Compositions and methods for inhibiting KRAS

Abstract

Provided herein are compounds, or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, as well as pharmaceutical compositions comprising them.Also provided herein are methods of using them to modulate (e.g., inhibit) KRAS (e.g., KRAS with G12D mutation) and treat disease or disorder in subjects who need such treatment, such as cancer.In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound represented by formula I or formula II, together with a pharma- ceutically acceptable carrier.

Description

[Technical Field]

[0001] STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under (1) Contract No. 75N91019D00024 awarded by the National Institutes of Health, and (2) Contract No. DE-AC52-07NA27344 awarded by the U.S. Department of Energy. The U.S. Government has certain rights in this invention.

[0002] Related Applications This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 150,011, filed February 16, 2021, and U.S. Provisional Patent Application No. 63 / 246,181, filed September 20, 2021, each of which is incorporated by reference in its entirety. [Background technology]

[0003] RAS mutations occur in approximately 20–30% of human cancers, including the majority of pancreatic ductal adenocarcinomas (PDAC), half of colorectal cancers, and one-third of all lung cancers. Given the highest RAS mutation frequency in the top three causes of cancer death in the United States (lung, colorectal, and pancreatic cancers), the development of anti-RAS therapies is a major priority and challenge in cancer research. RAS proteins, apart from the GDP / GTP-binding site, were thought to present no suitable pocket for drug binding. Unfortunately, RAS proteins bind these nucleotides with extremely high (picomolar) affinity, making the development of effective nucleotide analogs virtually impossible. Attempts to block downstream pathways of RAS in hopes of providing clinical benefit to patients with RAS-driven cancers have generally been disappointing. Recently, allele-specific covalent KRASG12C inhibitors have entered clinical trials, and early clinical data suggest some efficacy, at least in lung cancer.

[0004] The three RAS genes (HRAS, NRAS, and KRAS) encode four 188-189 amino acid proteins that share 82%-90% amino acid sequence identity and nearly identical structural and biochemical properties. However, they are expressed differently and mutated at different frequencies in cancer. KRAS is the most frequently mutated oncogene in cancer, and KRAS mutations are generally associated with poor prognosis and resistance to treatment. There is high selectivity for cancer types among RAS genes. KRAS mutations are predominantly found in lung, colorectal, and pancreatic cancers, whereas NRAS mutations are predominantly found in cutaneous melanoma and acute myeloid leukemia, and HRAS mutations are found in bladder cancer and head and neck squamous cell carcinoma.

[0005] KRAS is activated by mutation in 94% of pancreatic cancers. Pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)) was the third leading cause of cancer death in the United States in 2016. Incidence rates of pancreatic cancer continue to increase and it is predicted to become the second leading cause of cancer death by 2020. With a lack of biomarkers for early detection, slow onset of symptoms once the cancer has already reached a metastatic stage, and a 5-year survival rate of 8%, pancreatic cancer is the deadliest cancer in the United States.

[0006] KRAS mutations are the initiating genetic step in pancreatic cancer, but continued mutant KRAS function is required for PDAC growth to be sustained. RNA interference-mediated KRAS inactivation in KRASG12D-induced PDAC resulted in rapid regression of tumor growth. These data support the importance of mutant KRAS as a therapeutic target in PDAC. Because 40% of PDAC cases are driven by KRASG12D mutations, inhibitors targeting this mutation are highly desirable. KRASG12D mutations also occur frequently in lung and colorectal cancers, making KRASG12D a desirable therapeutic target for direct G12D allele-specific inhibitors. Summary of the Invention [Means for solving the problem]

[0007] In one aspect, the disclosure provides a composition comprising a compound of Formula I or Formula II: [ka] or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is as set forth herein. In some embodiments, the compounds provided herein, or salts, esters, tautomers, zwitterionic forms, or stereoisomers thereof, are capable of modulating the activity of a KRAS protein, such as a KRAS protein having a G12D mutation.

[0008] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula I or Formula II in combination with a pharmaceutically acceptable carrier.

[0009] In a further aspect, the present disclosure provides methods of inhibiting KRAS activity in a human or animal subject to treat diseases such as cancer, including pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, and lung cancer.

[0010] In another aspect, the present disclosure provides the use of a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition (e.g., cancer) that is ameliorated, treated, inhibited, or alleviated by the inhibition of KRAS, including KRAS having a G12D mutation. In some embodiments, the disease, disorder, or condition is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer.

