiments, Q 1 is NR f and Q 2 is NR f and Q 3 is NR f and Q 4 is CR g is. In still other embodiments, Q 1 is CR g and Q 2 is NR f and Q 3 is CR g and Q 4 is NR f is. In still other embodiments, Q 1 is CR g and Q 2 is NR f and Q 3 is NR f and Q 4 is CR g is. In some embodiments, R f is hydrogen, methyl, or absent. In certain embodiments, R f is hydrogen or absent. In some embodiments, R g is hydrogen. In some embodiments, R g is absent.

[0176] In one embodiment,

Chemical formula

Chemical formula

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0177] In one embodiment, the compound is any one of the following formulas:

Chemical Formula

[0178] In one embodiment, the compound is any one of the following formulas:

Chemical Formula

[0179] In one embodiment, the compound is of the following formula:

Chemical formula

[0180] In certain embodiments, the compound of formula (III) is of formula (III-I-1):

Chemical formula

[0181] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-2):

Chem.

[0182] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-3):

Chem.

[0183] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-4):

Chem.

[0184] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-5): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0185] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-6): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0186] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-7): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0187] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-8): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0188] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-9): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0189] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-10): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0190] In certain embodiments, the compound of formula (III) is a compound of formula (III-I-11): [Chemical formula] is a compound or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined herein.

[0191] In certain embodiments, the compound of formula (III) is of formula (III-I-12):

Chemical formula

[0192] In certain embodiments, the compound of formula (III) is of formula (III-I-13):

Chemical formula

[0193] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 1 is

Chemical formula

[0194] In one embodiment of any of Formulas (III-I-1) to (III-I-13), R 6 , R 7 , R 8 , and R 9 each independently is H, halogen, C 1~4 alkyl, or C 1~4 haloalkyl. In certain embodiments, R 7 and R 9 are H, and R 6 and R 8 each independently is halogen or C 1~4 alkyl.

[0195] In one embodiment of any of Formulas (III-I-1) to (III-I-13), R 11 and R 12 each independently is H or C 1~4 alkyl. In certain embodiments, R 11 is H, and R 12 is C1-C4 alkyl. In certain embodiments, R 12 is H, and R 11 is C 1~4 alkyl.

[0196] In one embodiment of any of Formulas (III-I-1) to (III-I-13), R 10 is H, halogen, or C1-C4 alkyl.

[0197] In one embodiment of any of Formulas (III-I-1) to (III-I-13), R 1 is

Chemical formula

[0198] In one embodiment of any of formula (III-A-1), (III-B-1), (III-C-1), (III-D-1), (III-E-1), (III-F-1), (III-G-1), (III-H-1), and (III-I-1) to (III-I-13), R 8 is optionally substituted C 1~4 alkyl, R 6 is halo. In one embodiment, the optionally substituted C 1~4 alkyl is methyl. In one embodiment, the halo is fluoro. In one embodiment, R 8 is methyl and R 6 is fluoro.

[0199] In some embodiments, herein, the following structure:

Chemical formula

[0200] In some embodiments, herein, the following structure:

Chemical formula

[0201] In some embodiments, herein, the following structure:

Chemical formula

[0202] Disclosed herein is a method for treating cancer, which comprises administering to a mammal in need of treating cancer a therapeutically effective amount of a compound disclosed herein. In some embodiments, the cancer is non-small cell lung cancer. In other embodiments, the cancer is squamous cell carcinoma of the head and neck. In certain embodiments, the non-small cell lung cancer has one or more ErbB family mutations. In other embodiments, the non-small cell lung cancer has one or more EGFR ex20 insertion mutations. In some embodiments, the non-small cell lung cancer has one or more HER2 ex20 insertion mutations. In certain embodiments, the mammal is a human. In some embodiments, the compound is administered orally or intravenously.

[0203] Method of Use In one aspect, provided herein is a method for preventing and / or treating a proliferative disease such as cancer in a subject (e.g., a subject in need of preventing and / or treating a proliferative disease such as cancer). The method comprises administering to the subject a compound of the present disclosure (e.g., an effective amount, e.g., a therapeutically effective amount).

[0204] Cancer is a disease of uncontrolled cell growth caused by changes in certain genes. Some of these changes occur in genes that encode receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth, and proliferation. Abnormal RTK activation can lead to excessive cell growth and thereby cancer. In general, an RTK has an N-terminal domain that binds to an extracellular ligand, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signaling.

[0205] Human EGFR, also known as ErbB1 or HER1, is a RTK encoded by the EGFR gene on chromosome 7. Multiple ligands of EGFR have been identified, including epidermal growth factor (EGF), transforming growth factor α (TGF-α), amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EPR), and epigen (EPGN). EGFR is thought to play an essential role in the development, proliferation, differentiation, and migration of mammalian cells. EGFR-deficient mice die within a few weeks after birth and exhibit improper development of various organs, including but not limited to the skin, gastrointestinal tract, and nervous system. In humans, EGFR overexpression and activating mutations are well-established causes of cancer. EGFR overexpression is found at high frequencies in a number of solid tumors and can be targeted by the following FDA-approved monoclonal antibodies: cetuximab, panitumumab, and necitumumab.

[0206] In some embodiments, the compounds of the present disclosure are regulators of HER2. Human HER2, also known as ErbB2, is an RTK encoded by the ERBB2 gene on chromosome 17. Although the ligand for HER2 is unknown, HER2 can regulate downstream signaling by heterodimerizing with other RTKs of the HER2 family, including EGFR. Mouse studies have demonstrated an essential role for HER2 in mammalian development and cell differentiation, particularly in the cardiac and nervous systems. HER2 deficiency is embryonically lethal in mice due to abnormal cardiac development, and conditional deletion of HER2 causes abnormalities in neuronal maturation, myelination, and migration. In humans, HER2 overexpression and activating mutations are known causes of cancer. HER2 overexpression is found in a number of solid tumors, most notably in 15 - 25% of breast cancers. HER2 amplification is observed in cancers including esophageal gastric cancer, breast cancer, peritoneal cancer, salivary gland cancer, bladder cancer, endometrial cancer, papillary cancer, small intestine cancer, vaginal cancer, cervical cancer, hepatobiliary cancer, ovarian cancer, colorectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer, appendiceal cancer, B lymphoblastic leukemia / lymphoma, melanoma, germ cell tumor, small cell lung cancer, mature B cell tumor, prostate cancer, soft tissue sarcoma, and glioma. Numerous targeted therapies for the treatment of HER2 - positive breast cancer have been developed, including monoclonal antibodies (trastuzumab and pertuzumab), antibody - drug conjugates (ado - trastuzumab emtansine and fam - trastuzumab deruxtecan), and small - molecule kinase inhibitors (lapatinib, neratinib, and tucatinib). Tucatinib, a very recently FDA - approved HER2 inhibitor, increased the objective response rate by 23% - 41% compared to placebo, extended the median progression - free survival by 5.6 - 7.8 months, and extended the median overall survival by 17.4 - 21.9 months. In contrast, HER2 exon 20 insertions are found in approximately 2% of NSCLC, but there are no approved targeted therapies for these mutations.

[0207] A number of existing HER2 therapies, including erlotinib, gefitinib, afatinib, dacomitinib, lapatinib, and neratinib, are also potent inhibitors of wild-type EGFR. This is a significant drawback as native EGFR plays an important role in epithelial biology, including the integrity of the skin and the inner lining of the gastrointestinal tract. Inhibition of wild-type EGFR is associated with common adverse reactions, including rash, diarrhea, and stomatitis. There is a need in the art for new therapies that selectively target mutant HER2 while sparing wild-type EGFR.

[0208] In one aspect, provided herein is a method of treating and / or preventing a proliferative disease, wherein inhibition of wild-type HER2 and / or mutant HER2 provides a therapeutic effect. In certain embodiments, provided herein is a method of treating and / or preventing a proliferative disease, wherein inhibition of exon 20 mutant HER2 protein provides a therapeutic effect.

[0209] In another aspect, provided herein is a method of inhibiting wild-type and / or mutant HER2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In another embodiment, provided herein is a method of inhibiting exon 20 mutant HER2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0210] In another aspect, there is provided a method of treating cancer, comprising administering to a mammal (e.g., a human subject) in need of treating cancer a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the cancer is a HER2-related cancer. In some embodiments, the HER2-related cancer is associated with HER2 overexpression and / or HER2 amplification and / or HER2 mutation(s).

[0211] In some embodiments, "associated with" indicates the cause of the cancer. In some embodiments, "associated with" indicates a characteristic of the cancer.

[0212] In another aspect, there is provided a method of treating cancer, comprising administering to a mammal (e.g., a human subject) in need of treating cancer a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the cancer is associated with a HER2 exon 20 mutation. In some embodiments, the HER2 exon 20 mutation is one or more from the group consisting of YVMA insertion, VC insertion, and GSP insertion. In some embodiments, the HER2 exon 20 mutation is one or more from the group consisting of YVMA insertion and VC insertion.

[0213] In certain embodiments, the HER2 exon 20 insertion mutations are one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, G778_S779insCPG, G780_P781dupGSP, Y772_A775dup, G778_P780dup, E770_A771insGIRD, G778_S779insLPS, M774_A775insAYVM, G778_S779insLPG, G778dup, G776delinsVC, M774delinsWLV, A775_G776insSVMA, and A775_G776insI. In certain embodiments, the HER2 exon 20 insertion mutations are one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, G778_S779insCPG, and G780_P781dupGSP. In certain embodiments, the HER2 exon 20 insertion mutations are one or more selected from A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, and G778_S779insCPG.

[0214] In another aspect, provided herein is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, wherein the cancer is characterized by HER2 overexpression, HER2 amplification, and / or HER2 exon 20 mutation(s).

[0215] In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is selected from brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic cancer.

[0216] In certain embodiments, the compounds provided herein are CNS permeable compounds. In one embodiment, after administration of a therapeutically effective amount of the compounds provided herein, the compound permeates the CNS (e.g., the blood-brain barrier) and still achieves a concentration in the CNS (e.g., the brain) sufficient to inhibit (e.g., selectively inhibit) HER2 overexpression and / or HER2 amplification and / or HER2 mutation(s).

[0217] In one embodiment, provided herein is a method of treating CNS metastases of cancer, comprising administering to a mammal (e.g., a human subject) in need of treating CNS metastases of cancer a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer thereof, a mixture of enantiomers, or a tautomer, or a pharmaceutically acceptable salt thereof. In one embodiment, the CNS metastasis is a brain metastasis. In one embodiment, the cancer is a HER-related cancer (e.g., related to HER2 overexpression, and / or HER2 amplification, and / or HER2 exon 20 mutation(s)).

[0218] In another embodiment, provided herein is a method of inhibiting exon 20 mutant HER2(s) in a subject in need of inhibiting exon 20 mutant HER2(s), comprising administering to a mammal (e.g., a human subject) a therapeutically effective amount of a compound described herein (e.g., formula (I) or any sub-formula) or a pharmaceutically acceptable salt thereof.

[0219] In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 about 10 to about 100 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 about 20 to about 80 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 about 30 to about 80 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 as compared to mutant EGFR(s) (e.g., EGFR exon 20). In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 about 10 to about 100 times as compared to mutant EGFR(s) (e.g., EGFR exon 20). In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2 about 20 to about 80 times as compared to mutant EGFR(s) (e.g., EGFR exon 20). In certain embodiments, the compounds of the present disclosure selectively inhibit mutant HER2(s) as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit mutant HER2(s) about 10 to about 100 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit mutant HER2(s) about 20 to about 100 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit exon 20 mutant HER2(s) as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit exon 20 mutant HER2(s) about 10 to about 100 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit exon 20 mutant HER2(s) about 20 to about 80 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit exon 30 mutant HER2(s) about 20 to about 80 times as compared to wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit mutant HER2(s) (e.g., HER2 exon 20) as compared to mutant EGFR(s) (e.g., EGFR exon 20).In certain embodiments, the compounds of the present disclosure inhibit mutant HER2(s) (e.g., HER2 exon 20) about 10 to about 100-fold selectively compared to mutant EGFR(s) (e.g., EGFR exon 20). In certain embodiments, the compounds of the present disclosure inhibit mutant HER2(s) (e.g., HER2 exon 20) about 20 to about 80-fold selectively compared to mutant EGFR(s) (e.g., EGFR exon 20). In some embodiments, the compounds of the present disclosure selectively inhibit exon 20 mutant HER2(s) compared to wild-type EGFR and / or exon 20 mutant EGFR(s). In some embodiments, the compounds of the present disclosure exhibit high selectivity compared to wild-type EGFR, in addition to an improved efficacy profile that spares wild-type EGFR compared to current therapies. Further, some of the compounds of the invention exhibit improved pharmacokinetic and pharmacological profiles. In some embodiments, the compounds described herein have minimal activity against related kinases (e.g., wt EGFR). Inhibition of wt EGFR causes undesirable side effects (e.g., diarrhea and rash) that can affect quality of life and treatment compliance.

[0220] In some embodiments, the human subject is identified or diagnosed as having a cancer associated with HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutation(s) (HER2-related cancer) (e.g., as determined using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject has a tumor that is positive for HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutation(s) (e.g., as determined using an assay or kit approved by a regulatory authority). The subject can be a subject whose tumor has HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutation(s) (e.g., where the tumor is identified using an assay or kit approved by a regulatory authority, such as the FDA). In some embodiments, the subject is suspected of having a HER2-related cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor having HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutation(s).

[0221] In some embodiments of any of the methods or uses described herein, assays used to determine whether a subject has HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (s) using a sample from the subject may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. The assay may utilize other detection methods known in the art for detecting HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (s) (see, e.g., the references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having HER2-related cancer, a subject having one or more symptoms of HER2-related cancer, and / or a subject at high risk of developing HER2-related cancer.

[0222] In some embodiments, HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (s) can be identified using a liquid biopsy (also variously referred to as a liquid biopsy or a liquid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or dysregulation of the HER2 gene, HER2 kinase, or the expression or activity or level of any of them. Liquid biopsies can be performed on biological samples that are relatively easily obtained from a subject (e.g., by simple blood draw), and are generally less invasive than conventional methods used to detect total tumor burden and / or dysregulation of the HER2 gene, HER2 kinase, or the expression or activity or level of any of them. In some embodiments, liquid biopsies can be used to detect the presence of HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (s) at an earlier stage than conventional methods. In some embodiments, biological samples used in liquid biopsies can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph fluid, cyst fluid, feces, ascites, and combinations thereof. In some embodiments, liquid biopsies can be used to detect circulating tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. In some embodiments, the cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, but not limited to, next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis) can be used to identify HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (s).

[0223] In some embodiments, the compounds of the present disclosure inhibit exon 20 mutant HER2 in a subject having NSCLC. In some embodiments, the exon 20 mutant HER2 is one or more from the group consisting of YVMA insertion, VC insertion, and GSP insertion. In some embodiments, the compounds of the present disclosure inhibit non-exon 20 mutant HER2. In some embodiments of the present disclosure, the compound selectively inhibits non-exon 20 mutant HER2(s) as compared to wild-type and / or (e.g., exon 20) mutant EGFR. In some embodiments, the non-exon 20 mutant HER2 is one or more from the group consisting of S310X, (e.g., S310F and S310Y), R678Q, V842I, L755S, G776V, and V777X. In some embodiments, the non-exon 20 mutation is one or more selected from L755S, S310F, R678Q, V842I, and V777X.

[0224] In some embodiments, provided herein is a method of inhibiting wild-type HER2 and / or mutant HER2 in a cell, comprising contacting the cell with a compound of the present disclosure. In some embodiments, the mutant HER2 has one or more exon 20 mutations.