[0011] In a further aspect, the present disclosure provides a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, for use as a medicament. In some embodiments, the medicament is used to treat a disease, disorder, or condition (e.g., cancer). In some embodiments, the disease, disorder, or condition is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides compounds of Formulas I and II, which may have useful KRAS inhibitory activity and may be used to treat or prevent diseases, disorders, or conditions in which KRAS plays an active role. In particular, certain compounds provided herein may have useful inhibitory activity of KRAS with a G12D mutation, whether in an active (GTP-bound) or inactive (GDP-bound) conformation. The present disclosure also provides pharmaceutical compositions comprising one or more compounds provided herein in combination with a pharmaceutically acceptable carrier, as well as methods for preparing and using such compounds and compositions. The present disclosure also provides methods for inhibiting KRAS, including KRAS with a G12D mutation, in an active or inactive conformation. In one aspect, the present disclosure provides a method for treating a disease mediated by KRAS, including KRAS with a G12D mutation, in a subject in need of such treatment, comprising administering a therapeutically effective amount of a compound or composition provided herein to the subject. Also provided herein is the use of certain compounds provided herein in the manufacture of a medicament for the treatment of a disease, disorder, or condition that is improved, treated, inhibited, or alleviated by inhibiting KRAS, including KRAS with a G12D mutation. In some embodiments, the disease, disorder, or condition is cancer.

[0013] When a range of values ​​is disclosed, where n1 and n2 are numerical values, and the expression "n1... to n2" or "between n1... and n2" is used, the expression is intended to include the numerical values ​​themselves and the range therebetween, unless otherwise specified. The range may be an integer or continuous value between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, compared to the range "1 to 3 μM (micromolar)," this range is intended to include 1 μM, 3 μM, and all values ​​therebetween, to any significant figure (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0014] As used herein, "about" is intended to qualify the numerical value it modifies, meaning that such value varies within a margin of error. Unless a specific margin of error, such as the standard deviation for the average value shown in a graph or table of data, is stated, the term "about" should be understood to mean not only a range encompassing the stated value, but also a range encompassed by rounding up or down to that numerical value, taking into account significant digits.

[0015] As used herein, "acyl," alone or in combination, refers to a carbonyl bonded to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bonded to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bonded to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0016] As used herein, "alkenyl," alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, an alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-), (-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include an "alkenylene" group.

[0017] "Alkynyl" refers to an alkyl group having at least two carbon atoms and at least one triple bond, with the indicated number of carbon atoms (i.e., C 2~6 refers to a straight or branched chain hydrocarbon having 2 to 6 carbons. Alkynyl refers to a C2, C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 2~7 , C 2~8 , C 2~9 , C 2~10 , C3, C 3~4 , C 3~5 , C 3~6 , C4, C 4~5 , C 4~6 , C5, C 5~6 and C. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hexatriynyl.

[0018] As used herein, "alkoxy," alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined herein. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0019] As used herein, "alkyl," alone or in combination, refers to a straight- or branched-chain alkyl radical containing 1 to 20 carbon atoms (e.g., C 1~20 In certain embodiments, alkyl contains 1 to 10 carbon atoms (e.g., C 1~10 In further embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C 1~8 In further embodiments, alkyl contains 1 to 6 carbon atoms (e.g., C 1~6 In further embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C 1~3 alkyl). Alkyl groups are unsubstituted or substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. As used herein, the term "alkylene," alone or in combination, means a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" can include an "alkylene" group.

[0020] As used herein, "alkylamino," alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups.

[0021] As used herein, "alkylthio," alone or in combination, refers to an alkyl thioether (RS-) radical, where the term alkyl is as defined herein and the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0022] As used herein, "amido" and "carbamoyl," alone or in combination, refer to an amino group, as described herein, attached to the parent molecular moiety through a carbonyl group, or vice versa. As used herein, an "amido" group includes "C-amido" and "N-amido" groups. As used herein, the term "C-amido," alone or in combination, refers to a -C(O)N(RR') group, where R and R' are as defined herein or by the specified specifically recited "R" group. In some embodiments, an "amido" group includes -C(O)NH, C 1~4 Alkylamides and di(C 1~4 As used herein, "C alkyl" amides include 1~4 The term "alkylamide" refers to -C(O)NH(C 1~4 alkyl), and C 1~4 Alkyl is as defined herein. As used herein, the term "N-amido," alone or in combination, refers to the group RC(O)N(R')-, where R and R' are as defined herein or by the specifically recited "R" group specified. As used herein, the term "acylamino," alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(O)NH-).

[0023] As used herein, "amino," alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be unsubstituted or substituted. Additionally, R and R' may combine to form an unsubstituted or substituted heterocycloalkyl. An "amino" group may be a primary amine (e.g., -NH), a secondary or disubstituted amine (e.g., -NHR where R is not hydrogen), or a tertiary or trisubstituted amine (e.g., -NRR', where neither R nor R' is hydrogen).

[0024] As used herein, "aryl," alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings, and such polycyclic ring systems are fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. The aryl moiety can contain, for example, 5 to 20 carbon atoms, for example, 5 to 12 carbon atoms, for example, 5 or 6 carbon atoms.