[0225] In some embodiments, provided herein is a method of increasing the level of HER2 (wild-type HER2 and / or mutant(s)) in a cell, comprising contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0226] In some embodiments, provided herein is a method of reducing phosphorylation of HER2 (wild-type HER2 and / or mutant(s)) in a cell, comprising contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In another embodiment, provided herein is a method of inhibiting HER2 having an exon 20 mutation in a cell, comprising contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0227] In some embodiments, provided herein is a method of inhibiting phosphorylation of wild-type HER2 and / or mutant HER2 in a cell, comprising contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. In some embodiments, the mutant HER2 has one or more exon 20 mutations.

[0228] In some embodiments, provided herein is a method of treating and / or preventing a disease and / or condition, wherein inhibition of wild-type and / or mutant HER2 is therapeutically useful. In another embodiment, provided herein is a method of treating or preventing a disease and / or condition, wherein inhibition of exon 20 mutant HER2 protein is therapeutically useful.

[0229] In some embodiments, provided herein is a method of inhibiting wild-type and / or mutant HER2 in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0230] The compounds of the present disclosure are useful for inhibiting HER2 in vitro or in vivo. Accordingly, provided herein is a method of inhibiting HER2 in a cell (e.g., a cell expressing HER2), the method comprising contacting the cell with a compound of the present disclosure (e.g., a compound of the present disclosure, e.g., a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In some embodiments, the cell is present in a subject such as a human (e.g., a subject having a disease, disorder, or condition described herein). Also provided herein is a method of inhibiting HER2 in a subject in need thereof (e.g., a subject having a disease, disorder, or condition described herein), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of the present disclosure, e.g., a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof).

[0231] In some embodiments, the cell is present in a mammal. In some embodiments, the cell is present in a human subject. In some embodiments, the cell is present in a human subject having cancer. In some embodiments, the cell is present in a human subject having cancer associated with HER2 overexpression and / or HER2 amplification and / or HER2 mutation(s). In some embodiments, the cell is isolated from a mammal (e.g., a human subject having cancer).

[0232] "Proliferative disease" refers to a disease caused by abnormal growth or abnormal expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be related to: (1) the pathological proliferation of cells that are normally quiescent; (2) the pathological migration of cells from their normal location (e.g., the metastasis of newly formed cells); (3) the pathological expression of proteases such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); and / or (4) pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Non-limiting examples of proliferative diseases include cancer (i.e., "malignant neoplasm"), benign neoplasm, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0233] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with the growth of normal tissue. A neoplasm or tumor can be "benign" or "malignant" depending on, for example, the degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis.

[0234] "Benign neoplasm" is generally well-differentiated, has a characteristically slower growth than malignant neoplasms, and remains localized to the site of origin. In addition, a benign neoplasm does not have the ability to infiltrate, invade, or metastasize to distant sites. Non-limiting examples of benign neoplasms include, but are not limited to, lipoma, chondroma, adenoma, acrochordon, senile angioma, seborrheic keratosis, nevus, and sebaceous hyperplasia.

[0235] In some cases, a benign tumor can give rise to a malignant neoplasm later, which can occur as a result of further genetic changes in a subpopulation of the tumor's tumor cells. Such tumors are referred to as "premalignant neoplasms". An exemplary premalignant neoplasm is teratoma.

[0236] A "malignant neoplasm" generally has a characteristically rapid growth that is poorly differentiated (anaplastic) and is associated with progressive invasion, infiltration, and destruction of surrounding tissues. Furthermore, a malignant neoplasm generally has the ability to metastasize to distant sites. The terms "metastasis", "metastatic", or "metastasize" refer to the spread or migration of cancer cells from a primary tumor or initial tumor to another organ or tissue, and are typically identifiable by the presence of a "secondary tumor" or "secondary cell mass" of the tissue type of the primary tumor or original tumor, which is not of the organ or tissue in which the secondary (metastatic) tumor is located.

[0237] In certain embodiments, the proliferative disorder is cancer. Accordingly, provided herein is a method of treating cancer in a subject (e.g., a subject in need of treating cancer), the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure.

[0238] The term "cancer" refers to a type of disease characterized by the development of abnormal cells that grow uncontrollably and have the ability to invade and destroy normal body tissues.

[0239] A wide variety of cancers, including solid tumors, leukemias, lymphomas, and myelomas, are suitable for the methods disclosed herein. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer includes solid tumors (e.g., colorectal tumors, breast tumors, prostate tumors, lung tumors, pancreatic tumors, kidney tumors, or ovarian tumors). Thus, in some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is selected from one or more of lung cancers, brain cancers (e.g., neuroblastoma, glioblastoma, anaplastic astrocytoma), gastrointestinal cancers, skin cancers, urogenital cancers, head and neck cancers, sarcomas, carcinoids, and neuroendocrine cancers. In various embodiments, the solid tumor cancer is breast cancer, bladder cancer, endometrial cancer, esophageal cancer, liver cancer, pancreatic cancer, lung cancer, cervical cancer, colon cancer, colorectal cancer, gastric cancer, kidney cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, virus-induced cancer, melanoma, or sarcoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In other embodiments, the cancer is liver cancer. In some embodiments, the cancer is sarcoma, bladder cancer, or kidney cancer. In some embodiments, the cancer is prostate cancer (e.g., castration-resistant prostate cancer, castration-sensitive prostate cancer). In other embodiments, the cancer is bladder cancer, pancreatic cancer, colorectal cancer, glioblastoma, kidney cancer, non-small cell lung cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer (e.g., anaplastic thyroid cancer), testicular cancer, or vulvar cancer. In some embodiments, the cancer is endometrial cancer, pancreatic cancer, testicular cancer, kidney cancer, melanoma, colorectal cancer, thyroid cancer, bladder cancer, pancreatic cancer, vulvar cancer, sarcoma, prostate cancer, lung cancer, or anal cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is renal cell carcinoma.

[0240] In some embodiments, the cancer is a non-solid tumor cancer. In some embodiments, the cancer is a blood cancer. Blood cancers that can be treated by the methods described herein include leukemia (e.g., acute leukemia, chronic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma), and multiple myeloma.Non-limiting examples of blood cancers include leukemia (e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), early T-cell precursor (ETP) acute lymphoblastic leukemia, chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large B-cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma, T-cell NHL, e.g., precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF) also known as idiopathic myeloid metaplasia (AMM), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); multiple myeloma (MM); plasmacytoma; familial hypereosinophilia; inflammatory myofibroblastic tumor; and immunocyte amyloidosis.In some embodiments, the blood cancer is selected from multiple myeloma, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, lymphocytic lymphoma, mycosis fungoides, chronic lymphocytic leukemia, chronic lymphocytic leukemia (CLL), mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or myelofibrosis.

[0241] Examples of cancers treatable by the methods described herein include, but are not limited to, adenocarcinoma of the breast, prostate, and colon; all types of bronchogenic carcinoma; myeloid; melanoma (e.g., metastatic melanoma); astrocytoma (e.g., anaplastic astrocytoma); hepatocellular carcinoma; neuroblastoma; papilloma; apudoma; disjunctive tumor; branchial tumor; malignant carcinoid syndrome; carcinoid heart disease; and neoplasms (e.g., Walker carcinoma, basal cell carcinoma, basal squamous cell carcinoma, Brown-Pearce carcinoma, ductal carcinoma, Ehrlich carcinoma, Krebs 2 carcinoma, Merkel cell carcinoma, mucinous carcinoma, lung cancer (e.g., large cell lung cancer, e.g., squamous cell carcinoma, non-small cell lung cancer (NSCLC)), oat cell carcinoma, papillary carcinoma, scirrhous carcinoma, bronchioloalveolar carcinoma, bronchogenic carcinoma, squamous cell carcinoma, and transitional cell carcinoma). Additional examples of cancers treatable by the methods described herein include, but are not limited to, histiocytic disorders; leukemia; malignant histiocytosis; Hodgkin's disease; leukemia; malignant histiocytosis; Hodgkin's disease; hypereosinophilia, immunoproliferative small; non-Hodgkin's lymphoma; plasma cell tumor; reticuloendotheliosis; melanoma (e.g., metastatic melanoma); chondroblastoma; chondroma; chondrosarcoma; fibrous carcinoma (e.g., myelofibrosis), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), kidney cancer, liver cancer, lung cancer (e.g., large cell lung cancer, e.g., squamous cell carcinoma), breast cancer (e.g., inflammatory breast cancer), ovarian cancer (e.g., high-grade serous ovarian cancer), endometrial cancer, uterine cancer, uterine sarcoma (e.g., uterine leiomyosarcoma), renal cell carcinoma, sarcoma (e.g., soft tissue sarcoma), malignant fibrous histiocytoma, fibrosarcoma (e.g., dermatofibrosarcoma protuberans); hepatocellular carcinoma; fibroma; fibrosarcoma; giant cell tumor; histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; pediatric malignant tumors, chordoma; craniopharyngioma; undifferentiated embryonal cell tumor; error tumor; mesenchymal cell tumor; mesonephroma; sarcoma; enamel epithelial tumor; cementoma; odontoma; teratoma; thymoma; trophoblastic tumor.The following additional types of cancer are also intended to be suitable for treatment: adenoma; cholangioma; cholesteatoma; cylindroma; cystadenocarcinoma; cystadenoma; granulosa cell tumor; male and female germ cell tumor; hepatocellular carcinoma, liver cancer; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma; Sertoli cell tumor; theca cell tumor; leiomyoma; leiomyosarcoma; myoblastoma; myoma; myosarcoma; rhabdomyoma; rhabdomyosarcoma; epithelioma; gangliocytoma; glioma; medulloblastoma; meningioma; neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neurogenic tumor; paraganglioma; non-chromaffin paraganglioma. Further examples of cancers treatable by the methods described herein include, but are not limited to, keratoangioma; eosinophilic vasculolymphoid hyperplasia; sclerosing hemangioma; hemangiomatosis; glomus hemangioma; hemangioendothelioma; hemangioma; perivascular cell tumor; hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma; pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes; fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukemia; liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovarian cancer; rhabdomyosarcoma; sarcoma; neoplasm; neurofibromatosis; and cervical dysplasia.

[0242] In certain embodiments, provided herein is a method of treating cancer, the method comprising administering to a subject in need of treating cancer a therapeutically effective amount of a compound described herein. In certain embodiments, the method of treating esophageal gastric cancer, breast cancer, peritoneal cancer, salivary gland cancer, bladder cancer, endometrial cancer, papillary cancer, small intestine cancer, vaginal cancer, cervical cancer, hepatobiliary cancer, ovarian cancer, colorectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer, appendiceal cancer, B-lymphoblastic leukemia / lymphoma, melanoma, germ cell tumor, small cell lung cancer, mature B-cell tumor, prostate cancer, soft tissue sarcoma, or glioma, the method comprising administering to a subject in need of treating esophageal gastric cancer, breast cancer, peritoneal cancer, salivary gland cancer, bladder cancer, endometrial cancer, papillary cancer, small intestine cancer, vaginal cancer, cervical cancer, hepatobiliary cancer, ovarian cancer, colorectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer, appendiceal cancer, B-lymphoblastic leukemia / lymphoma, melanoma, germ cell tumor, small cell lung cancer, mature B-cell tumor, prostate cancer, soft tissue sarcoma, or glioma a therapeutically effective amount of a compound described herein. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is NSCLC.

[0243] HPV-related cancers are also treatable by the methods described herein. Non-limiting examples of HPV-related cancers include cervical cancer, oropharyngeal cancer, anal cancer, vulvar / vaginal cancer, and penile cancer.

[0244] Liver cancers, such as hepatocellular cancer (HCC) (e.g., hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangioma, and biliary tract cancers (e.g., cholangiocarcinoma) are also treatable by the methods described herein.

[0245] Cancers of the musculoskeletal system can also be treated by the methods described herein. Non-limiting examples of cancers of the musculoskeletal system include bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing's sarcoma, chordoma, malignant giant cell tumor, chordoma, chondrosarcoma, osteochondroma, benign chondroma, chondroblastoma, chondromyxoid fibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, and synovial tumors.

[0246] Cancers of the nervous system can also be treated by the methods described herein. Non-limiting examples of cancers of the nervous system include brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastoma, glioblastoma multiforme, medulloblastoma, ependymoma, germ cell tumor (i.e., pineal tumor), oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, craniopharyngioma), spinal cord cancer, neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroblastoma, primitive neuroectodermal tumor (PNT), meningiomatosis (e.g., meningioma, meningiosarcoma, gliomatosis), skull cancer, acoustic neuroma, ependymoma, hemangioblastoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), pleomorphic xanthoastrocytoma (PXA), and pediatric PXA.

[0247] Endocrine / exocrine cancers can also be treated by the methods described herein. Non-limiting examples of endocrine / exocrine cancers include thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor, tubular adenocarcinoma, insulinoma, glucagonoma, VIPoma), adrenal cancer, neuroendocrine cancer (e.g., gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), sebaceous adenocarcinoma, and sweat gland cancer (e.g., sweat gland carcinoma).

[0248] Head and neck cancers, such as head and neck squamous cell carcinoma (SCCHN) and adenoid cystic carcinoma, can also be treated by the methods described herein.

[0249] Oral cancers, such as buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, hypopharynx cancer (e.g., hypopharyngeal carcinoma), laryngeal cancer (e.g., laryngeal carcinoma, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), and salivary gland cancer can also be treated by the methods described herein.

[0250] Esophageal cancers, such as esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett's adenocarcinoma, and esophageal leiomyosarcoma can also be treated by the methods described herein.

[0251] Digestive tract cancers can also be treated by the methods described herein. Non-limiting examples of digestive tract cancers include anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gallbladder cancer, gastric cancer (e.g., stomach cancer (e.g., gastric adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendiceal cancer, small bowel carcinoma (e.g., small bowel adenocarcinoma)), small intestine cancer, large bowel cancer, and large intestine cancer.

[0252] Cardiovascular cancers can also be treated by the methods described herein. Non-limiting examples of cardiovascular cancers include primary cardiac tumors, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangioendothelioma), endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), left atrial myxoma, and cardiac rhabdomyoma.

[0253] Lung cancers can also be treated by the methods described herein. Non-limiting examples of lung cancers include bronchial cancer (e.g., bronchogenic lung cancer, bronchial adenoma), alveolar adenocarcinoma, mesothelioma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, chondroid hamartoma, and papillary adenocarcinoma.

[0254] Genitourinary cancers are also treatable by the methods described herein. Non-limiting examples of genitourinary cancers include bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., nephroblastoma, also known as Wilms tumor, renal cell carcinoma), testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell carcinoma, prostate cancer (e.g., prostatic adenocarcinoma), and penile cancer (e.g., Paget's disease of the penis and scrotum).

[0255] Gynecological cancers are also treatable by the methods described herein. Non-limiting examples of gynecological cancers include breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer, triple-negative breast cancer, HER-2 positive breast cancer, HER2 negative breast cancer), endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial cancer), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell carcinoma, and vulvar cancer (e.g., Paget's disease of the vulva), vaginal cancer, and fallopian tube cancer.

[0256] Skin cancers are also treatable by the methods described herein. Non-limiting examples of skin cancers include squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), and dermatofibroma.

[0257] Soft tissue cancers, such as intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, and teratomas are also treatable by the methods described herein.

[0258] Myeloproliferative tumors are also treatable by the methods described herein. Non-limiting examples of myeloproliferative tumors include myelofibrosis, polycythemia vera, and essential thrombocythemia.

[0259] Fibrous cancer can also be treated by the methods described herein. As used herein, "fibrous cancer" is cancer with fibrosis. Fibrosis can precede cancer or the treatment of cancer in fibrous cancer (e.g., can be the cause of cancer or the treatment of cancer), or can occur after them (e.g., can be caused by them). Additionally or alternatively, fibrosis can co-exist with cancer in fibrous cancer. Non-limiting examples of fibrous cancer include myelofibrosis, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), kidney cancer, liver cancer, lung cancer (e.g., large cell lung cancer, e.g., squamous cell carcinoma), breast cancer (e.g., inflammatory breast cancer), ovarian cancer (e.g., high-grade serous ovarian cancer), endometrial cancer, uterine cancer, uterine sarcoma (e.g., uterine leiomyosarcoma), renal cell cancer, sarcoma (e.g., soft tissue sarcoma), malignant fibrous histiocytoma, fibrosarcoma (e.g., dermatofibrosarcoma protuberans), gastric cancer, esophageal cancer, head and neck cancer, cervical cancer, vulvar cancer, and hepatocellular cancer (e.g., hepatocellular carcinoma). In some embodiments, fibrous cancer is solid tumor cancer (e.g., kidney cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, and / or pancreatic cancer). In some embodiments, fibrous cancer is a cancer tumor of internal organs (e.g., pancreas, lung, kidney, liver).

[0260] Additional examples of cancers treatable by the methods described herein include, but are not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenocortical carcinoma; pediatric adrenocortical carcinoma; AIDS-related cancers (e.g., Kaposi's sarcoma, AIDS-related lymphoma, primary central nervous system lymphoma); anal cancer; anal carcinoma; appendiceal cancer; pediatric astrocytoma; pediatric central nervous system (CNS) atypical teratoid / rhabdoid tumor; CNS neoplasms (e.g., primary central nervous system lymphoma, spinal cord tumors, medulloblastoma, brainstem glioma, or pituitary adenoma), Barrett's esophagus (e.g., pre-malignant syndrome), and fungating polypoid tumors, basal cell carcinoma of the skin; bile duct cancer; bladder cancer; pediatric bladder cancer; bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma); brain tumor / cancer; breast cancer; Burkitt lymphoma; carcinoid tumor (gastrointestinal); pediatric carcinoid tumor; pediatric heart tumor (cardiac tumor); pediatric germinoma; pediatric embryonal cell tumor; primary central nervous system lymphoma; cervical cancer; pediatric cervical cancer; bile duct cancer; pediatric chordoma; chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); chronic myeloproliferative tumor; colorectal cancer; pediatric colorectal cancer; pediatric craniopharyngioma; cutaneous T-cell lymphoma (e.g., fungating polypoid tumors and Sézary syndrome); ductal carcinoma in situ (DCIS); pediatric central nervous system germinoma; endocrine cancers (e.g., thyroid, pancreas, parathyroid, or adrenal cancer), endometrial cancer (uterine cancer); pediatric ependymoma; esophageal cancer; pediatric esophageal cancer; neuroepithelial tumors; Ewing's sarcoma; pediatric extracranial embryonal cell tumor; extragonadal embryonal cell tumor; eye cancer; pediatric intraocular melanoma; intraocular melanoma; retinoblastoma; fallopian tube cancer; malignant fibrous histiocytoma and osteosarcoma of bone; gallbladder cancer; gastric cancer (gastric cancer); pediatric gastric cancer (gastric cancer); gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); pediatric gastrointestinal stromal tumor; germ cell tumor; pediatric central nervous system germ cell tumor (e.g., pediatric extracranial embryonal cell tumor, extragonadal embryonal cell tumor, ovarian germ cell tumor, testicular cancer); gestational trophoblastic disease; gynecologic tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), hairy cell leukemia; head and neck cancer; pediatric heart tumor; hepatocellular carcinoma (liver cancer); Langerhans cell histiocytosis; Hodgkin lymphoma; hypopharyngeal cancer; cutaneous melanoma or intraocular melanoma; pediatric intraocular melanoma;Islet cell tumor, pancreatic neuroendocrine tumor; Kaposi's sarcoma; kidney (renal cell) cancer; Langerhans cell histiocytosis; laryngeal cancer; leukemia; lip and oral cavity cancer; liver cancer; lung cancer (non-small cell and small cell); pediatric lung cancer; lymphoma; male breast cancer; malignant fibrous histiocytoma and osteosarcoma of bone; melanoma; pediatric melanoma; intraocular melanoma (uveal melanoma); pediatric intraocular melanoma; Merkel cell carcinoma; malignant mesothelioma; pediatric mesothelioma; metastatic cancer; metastatic squamous neck cancer of unknown primary; midline carcinoma with NUT gene alteration; oral cancer; multiple endocrine neoplasia syndrome; multiple myeloma / plasma cell neoplasm; fungating polyp; myelodysplastic syndrome, myelodysplastic neoplasm / myeloproliferative neoplasm; chronic myelogenous leukemia (CML); acute myelogenous leukemia (AML); chronic myeloproliferative neoplasm; nasal and paranasal cavity cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin lymphoma; non-small cell lung cancer; oral cancer, lip and oral cavity cancer, and oropharyngeal cancer; osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer; pediatric ovarian cancer; pancreatic cancer; pediatric pancreatic cancer; pancreatic neuroendocrine tumor; papillomatosis (juvenile laryngeal papillomatosis); paraganglioma; pediatric paraganglioma; paranasal cavity and nasal cancer; parathyroid cancer; penile cancer; pharyngeal cancer; pheochromocytoma; pediatric pheochromocytoma; pituitary tumor; plasma cell neoplasm / multiple myeloma; pleuropulmonary blastoma; breast cancer during pregnancy; primary central nervous system (CNS) lymphoma; primary peritoneal cancer; prostate cancer; rectal cancer; recurrent cancer; renal cell (kidney) cancer; retinoblastoma; pediatric rhabdomyosarcoma; salivary gland cancer; sarcoma (e.g., pediatric rhabdomyosarcoma, pediatric hemangioma, Ewing sarcoma, Kaposi's sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma); Sézary syndrome; skin cancer; pediatric skin cancer; small cell lung cancer; small intestine cancer; soft tissue sarcoma; squamous cell carcinoma of the skin; metastatic squamous neck cancer of unknown primary; stomach cancer (gastric cancer); pediatric stomach cancer (gastric cancer); cutaneous T-cell lymphoma (e.g., fungating polyp and Sézary syndrome); testicular cancer; pediatric testicular cancer; throat cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer); thymoma and thymic carcinoma; thyroid cancer; transitional cell carcinoma of the renal pelvis and ureter; ureter and renal pelvis (e.g., renal cell cancer, renal pelvic cancer), benign prostatic hyperplasia, parathyroid cancer, transitional cell carcinoma; urethral cancer; uterine (endometrial) cancer; uterine sarcoma; vaginal cancer; pediatric vaginal cancer; hemangioma; vulvar cancer;And Wilms' tumor and other pediatric kidney tumors are included;

[0261] Metastases of the cancers described above can also be treated by the methods described herein. Thus, in some embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is a pre-metastatic cancer.

[0262] In certain embodiments, the cancer is a rare cancer. The term "rare cancer" refers to a cancer that occurs in a relatively small number of patients.

[0263] In some embodiments, a proliferative disorder such as cancer (e.g., fibrotic cancer) is treated by targeting tumor stromal cells (e.g., in the tumor microenvironment), such as cancer-associated fibroblasts (CAFs), astrocytes, or myofibroblasts and / or immune cells (e.g., tumor-associated immune cells, e.g., in the tumor immune microenvironment), e.g., by modulating the tumor stromal microenvironment and / or the tumor immune microenvironment.

[0264] Also provided herein is a method for targeting tumor stromal cells or immune cells (e.g., tumor-associated immune cells) and / or modulating (e.g., normalizing) the tumor microenvironment (e.g., the tumor stromal microenvironment and / or the tumor immune microenvironment) in vivo or in vitro, the method comprising contacting the tumor stromal cells or immune cells (e.g., tumor-associated immune cells) with a compound of the disclosure. In certain embodiments, the inhibition occurs in vivo in a subject. In certain embodiments, the inhibition occurs in vitro (e.g., in a cell line, tissue, or biological sample). In certain embodiments, the tumor stromal cells are cancer-associated fibroblasts (CAFs), astrocytes, or myofibroblasts.

[0265] While not wishing to be bound by any particular theory, it is believed that certain compounds can normalize the tumor microenvironment, thereby improving vascular perfusion and drug delivery. Enhanced drug delivery is expected to enhance the effectiveness of drugs, such as immunomodulatory agents (e.g., immuno-oncology agents) including any of the immunomodulatory agents described herein. Accordingly, provided herein are methods for modulating (e.g., normalizing) the tumor microenvironment (e.g., the tumor stromal microenvironment and / or the tumor immune microenvironment) in vivo or in vitro, the method comprising contacting the tumor with a compound of the disclosure.

[0266] Also provided herein is a method of inhibiting viral infection and / or viral replication in a subject in need thereof, the method comprising administering to the subject an effective amount (e.g., a therapeutically effective amount, a prophylactically effective amount) of a compound of the disclosure.

[0267] The compounds of the disclosure can be administered as monotherapy or as part of combination therapy with other therapeutic agents and / or therapies as described herein. Accordingly, in some embodiments, the methods described herein further comprise administering to the subject one or more additional therapies (e.g., one or more additional therapeutic agents). The compounds of the disclosure and the additional therapy(ies) can be co-administered, for example, simultaneously or substantially simultaneously. The compounds of the disclosure and the additional therapy(ies) can also or alternatively be administered sequentially at approximately the same time or at different times. For example, the compounds of the disclosure can be administered before the additional therapy(ies). Or the compounds of the disclosure can be administered after the additional therapy(ies). Suitable additional therapies for use in the methods disclosed herein include those described herein in the context of combinations.

[0268] Therapeutic agents (e.g., the compounds of the present disclosure) and pharmaceutical compositions thereof can be administered by various routes of administration, including, depending on the compound and the particular disease being treated, for example, oral administration route, feed administration route, topical administration route, transdermal administration route, rectal administration route, parenteral administration route (e.g., intraarterial, intravenous, intramuscular, subcutaneous injection, intradermal injection), intravenous infusion administration route, and inhalation administration route (e.g., intratracheal, intranasal, or oral inhalation, intranasal instillation). Administration can be local or systemic, as needed. The preferred mode of administration can vary depending on the particular compound selected. In some embodiments, the therapeutic agent (e.g., the compounds of the present disclosure) is administered orally. In some embodiments, the therapeutic agent (e.g., the compounds of the present disclosure) is administered intravenously.

[0269] Combination therapy The term "combination therapy" refers to the administration of two or more therapeutic agents for treating a disease, disorder, or condition described herein. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, e.g., in a single capsule having a defined ratio of active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (e.g., capsules, powders, and liquids) for each active ingredient. Such administration also includes sequential use of the various therapeutic agents, either at approximately the same time or at different times. The therapeutic agents in combination therapy can be administered by the same route of administration or different routes of administration. Powders and / or liquids can be reconstituted or diluted to the desired dose prior to administration. Usually, the treatment regimen provides a beneficial effect of the drug combination in the treatment of the conditions or disorders described herein.

[0270] Therapies used in combination with the compounds of the present disclosure may include agents known to modulate one or more of other pathway(s) other than the pathway(s) modulated by the compounds of the present disclosure, other component(s) (e.g., enzyme) of the same pathway as the pathway modulated by the compounds of the present disclosure, or even the same target (e.g., target enzyme(s)) as the target modulated by the compounds of the present disclosure. In one aspect, the combination therapy may include, for example, a compound of the present disclosure, as well as chemotherapeutic agents, immunomodulators, and / or radiation therapy, to provide a synergistic or additive therapeutic effect.

[0271] Examples of therapies used in combination with the compounds of the present disclosure (e.g., in combination therapy, in a drug combination) include standard therapies and / or standard treatment regimens (e.g., standard treatment drugs), such as first-line standard therapy (e.g., chemotherapy), intermediate second-line standard therapy (e.g., chemotherapy), or last-line standard therapy (e.g., chemotherapy). Standard treatment is the therapy that a clinician should use for a particular type of patient, disease, and / or clinical condition. In many cases, organizations such as the National Comprehensive Cancer Network (NCCN) publish guidelines and / or treatment algorithms that describe the best practices for treating a particular patient, disease, and / or clinical condition. See nccn.org. These guidelines often define, describe, and / or summarize standard treatment.

[0272] In some embodiments, a method of treating or preventing cancer may include administering a compound of formula (I), (I-i), (I-i-a), (I-i-a1), (I-i-a2), (a-I), (II), or (III), or any of the embodiments thereof disclosed herein, in combination with one or more other chemotherapeutic agent(s).

[0273] In some embodiments, one or more immunomodulatory agents can be used in combination with the compounds of the present disclosure. Non-limiting examples of immunomodulatory agents (e.g., immuno-oncology agents) include: afucosylated antibodies (available from ROCHE®); pegfilgrastim (NEULASTA®); lenalidomide (CC-5013, REVLIMID®); thalidomide (THALOMID®); actimid (CC4047); and IRX-2 (a mixture of human cytokines including interleukin 1, interleukin 2, and interferon γ, CAS 951209-71-5, available from IRX Therapeutics).

[0274] In certain embodiments, the immunomodulatory agent is a chimeric antigen receptor T cell (CAR-T) therapy, such as tisagenlecleucel (Novartis), axicabtagene ciloleucel (Kite), and tocilizumab (Actemra; Roche).

[0275] In certain embodiments, the immunomodulatory agent is an immune checkpoint inhibitor, such as a PD-1 inhibitor, a PD-L1 inhibitor, a cytotoxic T lymphocyte associated modulator (e.g., a CTLA-4 inhibitor), a LAG-3 inhibitor, a TIM-3 inhibitor.

[0276] In certain embodiments, the immunomodulatory agent is a PD-1 inhibitor, such as pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®) and other anti-PD-1 antibodies (disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2):134-44, US8,354,509, and WO2009 / 114335, which are incorporated by reference in their entirety), nivolumab (also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®) and other anti-PD-1 antibodies (US8,008,449 and those disclosed in WO2006 / 121168 (which are incorporated herein by reference in their entirety), also known as semi-primab (LIBTAYO (registered trademark)), sintilimab, spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), dostarlimab (TSR-042), PF-06801591 (Pfizer), sintilimab, tripalizumab, tislelizumab (BGB-A317), camrelizumab (INCSHR1210, SHR-1210), AMP-224 (Amplimmune), CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IBI308 (Innovent Biologics), SHR-1210 (Hengrui Medicine) also known as INCSHR1210 (Incyte), BGBA317 (Beigene), BGB-108 (Beigene), BAT-I306 (Bio-Thera Solutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologics; Hanzhong Biologics), LZM009 (Livzon), HLX-10 (Henlius Biotech), MEDI0680 (Medimmune), PDF001 (Novartis), PF-06801591 (Pfizer), pidilizumab (CureTech) also known as CT-011 and other anti-PD-1 antibodies (Rosenblatt, J. et al. (2011) J Immunotherapy 34(5):409-18, US7,695,715, US 7,332,582, and US8,686,119 (all of which are incorporated by reference), REGN2810 (Regeneron), as well as TSR-042 (Tesaro), also known as ANB011, or CS1003 (CStone Pharmaceuticals). MEDI0680 (Medimmune) is also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US9,205,148 and WO2012 / 145493 (all of which are incorporated by reference). Further known anti-PD-1 antibody molecules include, for example, those described in WO2015 / 112800, WO2016 / 092419, WO2015 / 085847, WO2014 / 179664, WO2014 / 194302, WO2014 / 209804, WO2015 / 200119, US8,735,553, US7,488,802, US8,927,697, US8,993,731, and US9,102,727 (all of which are incorporated by reference). In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule described in US2015 / 0210769 entitled "Antibody Molecules to PD-1 and Uses Thereof" published on July 30, 2015 (the whole of which is incorporated by reference). In one embodiment, the anti-PD-1 antibody molecule comprises the CDRs, variable regions, heavy chains, and / or light chains of BAP049-Clone-E or BAP049-Clone-B disclosed in US2015 / 0210769. The antibody molecules described herein can be produced by the vectors, host cells, and methods described in US2015 / 0210769 (the whole of which is incorporated by reference). In one embodiment, the PD-1 inhibitor is, for example, US8,907,A peptide that inhibits the PD-1 signaling pathway as described in 053 (which is incorporated by reference in its entirety). In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular portion of PD-L1 or PD-L2 or a PD-1 binding portion fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224 (e.g., B7-DCIg (Amplimmune) disclosed in WO2010 / 027827 and WO2011 / 066342 (which are incorporated by reference in their entirety).