[0025] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0026] The terms "arylalkoxy" or "araloxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0027] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0028] The term "aryloxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxygen.

[0029] As used herein, "carbamate," alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which can be attached to the parent molecular moiety through either the nitrogen terminus or the acid terminus, and is unsubstituted or substituted as defined herein.

[0030] As used herein, "O-carbamyl," alone or in combination, refers to an --OC(O)NRR' group, where R and R' are as defined herein.

[0031] As used herein, "N-carbamyl," alone or in combination, refers to an ROC(O)NR'- group, where R and R' are as defined herein.

[0032] As used herein, "carbonyl" when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.

[0033] As used herein, "carboxyl" or "carboxy" refers to -C(O)OH or the corresponding "carboxylate" anion, e.g., as in a carboxylic acid salt. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

[0034] As used herein, "cyano," alone or in combination, refers to --CN.

[0035] As used herein, "cycloalkyl" or alternatively "carbocycle," alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing 3 to 12 carbon atom ring members, and may be a benzo-fused ring system, unsubstituted or substituted as defined herein. Carbocycles can include bridged and / or spirocyclic ring systems (e.g., systems containing two rings that share one carbon atom). The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In certain embodiments, the cycloalkyl (or cycloalkenyl) group contains 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused ring systems such as decahydronaphthalene and octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated forms. Examples of the latter type of isomer are generally bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0036] As used herein, "ester," alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0037] As used herein, "ether," alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0038] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0039] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0040] As used herein, "haloalkyl," alone or in combination, refers to an alkyl radical having the meaning described herein in which one or more hydrogens have been replaced with halogen. Specifically included are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. By way of example, a monohaloalkyl radical can have an iodo, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0041] As used herein, "heteroalkyl," alone or in combination, refers to a stable, straight or branched hydrocarbon chain that is fully saturated or has 1 to 3 degrees of unsaturation, and consists of the specified number of carbon atoms and 1 to 3 selected heteroatoms selected from N, O, and S, where the N and S atoms may be optionally oxidized, and the N heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

[0042] As used herein, "heteroaryl," alone or in combination, refers to a 3- to 15-membered aromatic monocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, and which ring or ring system contains at least one atom selected from N, O, and S. In certain embodiments, the heteroaryl contains 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the alkenyl contains 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocycle is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0043] As used herein, "heterocycloalkyl" and, interchangeably, "heterocycle," alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl contains 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl contains 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl contains 3 to 8 heteroatoms in each ring. In further embodiments, the heterocycloalkyl contains 3 to 7 heteroatoms in each ring. In even further embodiments, the heterocycloalkyl contains 5 to 6 heteroatoms in each ring. Heterocycles can include bridged ring systems and / or spirocyclic systems (e.g., systems containing two rings that share one atom, such as one carbon atom). "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and fused carbocyclic and benzofused ring systems; both terms also include systems in which a heterocycle is fused with an aryl group or an additional heterocyclic group as defined herein. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. A heterocycle group may be unsubstituted or substituted, unless specifically prohibited.

[0044] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, ie, --NN--.

[0045] As used herein, "hydroxy," alone or in combination, refers to --OH.

[0046] The term "hydroxyalkyl," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an alkyl group.

[0047] As used herein, "iminohydroxy," alone or in combination, refers to =N(OH) and =NO-.

[0048] As used herein, "lower amino," alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which is unsubstituted or substituted.

[0049] As used herein, "mercaptyl," alone or in combination, refers to an RS-group, with R as defined herein.

[0050] As used herein, alone or in combination, "nitro" refers to --NO.sub.2.

[0051] As used herein, "oxy" or "oxa," alone or in combination, refers to --O--.

[0052] As used herein, "oxo," alone or in combination, refers to =O.

[0053] "Perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms have been replaced with halogen atoms.

[0054] As used herein, "perhaloalkyl," alone or in combination, refers to an alkyl group in which all of the hydrogen atoms have been replaced with halogen atoms.

[0055] As used herein with respect to a chemical structure or portion thereof, "ring" or its equivalent "cycle" means a group in which all atoms are members of a common ring structure. The ring may be saturated or unsaturated (including aromatic) and may have 3 to 9 members, unless otherwise specified. When the ring is heterocyclic, it may contain B, N, O, S, C(O), S(O), or a combination thereof. m and 1 to 4 heteroatoms or heteroatom-containing groups selected from the following. Unless specifically prohibited, rings are unsubstituted or substituted. Two or more rings may be fused (e.g., two or more rings may share a bond and two common atoms). Two or more rings may be linked to each other in a spiro configuration, such that only one atom is shared between the two rings. Additionally or alternatively, two or more rings may be configured in a bridged configuration, such that three or more atoms are shared between the two or more rings.