[0277] In certain embodiments, the immunomodulatory agent is a PD-L1 inhibitor, such as atezolizumab (MPDL3280A, RG7446, RO5541267, YW243.55.S70, or also known as TECENTRIQ®) and other anti-PD-L1 antibodies disclosed in US8,217,149, which is incorporated by reference in its entirety, avelumab (BAVENCIO®, also known as MSB0010718C) and other anti-PD-L1 antibodies disclosed in WO2013 / 079174, which is incorporated by reference in its entirety, durvalumab (IMFINZI® or MEDI4736) and other anti-PD-L1 antibodies disclosed in US8,779,108, which is incorporated by reference in its entirety, FAZ053 (Novartis), and BMS-936559 (Bristol-Myers Squibb). In certain embodiments, the PD-L1 inhibitor is KN035 (Alphamab; 3DMed; Ascletis Pharma), enobafolimab (TRACON Pharmaceuticals), BMS 936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals, Ligand Pharmaceuticals), CX-072 (CytomX Therapeutics), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STI-A1014 (Zhaoke Pharm; Lee’s Pharm, Lonza, Sorrento Therapeutics, NantWorks), LYN00102 (Lynkcell), A167 (Harbour BioMed, Kelun Group), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences), or HLX-20 (Henlius Biotech). In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (Bristol-Myers Squibb), also known as MDX-1105 or 12A4.BMS-936559 and other anti-PD-L1 antibodies are disclosed in US7,943,743 and WO2015 / 081158 (which are incorporated by reference in their entirety). In certain embodiments, the PD-L1 inhibitor is cobelimumab (Fortress Biotech), LY3300054 or rodapolimab (Eli Lilly), GS-4224 (Gilead Sciences), STI-A1015 (Yuhan, Sorrento Therapeutics), BCD-135 (BIOCAD), cobelimumab (Dana-Farber Cancer Institute, TG Therapeutics), APL-502 (Apollomics), AK106 (Akeso Biopharma), MSB2311 (Transcenta Holding), TG-1501 (TG Therapeutics), or FAZ053 (Novartis). In certain embodiments, the PD-L1 inhibitor is MT-6035 (Molecular Templates), icariin or ZKAB001 (Lonza, Lee’s Pharmaceutical Holdings, Sorrento Therapeutics, Shenogen Pharma Group), TRIDENT antibody (MacroGenics, Zai Lab), YBL-007 (Anh-Gook Pharmaceutical, Y-Biologics), HTI-1316 (Hengrui Therapeutics), PD-L1 Oncology Project (Weizmann Institute of Sciences), JS003 (Shanghai Junshi Biosciences), ND021 (Numab Therapeutics, CStone Pharmaceuticals), Toca 521 (Tocagen), or STT01 (STCube). In certain embodiments, the PD-L1 inhibitor is DB004 (DotBio), MT-5050 (Molecular Templates), KD036 (Kadmon). In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule.In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule disclosed in US2016 / 0108123 entitled "Antibody Molecules to PD-L1 and Uses Thereof" published on April 21, 2016 (incorporated by reference in its entirety). In one embodiment, the anti-PD-L1 antibody molecule comprises the CDRs, variable regions, heavy chains, and / or light chains of BAP058-Clone O or BAP058-Clone N disclosed in US2016 / 0108123 (incorporated by reference in its entirety). Further known anti-PD-L1 antibodies include, for example, those described in WO2015 / 181342, WO2014 / 100079, WO2016 / 000619, WO2014 / 022758, WO2014 / 055897, WO2015 / 061668, WO2013 / 079174, WO2012 / 145493, WO2015 / 112805, WO2015 / 109124, WO2015 / 195163, US8,168,179, US8,552,154, US8,460,927, and US9,175,082 (incorporated by reference in their entirety).

[0278] In certain embodiments, the immunomodulatory agent is a CTLA-4 inhibitor, such as ipilimumab (YERVOY®), tremelimumab, ALPN-202 (Alpine Immune Sciences), RP2 (Replimune), BMS-986249 (Bristol-Myers Squibb), BMS-986218 (Bristol-Myers Squibb), zalifrelimab (Agenus, Ludwig Institute for Cancer Research, UroGen Pharma, Recepta Biopharma), BCD-217 (BIOCAD), Onc-392 (Pfizer, OncoImmune), IBI310 (Innovent Biologics), KN046 (Alphamab), MK-1308 (Merck & Co), REGN4659 (Regeneron Pharmaceuticals), XmAb20717 (Xencor), XmAb22841 (Xencor), anti-CTLA-4 NF (Bristol-Myers Squibb), MEDI5752 (AstraZeneca), AGEN1181 (Agenus), MGD019 (MacroGenics), ATOR-1015 (Alligator Bioscience), BCD-145 (BIOCAD), PSB205 (Sound Biologics), CS1002 (CStone Pharmaceuticals), ADU-1604 (Aduro Biotech), PF-06753512 (Pfizer), BioInvent-Transgene Research Program (Transgene), AGEN2041 (Agenus, Recepta Biopharam), ATOR-1144 (Alligator Bioscience), CTLA-4 Research Project (Sorrento Therapeutics), PD-L1 / CTLA-4 Research Project (Sorrento Therapeutics), HLX13 (Shanghai Henlius Biotech), ISA203 (ISA Pharmaceuticals), PRS-300 series A (PierisPharmaceuticals), BA3071 (BioAtla), CTLA4 Cancer Research Program (Biosortia Pharmaceuticals), RP3 (Replimune), CG0161 (Cold Genesys), APL-509 (Apollomics, JSR), AGEN2041 (Ludwig Institute for Cancer Research), APC 101 (Advanced Proteome), CTLA-4 inhibitor (Advanced Proteome), BA3071 (BeiGene), BPI-002 (BeyondSpring Pharmaceuticals), CTLA-4 antibody (Tikcro Technologies), Immuno-Oncology Research Program II (OliPass), PBP1701 (Prestige BioPharma), DB002 (DotBio), DB003 (DotBio), OR-2299 (OncoResponse), and NK044 (Alphamab).

[0279] In some embodiments, the immunomodulatory agent is a LAG-3 inhibitor, such as LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), and TSR-033 (Tesaro). In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is the anti-LAG-3 antibody molecule disclosed in US2015 / 0259420, entitled "Antibody Molecules to LAG-3 and Uses Thereof", published on September 17, 2015, which is incorporated by reference in its entirety. In one embodiment, the anti-LAG-3 antibody molecule comprises the CDRs, variable regions, heavy chains, and / or light chains of BAP050-Clone I or BAP050-Clone J disclosed in US2015 / 0259420. In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (Bristol-Myers Squibb), also known as BMS986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO2015 / 116539 and US9,505,839, which are incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781 (GSK and Prima BioMed). IMP731 and other anti-LAG-3 antibodies are disclosed in WO2008 / 132601 and US9,244,059, which are incorporated by reference in their entirety. In one embodiment, the anti-LAG-3 antibody molecule is IMP761 (Prima BioMed). Further known anti-LAG-3 antibodies include, for example, those described in WO2008 / 132601, WO2010 / 019570, WO2014 / 140180, WO2015 / 116539, WO2015 / 200119, WO2016 / 028672, US9,244,059, US9,505,839, which are incorporated by reference in their entirety.In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, for example, IMP321 (Prima BioMed) disclosed in WO2009 / 044273, which is incorporated by reference in its entirety.

[0280] In some embodiments, the immunomodulatory agent is a TIM-3 inhibitor, for example, MGB453 (Novartis) and TSR-022 (Tesaro). In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule disclosed in US2015 / 0218274 entitled "Antibody Molecules to TIM-3 and Uses Thereof", published on August 6, 2015, which is incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule comprises the CDRs, variable regions, heavy chains, and / or light chains of ABTIM3-hum11 or ABTIM3-hum03 disclosed in US2015 / 0218274 (which is incorporated by reference in its entirety). In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more (or collectively all) of the CDR sequences of APE5137 or APE5121, the heavy or light chain variable region sequences, or the heavy or light chain sequences. APE5137, APE5121, and other anti-TIM-3 antibodies are disclosed in WO2016 / 161270, which is incorporated by reference in its entirety. In one embodiment, the anti-TIM-3 antibody molecule is the antibody clone F38-2E2. Further known anti-TIM-3 antibodies include, for example, those described in WO2016 / 111947, WO2016 / 071448, WO2016 / 144803, US8,552,156, US8,841,418, and US9,163,087, which are incorporated by reference in their entireties.

[0281] In some embodiments, platinum analogs can be used in combination with the compounds of the present disclosure. In certain embodiments, platinum analogs (e.g., cisplatin, paclitaxel, carboplatin) and combination therapies comprising platinum analogs (e.g., docetaxel and carboplatin; paclitaxel and carboplatin; carboplatin and liposomal doxorubicin (dox)) can be used in combination with the compounds of the present disclosure.

[0282] In some embodiments, exemplary chemotherapeutic agents that can be co-administered with the compounds of the present disclosure include the following: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, ado-trastuzumab emtansine, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (BCG), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxybirudin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, fam-trastuzumab deruxtecan, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea,Idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonaporphyrin, topotecan, trametinib, trastuzumab, tretinoin, verubecestat, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be co-administered with the compounds of the present disclosure include the following: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that can be co-administered with the compounds of the present disclosure include the following: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,1-Amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, suramin, and tonaporfirin.,

[0283] Numerous combination therapies for the treatment of cancer have been developed. In certain embodiments, the compounds of the present disclosure (e.g., compounds of formula (I) or (II) or (III)) can be co-administered with one or more combination therapies. Examples of combination therapies with which the compounds of the present disclosure can be co-administered are included below. [Table 1] TIFF0007696443000210.tif233165TIFF0007696443000211.tif236165TIFF0007696443000212.tif233165TIFF0007696443000213.tif230165TIFF0007696443000214.tif229165TIFF0007696443000215.tif83165

[0284] In certain embodiments, the combination therapies of the present disclosure include co - administration with other types of chemotherapeutic agents, such as tumor immunotherapeutic agents. Cancer cells often have specific cell - surface antigens that can be recognized by the immune system. Thus, tumor immunotherapeutic agents, such as monoclonal antibodies, can selectively bind to cancer - cell antigens and cause cell death. Other tumor immunotherapeutic agents can inhibit the inhibition of the innate immune response mediated by tumors or otherwise activate the immune response, thereby promoting the recognition of tumors by the immune system. Exemplary tumor immunotherapeutic antibody drugs include, but are not limited to, abagovomab, adecatumumab, afucosylated anti - HER2 antibody, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS - 936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelmab, ipilimumab, isatuximab, lanbritumomab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, orlatumumab, pembrolizumab, pidilizumab, rituximab, tislelizumab, samalizumab, and tremelimumab. In some embodiments, the tumor immunotherapeutic antibody drug is selected from anti - CD73 monoclonal antibody (mAb), anti - CD39 mAb, anti - PD - 1 mAb, and anti - CTLA4 mAb. Thus, in some embodiments, the methods of the present disclosure include co - administration of one or more tumor immunotherapeutic agents, such as the agents described above.

[0285] In some embodiments, the combination therapy includes co - administration of a compound of the present disclosure, such as a compound of formula (I) or (II) or (III), with an SH2 inhibitor, such as CGP78850, CPG85793, C90, C126, G7 - 18NATE, G7 - B1, and NSC642056.

[0286] In some embodiments, the combination therapy includes co - administration of a compound of the present disclosure, such as a compound of formula (I) or (II) or (III), with a MEK inhibitor, such as trametinib, cobimetinib, binimetinib, selumetinib, PD - 325901, CI - 1040, and TAK - 733.

[0287] In some embodiments, the combination therapy comprises co - administration of a compound of the present disclosure, e.g., a compound of formula (I) or (II) or (III), with a MET inhibitor selected from JNJ - 38877605, PF - 04217903, foretinib, AMG458, cibantinib, cabozantinib, capmatinib hydrochloride, tepotinib hydrochloride, savolitinib, and crizotinib.

[0288] In some embodiments, the combination therapy comprises co - administration of a compound of the present disclosure, such as a compound of formula (I) or (II) or (III), with an SHP2 inhibitor selected from TNO - 155, RMC - 4630, JAB - 3068, or RLY - 1971.

[0289] In some embodiments, an ataxia - telangiectasia mutated (ATM) kinase inhibitor can be used in combination with a compound of the present disclosure. Non - limiting examples of ATM inhibitors include M - 4076 and AZD - 1390.

[0290] In some embodiments, the combination therapy comprises co - administration of a compound of the present disclosure with an EGFR inhibitor selected from osimertinib, gefitinib, erlotinib, afatinib, or dacomitinib.

[0291] In some embodiments, the combination therapy comprises co - administration of a compound of the present disclosure with a RAS inhibitor selected from aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0292] In some embodiments, the combination therapy comprises co - administration of a compound of the present disclosure with anti - PD - 1 therapy. In certain embodiments, the combination therapy comprises co - administration of a compound of the present disclosure with oxaliplatin. In other embodiments, the combination therapy comprises co - administration of a compound of the present disclosure with doxorubicin.

[0293] In certain embodiments, the compounds of the disclosure can be co-administered with non-chemical cancer therapies. In certain embodiments, the compounds of the disclosure can be co-administered with radiation therapy. In certain embodiments, the compounds of the disclosure can be co-administered with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0294] In some cases, it may be advantageous to administer the compounds of the disclosure in combination with one or more additional therapeutic agents(s). For example, for treating cancer, the compounds of the disclosure (e.g., a compound of formula I or a sub-formula thereof, or a pharmaceutically acceptable salt of the foregoing) can be advantageously administered in combination with one or more additional therapeutic agents independently selected from, for example, anti-cancer agents (e.g., chemotherapeutic agents), anti-allergy agents, anti-emetic agents, analgesics, immunomodulators, and cytoprotective agents.

[0295] In some embodiments, the compounds of the present disclosure are administered in combination with radiation therapy. Non-limiting examples of radiation therapy include external beam radiotherapy, brachytherapy, interstitial radiotherapy, stereotactic radiotherapy, total body radiotherapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially confined radioactive material inserted into or near a tumor site or other proliferative tissue disease site in the body. This term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, and radioisotopes of Lu). Radiation sources suitable for use as cell conditioners include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I125, I131, Yb169, Ir192 as a solid source, I125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material can be a liquid made from a solution of any radionuclide(s), such as a solution of I125 or I131, or the radioactive liquid can be manufactured using a suitable liquid slurry containing small particles of a solid radionuclide such as Au198, Y90, etc. Further, the radionuclide(s) can be incorporated into a gel or radioactive microspheres.

[0296] The compounds of the present disclosure can be effective in sensitizing abnormal cells to radiation therapy. Accordingly, provided herein is a method for sensitizing abnormal cells in a subject (e.g., a subject in need of sensitizing abnormal cells to treatment with radiation) to treatment with radiation, the method comprising administering to the subject an effective amount of a compound of the present disclosure effective to sensitize the abnormal cells to treatment with radiation. The amount of a compound of the present disclosure effective to sensitize abnormal cells to treatment with radiation can be determined by one of ordinary skill in the art, for example, according to the means for determining an effective amount described herein.

[0297] In some embodiments, the standard of care includes radiation therapy.

[0298] DNA damaging agents can also be used in combination with the compounds of the present disclosure. As used herein, "DNA damaging agent" refers to any agent that directly or indirectly damages DNA such that the damage can be repaired by homologous recombination. Non-limiting examples of DNA damaging agents are DNA damaging substances, chemotherapeutic agents, radiochemotherapy, and ionizing or ultraviolet radiation. Non-limiting examples of DNA damaging chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, plant alkaloids, plant extracts, and radioisotopes.Non-limiting examples of DNA-damaging chemotherapeutic agents include DNA-damaging agents such as 5-fluorouracil (5-FU), capecitabine, gemcitabine, temozolomide, S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid), 5-ethynyluracil, arabinosylcytosine (ara-C), 5-azacytidine (5-AC), 2’,2’-difluoro-2’-deoxycytidine (dFdC), purine antimetabolites (e.g., mercaptopurine, azathioprine, thioguanine), gemcitabine hydrochloride (Gemzar), pentostatin, allopurinol, 2-fluoro-arabinosyladenine (2F-ara-A), hydroxyurea, sulfamustard (bis(2-chloroethyl)sulfide), mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, AZQ, mitomycin C, dianhydrogalactitol, dibromodulcitol, alkyl sulfonates (busulfan), nitrosoureas (BCNU, CCNU, 4-methyl CCNU, or ACNU), procarbazine, dacarbazine, rebeccamycin, anthracyclines such as doxorubicin (adriamycin; ADR), daunorubicin (cerubidine), idarubicin (idarubicin), and epirubicin (Ellence), anthracycline analogs such as mitoxantrone, actinomycin D, topoisomerase inhibitors (e.g., non-intercalating topoisomerase inhibitors such as epipodophyllotoxins (etoposide or VP16, teniposide or VM-26)), PARP inhibitors, podophyllotoxin, bleomycin (Blea), peplomycin, compounds that form adducts with nucleic acids such as platinum derivatives such as cisplatin (CDDP), trans analogs of cisplatin, carboplatin, iproplatin, tetraplatin, and oxaliplatin, and camptothecin, topotecan, irinotecan (CPT-11), and SN-38. Radiation such as ultraviolet (UV), infrared (IR), or alpha, beta, or gamma radiation is also a DNA-damaging agent.

[0299] In some embodiments, the standard treatment includes a DNA-damaging agent such as a DNA crosslinking agent.

[0300] Agents that induce endoplasmic reticulum (ER) stress can also be used in combination with the compounds of the present disclosure. Non-limiting examples of agents that induce ER stress include agents that increase the level of reactive oxygen species (ROS) (e.g., napabucasin), chaperone inhibitors, HSP90 inhibitors, HSP70 inhibitors, PDI inhibitors, and proteasome inhibitors. Further non-limiting examples of agents that induce ER stress include GSK2606414, GSK2656157, STF-083010, TKIs (e.g., sorafenib), phospho-eIF2α phosphatase (e.g., Sal003), diindolylmethane derivatives, proteasome inhibitors (e.g., bortezomib), leptostridin A, andrographolide, tolfenamic acid, cantharidin, carnosinic acid, castichin, cryptotanshinone, curcumin, flavokawain B, fucoidan, 2-3,4-dihydroxyphenylethanol, 7-dimethoxyflavone, SMIP004 (N-(4-butyl-2-methylphenyl)acetamide), licocarcon A, neferin, peonol, paradaxin, parthenolide, piperine, polyphenone E, polyphyllin D, resveratrol, dehydrocostuslactone, γ-tocotrienol, ω-hydroxyundeca-9-enoic acid, ampelopsin, aldisianone, genistein, guggiferone H, guggulsterone, marcanthine M, sarsasapogenin, saxifragifolin, prodigiosin, quercetin, honokiol, brefeldin A, α-succinyl tocopheryl, berkarin A, succinic acid vitamin E, ultrafine, and zerumbone. See, for example, Walczak, A., et al. Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 5729710 (the entire content of which is incorporated herein by reference).

[0301] Particularly interesting anticancer agents for use in combination with the compounds of the present disclosure include the following.

[0302] Topoisomerase inhibitors, such as type I topoisomerase inhibitors, such as irinotecan, topotecan, and camptothecin, and type II topoisomerase inhibitors, such as etoposide, doxorubicin, and epirubicin.

[0303] Poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, and iniparib.

[0304] In some embodiments, the compounds of the present disclosure are administered in combination with DNA crosslinking agents, such as cisplatin, carboplatin, and oxaliplatin.

[0305] Agents that increase the level of reactive oxygen species (ROS), such as napabucasin.

[0306] PARP inhibitors, such as olaparib, rucaparib, niraparib, veliparib, and talazoparib.

[0307] Purine antimetabolites and / or inhibitors of de novo purine synthesis, such as pemetrexed (Alimta®), gemcitabine (Gemzar®), 5-fluorouracil (Adrucil®, Carac®, and Efudex®), methotrexate (Trexall®), capecitabine (Xeloda®), floxuridine (FUDR®), decitabine (Dacogen®), azacitidine (Vidaza® and Azadine®), 6-mercaptopurine (Purinethol®), cladribine (Leustatin®, Litak®, and Movectro®), fludarabine (Fludara®), pentostatin (Nipent®), nelarabine (Arranon®), clofarabine (Clolar® and Evoltra®), and cytarabine (Cytosar®).

[0308] Anti-angiogenic agents, such as matrix metalloproteinase (MMP) inhibitors (e.g., MMP-2 inhibitor, MMP-9 inhibitor), rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab, and COX-II inhibitors, such as CELEBREX™ (celecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172 (published Oct. 24, 1996), WO96 / 27583 (published Mar. 7, 1996), European Patent Application No. 97304971.1 (filed Jul. 8, 1997), European Patent Application No. 99308617.2 (filed Oct. 29, 1999), WO98 / 07697 (published Feb. 26, 1998), WO98 / 03516 (published Jan. 29, 1998), WO98 / 34918 (published Aug. 13, 1998), WO98 / 34915 (published Aug. 13, 1998), WO98 / 33768 (published Aug. 6, 1998), WO98 / 30566 (published Jul. 16, 1998), European Patent Application Publication No. 606,046 (published Jul. 13, 1994), European Patent Application Publication No. 931,788 (published Jul. 28, 1999), WO90 / 05719 (published May 31, 1990), WO99 / 52910 (published Oct. 21, 1999), WO99 / 52889 (published Oct. 21, 1999), WO99 / 29667 (published Jun. 17, 1999), PCT International Patent Application No. PCT / IB98 / 01113 (filed Jul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25, 1999), United Kingdom Patent Application No. 9912961.1 (filed Jun. 3, 1999), United States Provisional Application No. 60 / 148,464 (filed Aug. 12, 1999), United States Patent No. 5,863,949 (issued Jan. 26, 1999), United States Patent No. 5,861,510 (issued Jan. 19, 1999), and European Patent Application Publication No. 780,386 (published Jun. 25, 1997) (all of which are incorporated herein by reference in their entirety).Specific examples of MMP-2 and / or MMP-9 inhibitors include those having little or no activity to inhibit MMP-1. Other specific examples include MMP inhibitors that selectively inhibit MMP-2 and / or MMP-9 as compared to other matrix metalloproteinases (e.g., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and / or MMP-13). In some embodiments, specific examples of useful MMP inhibitors include AG-3340, RO323555, and RS13-0830.

[0309] In some embodiments, the compounds of the present disclosure are administered in combination with an autophagy inhibitor, such as chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, an autophagy-inhibiting algal toxin that inhibits protein phosphatase type 2A or type 1, an analog of cAMP, and a drug that increases cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine, and, without limitation, an antisense or siRNA that inhibits the expression of a protein (associated with autophagy) including ATG5.

[0310] In some embodiments, the compounds of the present disclosure are administered in combination with a B-cell lymphoma 2 (BCL-2) inhibitor, such as venetoclax.

[0311] In some embodiments, the compounds of the present disclosure are administered in combination with a B-cell receptor signaling antagonist, such as a Bruton's tyrosine kinase (BTK) inhibitor (e.g., ibrutinib).

[0312] In some embodiments, the compounds of the present disclosure are administered in combination with a bromodomain inhibitor. The bromodomain inhibitor inhibits at least one bromodomain protein, such as Brd2, Brd3, Brd4, and / or BrdT, such as Brd4. Non-limiting examples of bromodomain inhibitors include JQ-1 (Nature 2010 Dec 23;468(7327):1067-73), BI2536 (ACS Chem.Biol.2014 May 16;9(5):1160-71; Boehringer Ingelheim), TG101209 (ACS Chem.Biol.2014 May 16;9(5):1160-71), OTX015 (Mol.Cancer Ther.November 201312;C244; Oncoethix), IBET762 (J Med Chem.2013 Oct 10;56(19):7498-500; GlaxoSmithKline), IBET151 (Bioorg.Med.Chem.Lett.2012 Apr 15;22(8):2968-72; GlaxoSmithKline), PFI-1 (J.Med.Chem.2012 Nov 26;55(22):9831-7, Cancer Res.2013 Jun 1;73(11):3336-46; Structural Genomics Consortium), CPI-0610 (Constellation Pharmaceuticals). In some embodiments, the bromodomain inhibitor is TG101209, BI2536, OTX015, C244, IBET762, IBET151, or PFI-1.

[0313] Histone deacetylase (HDAC) inhibitors. HDAC proteins can be classified into classes based on their homology to yeast HDAC proteins: class I, consisting of HDAC1, HDAC2, HDAC3, and HDAC8; class IIa, consisting of HDAC4, HDAC5, HDAC7, and HDAC9; class IIb, consisting of HDAC6 and HDAC10; and class IV, consisting of HDAC11. Non-limiting examples of HDAC inhibitors include trichostatin A, vorinostat (Proc. Natl. Acad. Sci. U.S.A. 1998 Mar 17;95(6):3003-7), givinostat, abexinostat (Mol. Cancer Ther. 2006 May;5(5):1309-17), belinostat (Mol. Cancer Ther. 2003 Aug;2(8):721-8), panobinostat (Clin. Cancer Res. 2006 Aug 1;12(15):4628-35), resminostat (Clin. Cancer Res. 2013 Oct 1;19(19):5494-504), chidamide (Clin. Cancer Res. 2013 Aug 1;19(15):4262-72), depsipeptide (Blood. 2001 Nov 1;98(9):2865-8), entinostat (Proc. Natl. Acad. Sci. U.S.A. 1999 Apr 13;96(8):4592-7), mocetinostat (Bioorg. Med. Chem. Lett. 2008 Feb 1;18(3):106771), and valproic acid (EMBO J. 2001 Dec 17;20(24):6969-78). In some embodiments, the HDAC inhibitor is panobinostat, vorinostat, MS275, belinostat, SAHA, or LBH589.

[0314] In some embodiments, the compounds of the present disclosure are administered in combination with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, such as erlotinib, osimertinib, cetuximab, gefitinib, necitumumab, lapatinib, neratinib, panitumumab, vandetanib, and necitumumab. The combinations of the compounds and EGFR inhibitors described herein may be useful for the treatment of cancers associated with EGFR dysregulation, such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and colorectal cancer. EGFR can be dysregulated due to activating mutations in, for example, exon 18, 19, 20, or 21. In certain embodiments, the EGFR inhibitor is erlotinib or osimertinib. In certain embodiments, the combination of the compounds of the present disclosure and an EGFR inhibitor is used to treat EGFR mutant NSCLC. In certain embodiments, the combination of the compounds of the present disclosure and an EGFR inhibitor is used to treat EGFR inhibitor-resistant cancers, for example, the compounds of the present disclosure sensitize the cancers to the EGFR inhibitor.

[0315] An EGFR antibody, such as cetuximab (Erbitux®).

[0316] A methylthioadenosine phosphorylase (MTAP) inhibitor, such as (3R,4S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4-((methylthio)methyl)pyrrolidin-3-ol (MT-DADMe-immucillin A, CAS: 653592-04-2).

[0317] Methylthioadenosine ((2R,3R,4S,5S)-2-(6-amino-9H-purin-9-yl)-5-((methylthio)methyl)tetrahydrofuran-3,4-diol, CAS: 2457-80-9).

[0318] An epidermal growth factor receptor (EGFR) inhibitor, such as erlotinib hydrochloride (Tarceva®) and gefitinib (Iressa®).

[0319] Epithelial-mesenchymal transition (MET) inhibitors, for example, capmatinib (INC280, CAS: 1029712-80-8).

[0320] In some embodiments, the compounds of the present disclosure are platelet-derived growth factor (PDGF) receptor inhibitors, for example, imatinib (Gleevec®); lenvatinib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT 869, available from Genentech); sunitinib malate (Sutent®); quizartinib (AC220, CAS: 950769-58-1); pazopanib (Votrient®); axitinib (Inlyta®); sorafenib (Nexavar®); brivanib (BIBF1120, CAS: 928326-83-4); teratinib (BAY57-9352, CAS: 332012-40-5); vandetanib dihydrochloride (PTK787, CAS: 212141-51-0); and motesanib diphosphate (AMG706, CAS: 857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in PCT Publication No. WO02 / 066470) and are administered in combination.

[0321] In some embodiments, HER2 (receptor-type protein tyrosine kinase erbB-2) antibodies can be used in combination with the compounds described herein. In some embodiments, the HER2 antibody or biological agent is fam-trastuzumab deruxtecan-nxki, trastuzumab, pertuzumab, ado-trastuzumab emtansine, or margetuximab-cmkb.

[0322] In some embodiments, the compounds of the present disclosure are administered in combination with a phosphoinositide 3-kinase (PI3K) inhibitor, such as 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publications WO09 / 036082 and WO09 / 055730); 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (also known as BKM120 or NVP-BKM120 and described in PCT Publication WO2007 / 084786); alpelisib (BYL719); (5Z)-5-[[4-(4-pyridinyl)-6-quinolyl]methylene]-2,4-thiazolidinedione (GSK1059615, CAS: 958852-01-2); 5-[8-methyl-9-(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-2-pyrimidinamine (VS-5584, CAS: 1246560-33-7); and everolimus (AFINITOR®).