[0056] As used herein, "sulfonate," "sulfonic acid," and "sulfonic" alone or in combination refer to the -SO3H group and its anion when sulfonic acid is used to form a salt.

[0057] As used herein, "sulfanyl," alone or in combination, refers to --S--.

[0058] As used herein, "sulfinyl," alone or in combination, refers to --S(O)--.

[0059] As used herein, alone or in combination, "sulfonyl" refers to -SO2.

[0060] "N-sulfonamido" refers to an RS(=O)2NR'- group, with R and R' as defined herein.

[0061] "S-sulfonamido" refers to a -S(=O)2NRR'- group, with R and R' as defined herein.

[0062] As used herein, "tautomer" refers to one of two or more isomers that rapidly interconvert, either alone or in combination. Generally, this interconversion is rapid enough that individual tautomers cannot be isolated in the absence of other tautomers. The ratio of the amounts of tautomers can depend on solvent composition, ionic strength, pH, and other solution parameters. The ratio of the amounts of tautomers can vary in a particular solution and in the microenvironment of a biomolecule binding site within the solution. Examples of tautomers known in the art include keto / enol, enamine / imine, and lactam / lactim tautomers. Examples of tautomers known in the art also include 2-hydroxypyridine / 2(1H)-pyridone and 2-aminopyridine / 2(1H)-iminopyridone tautomers.

[0063] As used herein, "thia" and "thio," alone or in combination, refer to the -S- group or ethers where the oxygen is replaced by sulfur. The oxidized derivatives of the thio group, i.e., sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0064] As used herein, "thiol," alone or in combination, refers to a --SH group.

[0065] As used herein, "thiocarbonyl" when alone includes thioformyl-C(S)H and in combination is a -C(S)- group.

[0066] "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.

[0067] "O-thiocarbamyl" refers to the group --OC(S)NRR', where R and R' are as defined herein.

[0068] "Thiocyanato" refers to the group -CNS.

[0069] Any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the last element of such a definition is the element that is attached to the parent moiety. For example, the composite group alkylamido represents an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group.