[0323] Cyclin-dependent kinase (CDK) inhibitors, such as ribociclib (LEE011, CAS: 1211441-98-3); aloisine A; alvocidib (also known as flavopiridol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone, and described in U.S. Patent No. 5,621,002); crizotinib (PF-02341066, CAS: 877399-52-5); 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1-methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one hydrochloride (P276-00, CAS: 920113-03-7); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazole-2-amine (RAF265, CAS: 927880-90-8); indisulam (E7070); roscovitine (CYC202); 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]piperidine-4-carboxamide (BMS 387032, CAS: 345627-80-7); 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid (MLN8054, CAS: 869363-13-3); 5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl-4-methyl-3-pyridinemethanamine (AG-024322, CAS: 837364-57-5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS: 844442-38-2);4-[2-Methyl-1-(1-methylethyl)-1H-imidazol-5-yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5438, CAS: 602306-29-6); palbociclib (PD-0332991); and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]oxy]-2-butanol (BAY 10000394).;

[0324] In some embodiments, the compounds of the present disclosure are p53-MDM2 inhibitors, such as (S)-1-(4-chloro-phenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl-[4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclohexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinolin-3-one, (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone (RG7112), 4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid (RG7388), SAR299155, 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (AMG232), {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S,3S)-2-hydroxy-3-pentanyl]-3-methyl-2-oxo-3-piperidinyl}acetic acid (AM-8553), (±)-4-[4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (Nutlin-3), 2-methyl-7-[phenyl(phenylamino)methyl]-8-quinolinol (NSC 66811), 1-N-[2-(1H-indol-3-yl)ethyl]-4-N-pyridin-4-ylbenzene-1,4-diamine (JNJ-26854165), 4-[4,5-bis(3,4-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-imidazole-1-carboxyl]-piperazin-2-one (Khellin-1), 4-[4,5-bis(4-trifluoromethylphenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-imidazole-1-carboxyl]-piperazin-2-one (Khellin-2), 5-[[3-(dimethylamino)propyl]amino]-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione dihydrochloride (HLI373), and trans-4-iodo-4'-boranyl-chalcone (SC204072) are administered in combination.,

[0325] In some embodiments, the compounds of the present disclosure are mitogen-activated protein kinase (MEK) inhibitors, such as XL-518 (also known as GDC-0973, CAS number: 1029872-29-4, available from ACC Corp.); selumetinib (5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide, also known as AZD6244 or ARRY 142886, described in PCT Publication No. WO2003 / 077914); 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide (also known as CI-1040 or PD184352, described in PCT Publication No. WO2000 / 035436); N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (also known as PD0325901, described in PCT Publication No. WO2002 / 006213); 2,3-bis[amino[(2-aminophenyl)thio]methylene]-butanedinitrile (also known as U0126, described in U.S. Patent No. 2,779,780); N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl]-1-[(2R)-2,3-dihydroxypropyl]-cyclopropanesulfonamide (also known as RDEA119 or BAY869766, described in PCT Publication No. WO2007 / 014011); (3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9;19-tetrahydro-1H-2-benzoxacyclotetradecin-1,7(8H)-dione (also known as E6201, described in PCT Publication No. WO2003 / 076424); 2'-amino-3'-methoxyflavone (also known as PD98059, Biaffin GmbH & Co., available from KG, Germany); (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS: 1035555-63-5); pimasertib (AS-703026, CAS: 1204531-26-9); trametinib dimethyl sulfoxide (GSK-1120212, CAS: 1204531-25-80); 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide (AZD 8330); 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)-5-[(3-oxo-[1,2]oxazinane-2-yl)methyl]benzamide (CH 4987655 or RO 4987655); and 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide (MEK162) are administered in combination.

[0326] B-RAF inhibitors, for example, regorafenib (BAY73-4506, CAS: 755037-03-7); tivozanib (AV951, CAS: 475108-18-0); vemurafenib (ZELBORAF (registered trademark), PLX-4032, CAS: 918504-65-1); encorafenib (also known as LGX818); 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-1H-benzimidazole-2-amine (RAF265, CAS: 927880-90-8); 5-[1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydroinden-1-one oxime (GDC-0879, CAS: 905281-76-7); 5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-(4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-inden-1-one oxime (GSK2118436 or SB590885); (+ / -)-(5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl)methyl carbamate (also known as XL-281 and BMS908662); dabrafenib (TAFINLAR (registered trademark)); and N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (also known as PLX4720).

[0327] In some embodiments, the compounds of the present disclosure are administered in combination with, for example, proteasome inhibitors, such as bortezomib (VELCADE®), N-5-benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucinal (PSI), carfilzomib and ixazomib, marizomib (NPI-0052), delanzomib (CEP-18770), and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (oprozomib, ONX-0912, PR-047) (e.g., bortezomib) for the treatment of, for example, multiple myeloma.

[0328] A number of chemotherapeutic agents can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors (e.g., paclitaxel, nab-paclitaxel), alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0329] In some embodiments, the compounds of the present disclosure are alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocon, meturedopa, and uredopa; ethyleneimine and methylamelamine including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chloronaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, calminomycin, cardinophilin, Casodex®, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rhodomycin, streptozocin, streptonigrin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,Didoxyruridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epithioestanol, mepitiostane, testolactone; anti-adrenergic agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demeclocycline; diaziquone; eflornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark); razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes such as paclitaxel (TAXOL (trademark), Bristol-Myers Squibb Oncology, Princeton, N.J.), docetaxel (TAXOTERE (registered trademark), Rhone-Poulenc Rorer, Antony, France), and cabazitaxel (JEVTANA, Sanofi Genzyme); retinoic acid; esperamicin; capecitabine; and are administered in combination with a secondary chemotherapy drug selected from any of the pharmaceutically acceptable salts, acids, or derivatives of the above. Further non-limiting examples of chemotherapy drugs used in combination with the compounds of the present disclosure (e.g., in combination therapy, in a drug combination) include bortezomib, capecitabine (Xeloda (registered trademark)), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin (registered trademark)), cisplatin (Platinol (registered trademark)), cladribine (Leustatin (registered trademark)),Cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), liposomal cytarabine injection (DepoCyt®), dacarbazine (DTIC-Dome®), doxorubicin hydrochloride (Adriamycin®, Rubex®), erlotinib, fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), FOLFIRINOX, gemcitabine (difluorodeoxycytidine), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), nab-paclitaxel, pentostatin, 6-thioguanine, thiotepa, and topotecan hydrochloride for injection (Hycamptin®). Further non-limiting examples of chemotherapeutic agents used in combination with the compounds of the present disclosure (e.g., in combination therapies, in drug combinations) include erlotinib, afatinib, gefitinib, GDC0941, MLN1117, BYL719 (alpelisib), BKM120 (buparlisib), CYT387, GLPG0634, baricitinib, lestaurtinib, momelotinib, pacritinib, ruxolitinib, TG101348, crizotinib, cibitinib, AMG337, cabozantinib, foretinib, ofatumumab, NVP-AEW541, dasatinib, ponatinib, saracatinib, bosutinib, trametinib, selumetinib, cobimetinib, PD0325901, RO5126766, axitinib, bevacizumab, cetuximab, hostamatinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pegaptanib, ranibizumab, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, vemurafenib, irinotecan, taxol, docetaxel, rapamycin, and MLN0128. In combination with the compounds of the present disclosure (e.g., in combination therapies,Further non-limiting examples of chemotherapeutic agents used in (a pharmaceutical combination) include capecitabine (Xeloda®), N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), liposomal cytarabine injection (DepoCyt®), dacarbazine (DTIC-Dome®), doxorubicin hydrochloride (Adriamycin®, Rubex®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), gemcitabine (difluorodeoxycytidine), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), pentostatin, 6-thioguanine, thiotepa, and topotecan hydrochloride for injection (Hycamptin®).

[0330] Generally prescribed anti-cancer agents can also be used in combination with the compounds of the present disclosure. Non-limiting examples of generally prescribed anti-cancer agents include Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Albosidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxin, Anti-neoplastic agent, Anti-tumor herb, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine, BIBW 2992, Bilycodal, Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy), Caliculin, Cell cycle non-specific anti-tumor agent, Dichloroacetic acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Feruginol, Holothurin, Phosphoestrol, ICE chemotherapy, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Lanikidal, Larotaxel, Lenalidomide, Lucanthone, Lartotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Orataxel, PAC-1, Porphyrin, Pixantrone, Proteasome inhibitor, Rebecamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Talikidal, Tegafur·Uracil, Temodal, Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126, or Zosquidar.

[0331] Chemotherapeutic cell regulators can also be used in combination with the compounds of the present disclosure. Non-limiting examples of chemotherapeutic cell regulators include antihormonal agents that act to modulate or inhibit the hormonal action on tumors, such as antiestrogen agents, such as tamoxifen (Nolvadex™), raloxifene, aromatase inhibitory 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogen agents, such as flutamide, nilutamide, bicalutamide, leuprorelin, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platin; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; and difluoromethylornithine (DMFO).

[0332] mTOR inhibitors can also be used in combination with the compounds of the present disclosure. Non-limiting examples of mTOR inhibitors include, for example, temsirolimus; everolimus (officially known as deforolimus, dimethylphosphinic acid (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4,92 Hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methylcyclohexyl, also known as AP23573 and MK8669, and described in PCT Publication No. WO03 / 064383); everolimus (Afinitor® or RAD001); rapamycin (AY22989, Sirolimus®); simapimod (CAS: 164301-51-3); temsirolimus, (5-{2,4-bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol (AZD8055); 2-amino-8-[trans-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (PF04691502, CAS: 1013101-36-4); and N

[0333] - [1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartyl-L-serine inner salt (SEQ ID NO: 1482) (SF1126, CAS: 936487-67-1), and XL765.Some patients may exhibit an allergic reaction to the compounds of the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)) during or after administration. Thus, in order to minimize the risk of allergic reaction, an anti-allergy agent may be administered in combination with the compounds of the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)). Suitable anti-allergy agents include corticosteroids (Knutson, S., et al., PLoS One, DOI:10.1371 / journal.pone.0111840 (2014)), such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, sodium hydrocortisone succinate, sodium hydrocortisone phosphate, sold under the trade names ALA-CORT®, hydrocortisone phosphate, SOLU-CORTEF®, HYDROCORT ACETATE®, and LANACORT®), prednisone (sold under the trade names DELTA-CORTEL®, ORAPRED®, PEDIAPRED®, and PRELONE®), prednisolone (sold under the trade names DELTASONE®, LIQUID RED®, METICORTEN®, and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, sodium methylprednisolone succinate, sold under the trade names DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, and SOLU-MEDROL®); antihistamines, such as diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, such as β-adrenergic receptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline (BRETHINE®).

[0334] Some patients may exhibit nausea during and after administration of the compounds described herein and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)). Thus, antiemetics can be used in combination with the compounds of the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)) to prevent nausea (upper stomach) and vomiting. Suitable antiemetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®), dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and ZUNRISA®), and combinations thereof.

[0335] Drugs for reducing pain experienced during the treatment period are often prescribed to make the patient more comfortable. Common over-the-counter analgesics, such as TYLENOL®, can also be used in combination with the compounds of the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)). Opioid analgesics, such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®), may be useful for moderate or severe pain and can be used in combination with the compounds of the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)).

[0336] To protect normal cells from treatment toxicity and to suppress organ toxicity, cytoprotective agents (e.g., neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline extravasation neutralizing agents, nutrients, etc.) can be used in combination with the compounds of the present disclosure as adjuvant therapy. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, mesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0337] To protect normal cells from treatment toxicity and to suppress organ toxicity, cytoprotective agents (e.g., neuroprotective agents, free radical scavengers, cardioprotective agents, anthracycline extravasation neutralizing agents, nutrients, etc.) can be used in combination with the compounds of the present disclosure as adjuvant therapy. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, mesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0338] In the combination therapies of the present disclosure, the compounds of the present disclosure and other therapeutic agents can be manufactured and / or formulated by the same or different manufacturers. Further, the compounds of the present invention and other therapeutic agents can be combined in combination therapies (i) before delivering the combination product to the physician (e.g., in the case of a kit containing the compounds of the present disclosure and other therapeutic agents); (ii) by the physician (or under the guidance of the physician) immediately prior to administration; or (iii) by the patient himself / herself, e.g., during sequential administration of the compounds of the present invention and other therapeutic agents.

[0339] Pharmaceutical composition In certain embodiments, the present disclosure provides a pharmaceutical formulation suitable for use in a human patient, comprising any of the above compounds (e.g., a compound of the present disclosure, e.g., a compound of formula (I) or (II) or (III)), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation may be for use in treating or preventing a condition or disease described herein. Any of the compounds of the present disclosure may be used in the manufacture of a medicament for treating any disease or condition disclosed herein.

[0340] The compositions and methods of the present disclosure can be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal, e.g., a human or non-human mammal. When administered to a subject, e.g., a human, the composition or compound is preferably administered as a pharmaceutical composition comprising, e.g., a compound of the present disclosure and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiological buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such a pharmaceutical composition is for administration to humans, particularly for invasive routes of administration (i.e., routes that avoid transport or diffusion through an epithelial barrier, e.g., injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to provide for delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage forms such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophiles for reconstitution, suspensions, creams, gels, ointments, aerosol sprays, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, e.g., an eye drop.

[0341] A pharmaceutically acceptable carrier can contain a physiologically acceptable agent that acts, for example, to stabilize a compound such as a compound of the present disclosure, to increase its solubility, or to increase its absorption, or to enable its manufacture. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of a pharmaceutically acceptable carrier containing a physiologically acceptable agent depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) can be, for example, a liposome or other polymeric matrix that may incorporate a compound of the present disclosure. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to manufacture and administer.

[0342] The phrase "pharmaceutically acceptable" as used herein refers to compounds, substances, compositions, and / or dosage forms that are suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment and that commensurate with a reasonable benefit / risk ratio.

[0343] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Some examples of materials that can function as pharmaceutically acceptable carriers include the following: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0344] The pharmaceutical composition (formulation) can be administered to a subject by any of a number of routes of administration, including, for example, oral (such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorption through the oral mucosa (such as sublingual), anal, rectal, or vaginal (such as in the form of pessaries, creams, or foams), parenteral (intramuscular, intravenous, subcutaneous, or intrathecal, for example, as a sterile solution or suspension), nasal, intraperitoneal, subcutaneous, transdermal (such as in the form of patches applied to the skin), and topical (such as creams, ointments, or sprays applied to the skin, or as eye drops). The compound may be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

[0345] The formulation can conveniently be provided in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound of the invention that produces a therapeutic effect. Generally, this amount will range from about 1 percent to about 99 percent active ingredient, preferably from about 5 percent to about 70 percent active ingredient, and most preferably from about 10 percent to about 30 percent, by weight of the total composition.

[0346] The methods for preparing these formulations or compositions include the step of mixing an active compound, such as a compound of the present disclosure, with a carrier and optionally one or more auxiliary components. Generally, the formulations are prepared by uniformly and homogeneously mixing the compounds of the present disclosure with a liquid carrier or a micronized solid carrier or both, and then, if necessary, shaping the product.

[0347] Formulations of the present disclosure suitable for oral administration can be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), lyophiles, powders, granules, or solutions or suspensions of aqueous or non-aqueous liquids, or water-in-oil or oil-in-water liquid emulsions, or elixirs or syrups, or pastilles (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. The composition or compound can also be administered as a bolus, a troche, or a paste.

[0348] For the preparation of solid dosage forms for oral administration (including capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules, etc.), the active compound is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, (3) humectants such as glycerol, (4) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) dissolution retardants such as paraffin, (6) absorption promoters such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, (10) complexing agents such as modified cyclodextrin and unmodified cyclodextrin, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets, and pills, the pharmaceutical composition may also contain a buffering agent. Solid compositions of the same type can also be used as fillers for soft gelatin capsules and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0349] Tablets can be produced by compression or molding, optionally with one or more auxiliary components. Compressed tablets can be prepared using binders (such as gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (such as sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets can be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent using a suitable machine.

[0350] Tablets and other solid dosage forms of pharmaceutical compositions, such as lozenges, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may optionally be imprinted or may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may be formulated, for example, using various proportions of hydroxypropylmethylcellulose, other polymeric matrices, liposomes, and / or microspheres to provide a desired release profile to effect sustained or controlled release of the active ingredient(s) contained therein. They may be sterilized, for example, by filtration through a bacteria-trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injectable medium immediately prior to use. These compositions may optionally contain an opacifying agent and may be compositions that release the active ingredient(s), optionally in a delayed manner, only in or preferentially in certain parts of the gastrointestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient(s) may, where appropriate, be in microencapsulated form, including one or more of the excipients described above.

[0351] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active ingredient, inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0352] In addition to the inert diluent, the oral composition may contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweeteners, flavoring agents, coloring agents, perfumes, and preservatives.

[0353] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0354] The formulation of a pharmaceutical composition for rectal, vaginal, or urethral administration can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates, which are solid at room temperature but liquid at body temperature, so that they can be provided as suppositories that melt in the rectal or vaginal cavity and release the active compound.

[0355] The formulation of a pharmaceutical composition for oral administration can be provided as a mouthwash or an oral spray or an oral ointment.

[0356] Alternatively or additionally, the composition can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such a device can be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0357] Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known to be appropriate in the art.

[0358] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0359] Ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicon, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0360] Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0361] Transdermal patches have the further advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption promoters may also be used to increase the flow through the skin of the compound. The rate of such flow can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0362] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also intended to be within the scope of the present disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124 (the contents of each of which are incorporated herein by reference). If desired, ophthalmic liquid formulations may have properties similar to or be compatible with tears, aqueous humor, or vitreous humor. The preferred route of administration is topical administration (e.g., topical administration such as by eye drops or implants).

[0363] As used herein, the terms "parenteral administration" and "administered parenterally" mean a mode of administration by conventional injection other than enteral administration and topical administration, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intraspinal, and intrasternal injection and infusion.

[0364] Pharmaceutical compositions suitable for parenteral administration include one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile solutions or dispersions for injection immediately before use, and the pharmaceutical compositions may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0365] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. For example, by using coating materials such as lecithin, and by maintaining the required particle size in the case of dispersions, and by using surfactants, appropriate fluidity can be maintained.

[0366] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The activities of microorganisms can be surely prevented by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc. It may be desirable to include, for example, sugars, sodium chloride, etc. in the compositions of the present invention. In addition, the long-term absorption of injectable dosage forms can be caused by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0367] In some cases, it may be desirable to delay the absorption of a drug by subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. In that case, the absorption rate of the drug depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, the delay in absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily medium.

[0368] Injectable depot forms are prepared by forming a microencapsulation matrix of the compound of interest in a biodegradable polymer such as polylactic acid - polyglycolide. Depending on the ratio of the drug to the polymer and the nature of the particular polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

[0369] When used in the methods of the present disclosure, the active compound can be administered by itself or, for example, as a pharmaceutical composition containing 0.1 - 99.5% (more preferably 0.5 - 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0370] The method of introduction can also be provided by a reloadable device or a biodegradable device. In recent years, various sustained - release polymer devices have been developed and tested in vivo for the controlled delivery of drugs including protein biopharmaceuticals. Various biocompatible polymers (including hydrogels), both biodegradable and non - biodegradable, can be used to form implants for the sustained release of compounds at specific target sites.

[0371] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention may vary to obtain an amount of the active ingredient effective to achieve the desired therapeutic response without being toxic to the patient, for a particular patient, composition, and mode of administration.

[0372] The selected dosage level depends on a variety of factors including the activity of the specific compound or combination of compounds used, or their esters, salts, or amides, the route of administration of the specific compound(s) used, the time of administration, the rate of excretion, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific compound(s) used, the age, sex, weight, condition, health status, and medical history of the subject to be treated, as well as similar factors well known in the medical arts.

[0373] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can initiate administration of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" means a concentration of the compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound will vary depending on the weight, sex, age, and medical history of the subject. Other factors that can affect the effective amount include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if appropriate, another type of therapeutic agent administered in combination with the compounds of the present disclosure. Larger total doses can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those of ordinary skill in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814 - 1882, incorporated herein by reference).

[0374] Generally, the appropriate daily amount of the active compound used in the compositions and methods of the present disclosure is the amount of the compound that is the lowest dosage effective to produce a therapeutic effect. Such effective dosages generally depend on the factors described above.

[0375] Optionally, the effective daily amount of the active compound can be administered as one, two, three, four, five, six, or more divided sub-doses, optionally in unit dosage forms, at appropriate intervals throughout the day. In certain embodiments of the present disclosure, the active compound can be administered one or two or three times a day. In certain embodiments, the active compound is administered once a day.

[0376] In certain embodiments, the compounds of the present disclosure can be used alone or co-administered with another type of therapeutic agent. As used herein, the phrase "co-administered" refers to any administration form of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which can include a synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered as the same formulation or as separate formulations simultaneously or sequentially. In certain embodiments, the different therapeutic compounds can be administered to each other within 1 hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or within one week. Thus, a subject undergoing such treatment can benefit from the combined effects of the different therapeutic compounds.

[0377] In certain embodiments, co-administration of the compounds of the present disclosure with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) results in improved efficacy compared to the individual administration of the compounds of the present disclosure (e.g., the compounds of formula (I) or (II) or (III)) or one or more additional therapeutic agents. In certain such embodiments, the co-administration results in an additive effect, where the additive effect refers to the sum of the effects of the individual administrations of the compounds of the present disclosure and one or more additional therapeutic agents.

[0378] This disclosure includes the use of pharmaceutically acceptable salts of the compounds of this disclosure in the compositions and methods of this disclosure. In certain embodiments, the salts of this disclosure that are contemplated include, but are not limited to, alkyl salts, dialkyl salts, trialkyl salts, or tetraalkylammonium salts. In certain embodiments, the salts of this disclosure that are contemplated include, but are not limited to, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, and zinc salts. In certain embodiments, the salts of this disclosure that are contemplated include, but are not limited to, Na salts, Ca salts, K salts, Mg salts, Zn salts, or other metal salts.

[0379] Pharmaceutically acceptable acid addition salts may also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvates can be derived from the crystallization solvent, can be inherent in the preparation or crystallization solvent, or can be incidental to such solvents.

[0380] Pharmaceutically acceptable anionic salts include acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, theocurate, and tosylate.

[0381] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, and coloring agents, release agents, coating agents, sweetening agents, flavoring agents and fragrances, preservatives, and antioxidants may also be present in the composition.

[0382] Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, etc., (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc., and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0383] Although the present disclosure has been generally described above, it will be more readily understood by reference to the following examples, which are included only for the purpose of illustration of certain aspects and embodiments of the present disclosure and are not intended to limit the present disclosure.

Examples

[0384] General synthesis procedure The starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Co., Bachem, etc., or can be prepared by methods well known in the art. The schemes are merely illustrative of some of the ways in which the compounds disclosed herein can be synthesized, and various modifications of these schemes can be made and will be suggested to those skilled in the art with reference to the present disclosure. The starting materials, intermediates, and final products of the reactions can be isolated and purified as necessary using conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, etc., and can be characterized using conventional means including physical constants and spectral data.

[0385] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure in a temperature range of about -78 °C to about 150 °C. [Table 2] TIFF0007696443000217.tif235165TIFF0007696443000218.tif176165

[0386] The compounds of the present invention can be prepared by various synthetic methods as further described and exemplified herein. The following general synthetic methods are representative and it will be understood by those skilled in the art that they are not intended to be limiting.

[0387] As demonstrated by the following examples, it will be understood by those skilled in the art that the starting materials and reaction conditions can be varied, the order of the reactions can be modified, and additional steps can be used to produce the compounds encompassed by the present disclosure. In some cases, protection of certain reactive functional groups may be required to achieve some of the above transformations. Generally, the need for such protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to the experienced organic chemist. The disclosures of all papers and references mentioned in this application, including patents, are incorporated herein by reference.

[0388] The preparation of the compounds of the present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or gist of the present disclosure to the specific procedures and compounds described therein.

[0389] Analytical methods LCMS data was collected using one of the following methods: [Table 3] TIFF0007696443000220.tif236165TIFF0007696443000221.tif192165TIFF0007696443000222.tif134165

[0390] Exemplary synthesis In the exemplified syntheses, for example, in the exemplified general synthetic schemes, several variable sub-variables are used. As used herein, each occurrence of X is independently CR5 or N, to the extent permitted by the valence, and R 1a is hydrogen, halogen, or optionally substituted alkyl, and R 2a is hydrogen, halogen, optionally substituted alkyl, or optionally substituted alkoxy, R5 is independently halo, optionally substituted alkyl, or optionally substituted alkoxy, and R 2b is hydrogen or optionally substituted alkyl, and R 1d is hydrogen, halo, or optionally substituted alkyl, and R 3a is halo, optionally substituted alkyl, or optionally substituted heterocyclyl, and R 4a is hydrogen, halo, or optionally substituted alkoxy, and R 5a is hydrogen, optionally substituted alkyl, or heterocyclyl, and R 6a is hydrogen or halo, alkenyl or alkynyl, each of which is optionally substituted by one or more occurrences of R a (R aas defined in the present application), each occurrence of A is C or N to the extent permitted by the valence, and PG is a nitrogen protecting group when bonded to nitrogen or an oxygen protecting group when bonded to oxygen.

[0391] The compounds illustrated in Figures 1 to 17 can be synthesized from the corresponding starting materials and commercially available reagents using the following procedures.

[0392] Synthesis of Intermediates Synthesis of 4-(benzo[d]oxazol-5-yloxy)-3-methylaniline 7

Chemical Structure

[0393] Step 2: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazole 3 (2.00 g, 8.16 mmol, 1.00 equiv) and H2O2 (30%, 50.00 mL, 2.00 equiv) in THF (60.00 mL) was stirred at 0 °C for 1 h and then concentrated under reduced pressure to give benzoxazol-5-ol 4 (crude product, 2.30 g) as a black oil, which was used in the next step without further purification. LCMS (ESI, m / z): 136 [M+H] + 。

[0394] Step 3: A mixture of benzoxazol-5-ol 4 (1.28 g, 8.16 mmol, 1.00 equiv), 1-fluoro-2-methyl-4-nitrobenzene 5 (1.39 g, 8.98 mmol, 1.10 equiv), and K2CO3 (3.38 g, 24.48 mmol, 3.00 equiv) in DMF (30.00 mL) was stirred at 50 °C for 16 h. The resulting mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0 - 20% MeOH in DCM) to give 5-(2-methyl-4-nitrophenoxy)benzoxazole 6 (610.0 mg, 28%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 2.43 (s, 3H). LCMS (ESI, m / z): 271 [M + H] + 。

[0395] Step 4: A mixture of 5-(2-methyl-4-nitrophenoxy)benzoxazole 6 (250.0 mg, 0.92 mmol, 1.00 equiv) and Pd / C (10% water-containing, 25.0 mg, 1 / 10 w / w) in EtOH (5.00 mL) was stirred at ambient temperature for 2 h under a H2 atmosphere, then filtered. The filtrate was concentrated under reduced pressure to give 4-(benzoxazol-5-yloxy)-3-methylaniline 7 (crude product, 210.0 mg) as a yellow solid, which was used in the next step without further purification. LCMS (ESI, m / z): 241 [M + H] + .

[0396] Synthesis of N-(4-(5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine 14 [Chemical formula] Step 1: To a stirred solution of 4-amino-2-methylphenol 8 (3.2 g, 25.9 mmol) in DMSO (50 mL) was added potassium tert-butoxide (7.0 g, 61.3 mmol). After stirring at room temperature for 0.5 h, 4,6-dichloropyridin-2-amine 9 (5.0 g, 30.7 mmol) was added. The reaction mixture was stirred at 80 °C for 18 h under N2. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (0 - 100% EtOAc in PE) to give 4-(4-amino-2-methylphenoxy)-6-chloropyridin-2-amine 10 (4.9 g, 52.2% yield) as a yellow solid. LCMS (ESI) (m / z): 250 [M+H] + .

[0397] Step 2: To a stirred solution of 4-(4-amino-2-methylphenoxy)-6-chloropyridine-2-amine 10 (3.0 g, 12.0 mmol) in DCM (20 mL) were added pyridine (1.4 g, 18.0 mmol) and acetic anhydride (1.2 g, 12.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h and then concentrated to dryness. The residue was purified by flash chromatography (0 - 33% EtOAc in PE) to give N-(4-((2-amino-6-chloropyridin-4-yl)oxy)-3-methylphenyl)acetamide 11 (2.5 g, 71.3% yield) as a yellow oil. LCMS (ESI) m / z: 292 [M+H] + .

[0398] Step 3: To a solution of N-(4-((2-amino-6-chloropyridin-4-yl)oxy)-3-methylphenyl)acetamide 11 (2.5 g, 8.6 mmol) in EtOH (20 mL) was added DMF-DMA (3.1 g, 25.7 mmol). The reaction mixture was degassed with N2 and stirred at 80 °C for 36 h. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (0 - 66% EtOAc in PE) to give (E)-N-(4-((2-chloro-6-(((dimethylamino)methylene)amino)pyridin-4-yl)oxy)-3-methylphenyl)acetamide 12 (2.5 g, 84.1% yield) as a yellow solid. LCMS ESI (m / z): 347 [M+H] + .

[0399] Step 4: To a stirred solution of (E)-N-(4-((2-chloro-6-(((dimethylamino)methylene)amino)pyridin-4-yl)oxy)-3-methylphenyl)acetamide 12 (1.0 g, 2.9 mmol) in MeOH (20 mL) were added hydroxylamine-O-sulfonic acid (0.3 g, 3.0 mmol) and pyridine (0.3 g, 4.3 mmol) at 0 °C. The mixture was degassed with N2 and stirred at room temperature for 18 h. The reaction was concentrated to dryness. The residue was dissolved in THF (20 mL), and trifluoroacetic anhydride (0.7 g, 3.5 mmol) was added. The reaction was stirred at 40 °C overnight, then quenched with ice water (0.5 mL) and concentrated to dryness. The residue was purified by flash chromatography (0 - 100% EtOAc in PE) to afford N-(4-((5-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)acetamide 13 (150 mg, 12.3% yield) as a yellow oil. LCMS ESI (m / z): 317 [M+H] + 。

[0400] Step 5: To a stirred solution of N-(4-((5-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)acetamide 13 (150 mg, 0.5 mmol) in MeOH (2 mL) was added concentrated HCl (0.2 mL, 12 N). The reaction was stirred at 80 °C for 18 h. The reaction was concentrated and purified by preparative TLC (DCM:MeOH = 10:1) to afford 4-((5-chloro-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylaniline 14 (80 mg, 61.5% yield) as a yellow solid. LCMS ESI (m / z): 275 [M+H] + 。

[0401] Synthesis of 4-((5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylaniline 16

Chemical Structure

[0402] Step 2: To a solution of N-[4-({5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl}oxy)-3-methylphenyl]acetamide 15 (140 mg, 0.5 mmol) in MeOH (5.0 mL) was added concentrated HCl (1.0 mL). The reaction mixture was stirred at 70 °C overnight. After cooling to 0 °C, the reaction mixture was neutralized with aqueous NH3 and then concentrated under reduced pressure. The residue was purified by preparative TLC (6% MeOH in DCM) to give 4-((5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylaniline 16 (42 mg, 34.7%) as a pale yellow solid. LCMS (ESI) m / z: 271 [M + H] + 。

[0403] Synthesis of 3-methyl-4-({5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}oxy)aniline 26

Chemical Structure

[0404] Step 2: To a stirred solution of 2,6-dibromo-4-(2-methyl-4-nitrophenoxy)pyridine 19 (4.40 g, 8.66 mmol) and diphenylmethanimine 20 (1.5 mL, 8.66 mmol) in dioxane (100 mL) were added Xantphos (1.0 g, 1.73 mmol), Pd2(dba)3 (0.79 g, 0.87 mmol), and Cs2CO3 (5.64 g, 17.3 mmol) at 25 °C. After stirring at 80 °C for 4 hours under N2, LCMS indicated that the reaction had proceeded well. Then, HCl (26 mL, 1 M) was added to this solution at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. Then, NaHCO3 solution was added to adjust the pH above 7. Then, the mixture was extracted with EtOAc (100 mL × 2). The combined organic solutions were dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 3:1) to afford 6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-amine 21 (1.21 g, 43.1% yield) as a yellow solid. LCMS (ESI) m / z: 324 / 326 [M+H] + .