[0070] As described herein, groups can be substituted or unsubstituted (e.g., "optionally substituted"). Unless otherwise specified, any group can be substituted with one or more substituents, such as one or more of the substituents provided herein. Examples of substituents with which a group can be substituted include, but are not limited to, the following groups or particular specified sets of groups, either alone or in combination: alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), alkanoyl (e.g., C 1~20 Alkanoyl, e.g., C 1~10 Alkanoyl, e.g., C 1~6 alkanoyl), heteroalkyl (e.g., heteroalkyl moieties containing 1 to 20 carbon atoms and 1 to 6 heteroatoms, e.g., heteroalkyl moieties containing 1 to 6 carbon atoms and 1 to 3 heteroatoms), haloalkyl (e.g., halo-substituted C 1~20 Alkyl, e.g. halo-substituted C 1~10 Alkyl, halo-substituted C 1~6 alkyl), haloalkenyl (e.g., halo-substituted C 2~20 Alkenyl, e.g., halo-substituted C 2~6 alkenyl), haloalkynyl (e.g., halo-substituted C 2~20Alkynyl, e.g., halo-substituted C 2~6 alkynyl), perhaloalkyl (e.g., C 1~20 Perhaloalkyl, e.g., C 1~6 Perhaloalkyl, e.g., C 1~3 perhaloalkyl), perhaloalkoxy (e.g., C 1~20 Perhaloalkoxy, e.g. C 1~6 perhaloalkoxy), phenyl, aryl (e.g., C 5~20 Aryl, e.g., C 5~10 Aryl, e.g., C 5~6 aryl), aryloxy (e.g., C 5~20 Aryloxy, e.g., C 5~10 Aryloxy, e.g., C 5~6 aryloxy), alkoxy (e.g., C 1~20 Alkoxy, e.g. C 1~10 Alkoxy, e.g., C 1~6 alkoxy), haloalkoxy (e.g., C 1~20 Haloalkoxy, e.g., C 1~10 Haloalkoxy, e.g., C 1~6 haloalkoxy), oxo, acyloxy (e.g., an acyloxy group containing 1 to 20 carbon atoms, e.g., 1 to 10 carbon atoms, e.g., 1 to 6 carbon atoms), carbonyl (e.g., C(O) or C=O), carboxyl (e.g., C(O)O), alkylcarbonyl (e.g., C 1~20 Alkylcarbonyl, e.g., C 1~10 Alkylcarbonyl, e.g., C 1~6 Alkylcarbonyl, e.g., C 1~3 alkylcarbonyl), carboxyl esters (e.g., C(O)OR, where R is, for example, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein), carboxamido, cyano (e.g., CN), hydrogen, halogen (e.g., iodine, bromine, chlorine, or fluorine), hydroxy, amino (e.g., NR'R", where R' and R" are independently, for example, hydrogen, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein), alkylamino (e.g., NR'R" where R' is alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), and R" is, for example, hydrogen, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein), arylamino (e.g., NR'R", where R' is aryl (e.g., C 5~20 Aryl, e.g., C 5~10 Aryl, e.g., C 5~6 aryl), and R" is, for example, hydrogen, alkyl (e.g., C1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein), amido (e.g., C(O)NR'R", where R' and R" are independently, for example, hydrogen, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein), nitro (e.g., NO), thiol (e.g., SH), alkylthio (e.g., C substituted with a thiol group). 1~20 Alkyl, e.g., C substituted with thiol groups 1~10 Alkyl, e.g., C substituted with thiol groups 1~6 Alkyl, e.g., C substituted with thiol groups 1~3 alkyl), haloalkylthio (e.g., C 1~20 Haloalkylthio, e.g., C 1~10 Haloalkylthio, e.g., C 1~6 Haloalkylthio, e.g., C 1~3 haloalkylthio), perhaloalkylthio (e.g., C 1~20 Perhaloalkylthio, e.g., C 1~10 Perhaloalkylthio, e.g., C 1~6 Perhaloalkylthio, e.g., C1~3 perhaloalkylthio), arylthiols (e.g., C 5~20 Aryl thiols, such as C 5~10 Aryl thiols, such as C 5~6 arylthiols), sulfonates (e.g., S(O)OR, where R is, for example, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6 alkynyl), any of which may be substituted with any group provided herein; sulfonic acid (e.g., S(O)OH); trisubstituted silyl (e.g., SiR'R"R*, where R', R", and R* are independently, for example, alkyl (e.g., C 1~20 Alkyl, e.g., C 1~10 Alkyl, e.g., C 1~6 Alkyl, e.g., C 1~3 alkyl), alkenyl (e.g., (e.g., C 2~20 Alkenyl, e.g., C 2~10 Alkenyl, e.g., C 2~6 alkenyl), or alkynyl (e.g., C 2~20 Alkynyl, e.g., C 2~10 Alkynyl, e.g., C 2~6alkynyl), any of which may be substituted with any group provided herein; optionally, trisubstituted silyl may be trimethylsilyl), N, SCH, C(O)CH, COCH, COH, pyridinyl, thiophene, furanyl, carbamate, and urea. Additional groups are contemplated. Where structurally possible, two substituents may be joined together to form a fused 5-, 6-, or 7-membered carbocyclic or heterocyclic ring consisting of 0-3 heteroatoms (e.g., N, O, S, etc.), forming, for example, methylenedioxy or ethylenedioxy. Unsubstituted or substituted groups may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCF). When a substituent is described without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents for a particular moiety can be defined as needed, and in such cases, the optional substitution is as defined, often immediately following the phrase "unsubstituted or substituted."

[0071] Unless otherwise defined, terms such as R, R', R'', and R*, by themselves and when presented without a number designation, refer to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which are unsubstituted or substituted (e.g., as described herein). Such R and R' groups should be understood as being unsubstituted or substituted as defined herein. Whether or not the R group is designated by a number, R, R', and R nAll R groups, including n=(1, 2, 3, ... n), all substituents, and all terms should be understood as independent of each other with respect to selection from a group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than once in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to the parent molecule from either end as depicted or may occupy a given position in the element chain. For example, an unsymmetrical group such as -C(O)N(R)- can be attached to the parent moiety at either the carbon or the nitrogen.

[0072] A "bond" refers to a covalent bond between two atoms, or between two moieties when the atoms connected by the bond are considered part of a larger substructure. Unless otherwise specified, bonds may be single, double, or triple. A dashed line between two atoms in a molecular diagram indicates that there may or may not be an additional bond at that position.