[0405] Step 3: To a stirred solution of 6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-amine 21 (1.21 g, 3.74 mmol) in toluene (20 mL) was added DMF-DMA (0.58 g, 4.86 mmol) at 25 °C. The reaction mixture was stirred at 80 °C overnight. LCMS indicated that the reaction proceeded well. The reaction mixture was then concentrated to afford the crude product (Z)-N’-[6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]-N,N-dimethylmethanimidamide 22 (1.42 g, 80.2% yield) as a brown oil. LCMS (ESI) m / z: 379 / 381 [M+H] + .

[0406] Step 4: To a stirred solution of (Z)-N’-[6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]-N,N-dimethylmethanimidamide 22 (1.42 g, 3.75 mmol) in i-PrOH (20 mL) was added hydroxylamine HCl salt (0.29 g, 4.12 mmol) at 25 °C. After stirring at 80 °C for 1 h, LCMS indicated that the reaction proceeded well. The mixture was diluted with DCM (60 mL) and washed with water (20 mL). The separated organic solution was dried over Na2SO4 and concentrated to afford the crude product (Z)-N’-[6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]-N-hydroxymethanimidamide 23 (1.38 g, 70.5% yield) as a yellow solid. LCMS (ESI) m / z: 367 / 369 [M+H] + .

[0407] Step 5: Trifluoroacetic anhydride (0.87 g, 4.13 mmol) was added to a stirred solution of (Z)-N’-[6-bromo-4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]-N-hydroxymethanimidamide 23 (1.38 g, 3.759 mmol) in THF (20 mL) at 25 °C. After stirring at 40 °C overnight under N2, LCMS indicated that the reaction had proceeded well. A NaHCO3 solution was added to the reaction mixture to adjust the pH above 7. The mixture was then extracted with EtOAc (20 mL × 2), dried over Na2SO4, and concentrated to dryness. The residue was purified by silica gel chromatography (PE:EtOAc = 2:1) to give 5-bromo-7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 24 (300 mg, 22.9% yield) as a yellow solid. LCMS (ESI) m / z: 349 / 351 [M+H] + 。

[0408] Step 6: Pd(dppf)Cl2 (126 mg, 0.17 mmol) and K2CO3 (238 mg, 1.72 mmol) were added to a stirred solution of 5-bromo-7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 24 (300 mg, 0.86 mmol) and methylboronic acid (61.7 mg, 1.03 mmol) in 1,4-dioxane (5 mL) and water (1 mL) at room temperature. The reaction was degassed three times under a N2 atmosphere and stirred at 80 °C overnight. The reaction was cooled to room temperature and diluted with EtOAC (25 mL). This organic solution was washed with brine (25 mL), dried over Na2SO4, and concentrated to give the crude product 5-methyl-7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 25 (244 mg, 80.0% yield) as a black solid. LCMS (ESI) m / z: 285 [M+H] + 。

[0409] Step 7: Iron powder (479 mg, 8.58 mmol) and NH4Cl (459 mg, 8.58 mmol) were added to a mixture of 5-methyl-7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 25 (244 mg, 0.86 mmol) in EtOH (5 mL) and water (1 mL). The mixture was stirred at 80 °C for 2 h. Then, the mixture was immediately filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 0:1) to give 3-methyl-4-({5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}oxy)aniline 26 (133 mg, 61.0% yield) as a yellow solid. LCMS (ESI) m / z: 255 [M+H] + .

[0410] Synthesis of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-(trifluoromethyl)aniline 31 [Chemical formula] Step 1: To a stirred mixture of Cs2CO3 (1.44 g, 4.44 mmol) in DMSO (10 mL) was added dropwise a solution of [1,2,4]triazolo[4,3-a]pyridin-7-ol 27 (500 mg, 3.70 mmol) and 1,3-difluoro-4-nitro-2-(trifluoromethyl)benzene 28 (1.68 g, 7.40 mmol) in DMSO (10 mL) at room temperature. The resulting mixture was then stirred at room temperature for 15 minutes. LCMS indicated that the reaction was complete. The reaction mixture was quenched by adding ice water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a mixture of 7-(3-fluoro-4-nitro-2-(trifluoromethyl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine 29 and 7-(3-fluoro-6-nitro-2-(trifluoromethyl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine 30 (1.10 g, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS ESI (m / z): 343 [M+H] + .

[0411] Step 2: To a solution of 7-(3-fluoro-4-nitro-2-(trifluoromethyl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine and 7-(3-fluoro-6-nitro-2-(trifluoromethyl)phenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.10 g, crude product) in EtOH (30 mL) and H2O (10 mL) were added Fe (0.90 g, 16.02 mmol) and NH4Cl (1.72 g, 32.11 mmol). The resulting mixture was then stirred at 75 °C for 1 h. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography using EtOAc in PE (0 - 10%, V / V) to afford 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-(trifluoromethyl)aniline 31 (320 mg, 27.6% yield over 2 steps) as a yellow solid. LCMS ESI (m / z): 313 [M+H] + .

[0412] Synthesis of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline 35 [Chemical formula] Step 1: To a stirred mixture of Cs2CO3 (21.7 g, 66.6 mmol) in DMSO (150 mL) was added dropwise a solution of 1,3-difluoro-2-methyl-4-nitrobenzene 32 (23.1 g, 133.5 mmol) and [1,2,4]triazolo[1,5-a]pyridin-7-ol 27 (9.0 g, 66.7 mmol) in DMSO (300 mL) at 80 °C over 1 hour. The resulting mixture was then stirred at 80 °C for an additional 0.5 hour. LCMS indicated completion of the reaction. The reaction mixture was cooled to room temperature, diluted with water (800 mL), and extracted with EtOAc (3 × 600 mL). The combined organic phases were washed with brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a mixture of 7-(3-fluoro-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 33 and 7-(3-fluoro-2-methyl-6-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 34 (21.1 g, crude product) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): 289 [M+H] + .

[0413] Step 2: To a mixture of 7-(3-fluoro-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine and 7-(3-fluoro-2-methyl-6-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (21.1 g, crude product) in EtOH (200 mL) was added Fe (18.7 g, 333.7 mmol), NH4Cl (35.4 g, 667.4 mmol), and water (60 mL). The resulting mixture was then stirred at 80 °C for 1 h. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with EtOAC (600 mL), and filtered. The filtrate was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a crude product. The crude product was purified by silica gel flash column chromatography using EtOAc in PE (30 - 70%, V / V) to give pure 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylaniline 35 (3.91 g, 22.7% yield over 2 steps) as a pale yellow solid and some of the crude product as a grey solid. LCMS (ESI, m / z): 259 [M+H] + .

[0414] Synthesis of 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline 38 [Chemical Structure] Step 1: A mixture of 1-methyl-1H-benzo[d]imidazol-5-ol 36 (5.5 g, 37.16 mmol, 1.00 equiv), 1,3-difluoro-2-methyl-4-nitrobenzene 32 (12.8 g, 74.32 mmol, 2.00 equiv), and K2CO3 (15.4 g, 111.48 mmol, 3.00 equiv) in DMF (50.0 mL) was stirred at ambient temperature for 16 h and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel (0 - 70% acetonitrile in water (containing 0.05% NH4HCO3)) to give 5-(3-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole 37 (1.4 g, 12%) as a yellow solid. LCMS (ESI, m / z): 304 [M + H] + .

[0415] Step 2: A mixture of 5-(3-fluoro-2-methyl-4-nitrophenoxy)-1-methyl-1H-benzo[d]imidazole 37 (1.4 g, 4.65 mmol, 1.00 equiv) and zinc powder (1.5 g, 23 mmol, 5.00 equiv) in MeOH (22.4 mL) and water (5.6 mL) was stirred at 70 °C for 3 h and then filtered through a pad of celite. The filtrate was diluted with water and the mixture was extracted three times with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 2-fluoro-3-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)aniline 38 (crude product, 3.0 g) as a yellow solid, which was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.00 - 6.96 (m, 2H), 6.60 (t, J = 9.0 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.96 (s, 2H), 3.88 (s, 3H), 1.95 (d, J = 5.4 Hz, 3H). LCMS (ESI, m / z): 274 [M + H] + .

[0416] Synthesis of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-(difluoromethyl)aniline 42

Chemical formula

[0417] Step 2: DIEA (6.68 g, 51.65 mmol, 3.00 equivalents) was added to a stirred mixture of 2-(difluoromethyl)-1,3-difluoro-4-nitrobenzene 40 (3.60 g, 17.21 mmol, 1.00 equivalent) and [1,2,4]triazolo[1,5-a]pyridin-7-ol 27 (2.56 g, 18.93 mmol, 1.10 equivalents) in acetonitrile (20.0 mL) at ambient temperature. The resulting mixture was stirred at this temperature for 4 hours, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0 - 60% EtOAc in petroleum ether) to give 7-[2-(difluoromethyl)-3-fluoro-4-nitrophenoxy]-[1,2,4]triazolo[1,5-a]pyridine 41 (850 mg, 14%) as a yellow solid. LCMS (ESI, m / z): 325 [M + H] + 。

[0418] Step 3: To a stirred mixture of 7-[2-(difluoromethyl)-3-fluoro-4-nitrophenoxy]-[1,2,4]triazolo[1,5-a]pyridine 41 (500.0 mg, 1.54 mmol, 1.00 equiv) in THF (10 mL) and water (2 mL) was added Zn powder (806.6 mg, 12.33 mmol, 8.00 equiv) and NH4Cl (659.9 mg, 12.33 mmol, 8.00 equiv). The resulting mixture was stirred at 70 °C for 3 h and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 3-(difluoromethyl)-2-fluoro-4-{[1,2,4]triazolo[1,5-a]pyridin-7-yloxy}aniline 42 (crude product, 420 mg) as a yellow solid, which was used in the next step without further purification. LCMS (ESI, m / z): 295 [M + H] + 。

[0419] Synthesis of 5-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-fluoro-4-methylpyridin-2-amine 49

Chemical Structure

[0420] Step 2: (4-Methoxyphenyl)methanamine (1.80 mL, 13.81 mmol) was added to a solution of 2-chloro-3-fluoro-5-iodo-4-methylpyridine 44 (2.50 g, 9.20 mmol) in NMP (10 mL). The resulting mixture was stirred at 120 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (2 × 25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash chromatography using EtOAc in PE (0 - 5%, V / V) to give 3-fluoro-5-iodo-N-(4-methoxybenzyl)-4-methylpyridin-2-amine 45 (1.40 g, 40.8% yield) as a yellow oil. LCMS ESI (m / z): 373 [M+H] + .

[0421] Step 3: To a solution of 3-fluoro-5-iodo-N-(4-methoxybenzyl)-4-methylpyridin-2-amine 45 (650 mg, 1.74 mmol) in TFA (10 mL) was added thioanisole (10 mg, 0.087 mmol). The resulting mixture was then degassed twice under N2 and stirred at room temperature for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue, which was basified to about pH 8 by adding saturated aqueous NaHCO3 and extracted with DCM (3 × 20 mL). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography using EtOAc (0 - 10%, V / V) in PE to give 3-fluoro-5-iodo-4-methylpyridin-2-amine 46 (410 mg, 93.1% yield) as a white solid. LCMS ESI (m / z): 253 [M+H] + .

[0422] Step 4: To a solution of 3-fluoro-5-iodo-4-methylpyridin-2-amine 46 (410 mg, 1.62 mmol) in toluene (10 mL) were added hexane-2,5-dione (557 mg, 4.88 mmol) and PTSA (14 mg, 0.081 mmol). The resulting mixture was then stirred at 120 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue. The residue was diluted with water (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with brine (2 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography using EtOAc (0 - 5%, V / V) in PE to give 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-fluoro-5-iodo-4-methylpyridine 47 (440 mg, 81.9% yield) as a yellow oil. LCMS ESI (m / z): 331[M+H] + .

[0423] Step 5: To a solution of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-fluoro-5-iodo-4-methylpyridine 47 (296 mg, 0.89 mmol) in NMP (15 mL) were added [1,2,4]triazolo[1,5-a]pyridin-7-ol (242 mg, 1.79 mmol), CuCl (27 mg, 0.26 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (64 mg, 0.44 mmol), and Cs2CO3 (584 mg, 1.79 mmol). The reaction mixture was degassed three times under N2 and stirred at 120 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography using EtOAc in PE (0 - 30%, V / V) to afford 7-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-5-fluoro-4-methylpyr...

Claims

1. as follows: 【Chemical Formula 1】 A compound represented by a formula selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

2. The compound is of the formula 【Chemical Formula 2】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

3. The compound is of the formula 【Chemical Formula 3】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

4. The compound is of the formula 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

5. The compound is of the formula 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

6. The compound is of the formula 【Chemical Formula 6】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

7. The compound is of the formula 【Chemical Formula 7】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

8. The compound is of the formula 【Chemical Formula 8】 or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

9. The compound is of the formula [Chemical Formula 9] or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

10. The compound is of the formula [Chemical Formula 10] or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

11. The compound is of the formula [Chemical Formula 11] or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

12. The compound is of the formula [Chemical Formula 12] or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

13. The compound is of the formula [Chemical Formula 13] as defined in claim 1.

14. The compound is of the formula [Chemical Formula 14] as defined in claim 1.

15. The compound is of the formula [Chemical Formula 15] as defined in claim 1.

16. The compound is of the formula [Chemical Formula 16] as defined in claim 1.

17. The compound is of the formula [Chemical Formula 17] as defined in claim 1. Claim 18 The compound is of the formula [Chemical Formula 18] The compound according to claim 1 Claim 19 The compound is of the formula [Chemical Formula 19] The compound according to claim 1 Claim 20 The compound is of the formula [Chemical Formula 20] The compound according to claim 1 Claim 21 The compound is of the formula [Chemical Formula 21] The compound according to claim 1 Claim 22 The compound is of the formula [Chemical Formula 22] The compound according to claim 1 Claim 23 The compound is of the formula [Chemical Formula 23] The compound according to claim 1 Claim 24 A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable excipient Claim 25 A pharmaceutical composition comprising the compound according to claim 2 or 13 and a pharmaceutically acceptable excipient Claim 26 A pharmaceutical composition comprising the compound according to claim 3 or 14 and a pharmaceutically acceptable excipient Claim 27 A pharmaceutical composition comprising the compound according to claim 4 or 15 and a pharmaceutically acceptable excipient Claim 28 A pharmaceutical composition comprising the compound according to claim 5 or 16 and a pharmaceutically acceptable excipient Claim 29 A pharmaceutical composition comprising the compound according to claim 6 or 17 and a pharmaceutically acceptable excipient. Claim 30 A pharmaceutical composition comprising the compound according to claim 7 or 18 and a pharmaceutically acceptable excipient. Claim 31 A pharmaceutical composition comprising the compound according to claim 8 or 19 and a pharmaceutically acceptable excipient. Claim 32 A pharmaceutical composition comprising the compound according to claim 9 or 20 and a pharmaceutically acceptable excipient. Claim 33 A pharmaceutical composition comprising the compound according to claim 10 or 21 and a pharmaceutically acceptable excipient. Claim 34 A pharmaceutical composition comprising the compound according to claim 11 or 22 and a pharmaceutically acceptable excipient. Claim 35 A pharmaceutical composition comprising the compound according to claim 12 or 23 and a pharmaceutically acceptable excipient.

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