[0073] Asymmetric centers may exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It is understood that the present disclosure encompasses all stereochemical isomers, including diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Starting compounds of particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, and all tautomers are provided by the present disclosure. Furthermore, compounds provided herein may include conformational isomers, where the compounds contain groups that can be oriented in different conformations relative to another moiety. Furthermore, the compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0074] "Combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, e.g., in a single dosage unit (e.g., capsule) having a fixed ratio of active ingredients, or in multiple separate dosage units (e.g., capsules) for each active ingredient. Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0075] As used herein, a "KRAS inhibitor" refers to an inhibitor of KRAS that has an IC50 of about 100 μM or less, more typically about 50 μM or less, with respect to KRAS activity, as measured in an assay generally described herein, such as a surface plasmon resonance KRAS-G12D protein binding assay and / or a KRASG12D protein-effector protein interaction disruption assay. 50 It is used to refer to compounds that exhibit "IC 50 " is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., KRAS) to half of its maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibitory activity against KRAS. In certain embodiments, a compound has an IC of about 50 μM or less against KRAS (e.g., KRAS with a G12D mutation) as measured in the KRAS assay described herein. 50 and in a further embodiment, the compound exhibits an IC of about 10 μM or less against KRAS (e.g., KRAS with a G12D mutation). 50 and in still further embodiments, the compound exhibits an IC of about 1 μM or less against KRAS (e.g., KRAS with a G12D mutation). 50 and in still further embodiments, the compound exhibits an IC of about 200 nM or less against KRAS (e.g., KRAS with a G12D mutation). 50In some embodiments, the compound exhibits an IC of less than about 50 μM, such as about 40 μM, 30 μM, 20 μM, 10 μM, 5 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, or less, against KRAS (e.g., KRAS with a G12D mutation). 50 In certain embodiments, the compound exhibits an IC of less than about 1 μM against KRAS (e.g., KRAS with a G12D mutation). 50 In some embodiments, the inhibitory activity of a KRAS inhibitor against a KRAS having a G12D mutation is greater than its inhibitory activity against a KRAS having another mutation, such as a G12C, G12R, G12S, G12A, or G12V mutation. For example, in some embodiments, the KRAS inhibitors provided herein have at least 2-fold, 5-fold, 10-fold, 20-fold, or more inhibitory activity against a KRAS having a G12D mutation compared to a KRAS having another mutation, such as a G12C mutation, such as a G12C, G12R, G12S, G12A, or G12V mutation. In some embodiments, the KRAS inhibitors provided herein have a higher inhibitory activity against an active KRAS having a G12D mutation than against an inactive KRAS having a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have a lower inhibitory activity against an active KRAS having a G12D mutation than against an inactive KRAS having a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have similar inhibitory activity against active KRAS with a G12D mutation and inactive KRAS. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against the K-RAS4a splice variant. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against the K-RAS4b splice variant. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against both the K-RAS4a and K-RAS4b splice variants.

[0076] A "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease, disorder, or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0077] The term "therapeutically acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient, that is free from excessive toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use.

[0078] The terms "treat," "therapeutic," and "treatment" refer to any indication of successful treatment or amelioration of an injury, condition, or state, including any objective or subjective parameter, such as remission, remission, disappearance of symptoms, or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, and / or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Treatment may be preemptive in nature, i.e., can include prevention of a disease, disorder, or state, prevention of the onset of one or more symptoms of a disease, disorder, or state, and / or prevention of worsening of a disease, disorder, or state. Prevention of a disease, disorder, or state can include protection from the disease altogether and / or prevention of the progression of the disease (e.g., to a later stage of the disease, disorder, or state). For example, preventing a disease may mean preventing the symptoms of a disease, disorder, or condition to a clinically significant or detectable level, rather than completely eliminating all effects associated with the disease at all levels.

[0079] "Patient" or "subject" refers to a living organism suffering from or likely to suffer from a disease, disorder, or condition treatable by administration of a compound or pharmaceutical composition provided herein. Non-limiting examples include humans, rats, mice, rabbits, hamsters, guinea pigs, hamsters, cats, dogs, non-human primates (e.g., monkeys), goats, pigs, sheep, cattle, deer, horses, and other non-mammals. Examples of mammals treatable by administration of a compound or pharmaceutical composition provided herein include, for example, rodents (e.g., rats, mice, squirrels, guinea pigs, hamsters, etc.), lagomorphs (e.g., rabbits, hares, etc.), primates (monkeys, apes, etc.), bovines (e.g., cattle), perissodactyls (e.g., horses), artiodactyls (e.g., bovines such as cattle, ovines such as sheep, caprines such as goats, and porcines such as pigs), and marsupials (e.g., kangaroos, wallabies, wallaroos, sugar gliders, etc.). In some embodiments, the patient or subject is a human. In some embodiments, the patient or subject is a companion animal such as a cat or dog. In some embodiments, the patient or subject is a livestock animal such as a goat, sheep, cow, pig, or horse. In some embodiments, the patient or subject is a primate (e.g., a monkey), a marsupial (e.g., a kangaroo, wallaby, wallaroo, sugar glider, etc.), or an exotic animal such as a non-domesticated or hybrid cat or dog.

[0080] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0081] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of and absorption by a subject of an active agent. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

[0082] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein may also exist as prodrugs. Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to yield the compounds. Furthermore, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound or parent drug. For example, a prodrug may be bioavailable by oral administration even when the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0083] The compounds disclosed herein may exist as therapeutically acceptable salts. The present disclosure includes compounds provided herein in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may also be useful in the preparation and purification of the target compounds. Base addition salts are also formed and are pharmaceutically acceptable.

[0084] As used herein, the term "therapeutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterionic form of a compound disclosed herein that is therapeutically acceptable as defined herein. Salts can be prepared during the final isolation and purification of the compound, or separately by reacting the free base form of the appropriate compound with an appropriate acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, and malonate. Salts include, but are not limited to, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate), and undecanoate. In addition, the basic group of the compounds disclosed herein can be quaternized with, for example, methyl chloride, bromide, and iodide, ethyl chloride, bromide, and iodide, propyl chloride, bromide, and iodide, and butyl chloride, bromide, and iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl chloride, bromide, and iodide, lauryl chloride, bromide, and iodide, myristyl chloride, bromide, and iodide, and steryl chloride, bromide, and iodide; and benzyl bromide and phenylethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.Salts can also be formed by coordination of the compounds with alkali metal or alkaline earth ions. Thus, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0085] Base addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0086] Salts of compounds can be prepared by reacting the free base form of the appropriate compound with a suitable acid.

[0087] "KRASG12D-positive cancer" refers to a cancer characterized by a KRASG12D mutation.

[0088] As used herein, a "combined therapeutically effective amount" refers to amounts of therapeutic agents that, when administered separately (chronologically staggered, especially sequentially) to a warm-blooded animal, especially a human being, exhibit an (additive, but preferably synergistic) interaction (combined therapeutic effect). Whether this is the case can be determined, inter alia, by following blood levels indicating that both compounds are present in the blood of the human being treated for at least a specified time interval.

[0089] As used herein, "synergistic effect" refers to the effect of at least two therapeutic agents, a KRASG12D inhibitor as defined herein and an additional agent, which may be an agent configured to treat a disease, disorder, or condition, or a symptom thereof. The effect may be, for example, delaying the progression of a symptom of a proliferative disease, such as cancer, particularly lung cancer, or a symptom thereof. Similarly, a "synergistically effective amount" refers to the amount required to achieve a synergistic effect.

[0090] "a," ​​"an," or "a(n)," when used herein with respect to a group of substituents or "substituents," means at least one. For example, if a compound is substituted with "an" alkyl or aryl, the compound is unsubstituted or substituted with at least one alkyl and / or at least one aryl, where each alkyl and / or aryl is optionally different. In another example, if a compound is substituted with "a" substituents, the compound is substituted with at least one substituent, where each substituent is optionally different.

[0091] compound In one aspect, the present disclosure provides a compound represented by formula (I): [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8, a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H, a 3- to 6-membered carbocyclic ring, and C 1~6 alkyl, provided that the alkyl is a 3- to 6-membered carbocyclic or C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocycle, 3- to 6-membered heterocycle, 5- to 6-membered heteroaryl, and phenyl, with the proviso that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocycle, heterocycle, heteroaryl, and phenyl is unsubstituted or substituted with one or more R14 is replaced by R 6 is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, with the proviso that any phenyl, monocyclic heteroaryl, bicyclic aryl, and bicyclic heteroaryl is unsubstituted or contains one or more R 15 is replaced by R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from H, heterocycle, and alkylheterocycle, provided that the heterocycle or alkylheterocycle is unsubstituted or contains one or more R 16 and the alkyl portion of any alkyl heterocycle is C 1~6 alkyl, Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is a halogen, -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is halogen, -OR 12 , -CN, -N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is halogen, -OR 12 , -CN, -N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, C 1~6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl, 3- to 6-membered heterocycle, and H, with the proviso that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, halogen, and a 3- to 6-membered carbocyclic ring; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0092] In some embodiments, the disclosure provides a compound of Formula I or a salt thereof (eg, a pharmaceutically acceptable salt).

[0093] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkylheterocycle. In some embodiments, R 8 is an alkyl heterocycle, provided that the alkyl portion of the alkyl heterocycle is C 1~6 In some embodiments, R 8is —CH (heterocycle). In some embodiments, the heterocycle of the heterocycle or alkylheterocycle contains 4 to 8 members including at least one heteroatom (e.g., 1 to 2 heteroatoms) selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8 includes a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, the heterocycle of the heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle of the heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is a 4-6 ... monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is a 4-6 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is —OCH. In some embodiments, at least one R 16 is halogen (e.g., F). In some embodiments, at least one R 16 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, each R 16 is a halogen, C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, each R 16 are independently selected from —F, —CH 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CH 2 CN, —OCH 3 , and —OCHF 2 .

[0094] In some embodiments, R 1 is selected from: [ka] However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R b is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0095] In some embodiments, R 1 teeth, [ka] is selected from.

[0096] In some embodiments, R 1 teeth, [ka] is selected from However, each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, and R a or R c C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, one R a is halogen, C 1~6 Alkyl and -OR 12 Selected from other R a is H. In some embodiments, one R a is halogen (e.g., F). In some embodiments, two R a is halogen (e.g., F). In some embodiments, one R a But, -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a But C 1~6 In some embodiments, two R a But C 1~6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0097] In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0098] In some embodiments, R 1 teeth, [ka] is selected from.

[0099] In some embodiments, R 1 teeth, [ka] is selected from.

[0100] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some such embodiments, R 16 is -N(R 12 )2, C 1~6 In some embodiments, R 16 is -N(C 1~6 alkyl), e.g., —N(CH). In some embodiments, R 16 is C 1~6 In some embodiments, R 16 is a bicyclic 6-membered heterocycle having one nitrogen atom. In some embodiments, R 1 teeth, [ka] is selected from the group consisting of:

[0101] In some embodiments, R 1 is hydrogen.

[0102] In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some such embodiments, each R 13 -OR 22 (e.g., —OH) and —CN. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is selected from -CH, -CHCH, -CHCHOH, -CHCHCN, and -CH(CH). 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0103] In some embodiments, R 3 is C 1~6 alkyl, C 1~6 Alkyl is one or more R 9 In some embodiments, R 3 is -N(R 17 )2 substituted C 1~6 alkyl, provided that each R 17 is C 1~6 In some embodiments, R 3 is a C substituted with -NH2, -NH(CH3), or -N(CH3)2 1~6 In some embodiments, R 3 is -N(R 17 )C(O)C 1~6 C substituted with alkyl (e.g., -N(H)C(O)CH3) 1~6 In some embodiments, R 3 -OR 17 (e.g., -OH) substituted C 1~6 It is alkyl.

[0104] In some embodiments, R 3 teeth, [ka] is selected from.

[0105] In some embodiments, R 3 is a carbocyclic ring, which is unsubstituted or has one or more R 10 In some embodiments, R 3 is a 4- to 6-membered carbocyclic ring, which is unsubstituted or has one or more R 10 In some embodiments, R 3 is a polycyclic carbocycle (e.g., a 5- to 6-membered bicyclic carbocycle). In some embodiments, R 3 is a monocyclic carbocyclic ring (e.g., a 4- to 6-membered monocyclic carbocyclic ring). 3 is -N(R 19 )2, and each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH2.

[0106] In some embodiments, R 3 teeth, [ka] is selected from.

[0107] In some embodiments, R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 10In some embodiments, R 3 is a polycyclic heterocycle (e.g., a 6- to 8-membered bicyclic heterocycle). In some embodiments, R 3 is a monocyclic heterocycle (e.g., a 4- to 6-membered monocyclic heterocycle). In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is unsubstituted or contains one or more R 10 wherein each R 10 is a halogen, -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, and C 1~6 alkyl, any C 1~6 The alkyl may be unsubstituted or may have one or more R 20 In some embodiments, R 3 is unsubstituted or is selected from the group consisting of -F, -CH3, -CH2F, -CH2CN, -C(O)CH3, -C(O)CH2NH2, -C(O)NH2, and [ka] In some embodiments, R is a heterocycle substituted with one or more groups selected from 3 is -N(R 19 )2, and each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a heterocycle substituted with -NH2.

[0108] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10is replaced by .

[0109] In some embodiments, R 3 teeth, [ka] is selected from.

[0110] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0111] In some embodiments, R 2 or R 3 contains an amino moiety (e.g., -NRR'). In some embodiments, R 2 or R 3 is an amino moiety (i.e., -N(R 17 )2 or -N(R 19 )2) has been replaced.

[0112] In some embodiments, R 2 and R 3 means that together with the atom to which they are attached (e.g., a nitrogen atom) are unsubstituted or contain one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom), form a 4-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3and together with the atom to which they are attached (e.g., a nitrogen atom), form a 4-7 membered heterocycle having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom), form a 7-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 In some such embodiments, each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R 11 -NH2, -NHCH3, -C(O)CH3, -C(O)NH2, -C(O)CH2NH2, -CH3, -CH2CH3, -CH(CH3)2, -CH2CN, -CH2C(O)NH2, -C(NH)NHCN, -CH2OH, and [ka] are independently selected from

[0113] In some embodiments, R 2 and R 3 together with the atom to which they are attached form a heterocyclic ring selected from: [ka] Any of these may be unsubstituted or may contain one or more R 11 is replaced by .

[0114] In some embodiments, R 2 and R 3 together with the atom to which they are attached form a heterocyclic ring selected from: [ka]

[0115] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0116] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] Any of these may be unsubstituted or may contain one or more R 11 is replaced by .

[0117] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0118] In some embodiments, R 2 and R 3 means, together with the nitrogen atom to which they are attached, unsubstituted or containing one or more R 11 and forming a heterocycle substituted with a heterocycle containing an additional nitrogen atom and / or a group containing an amino moiety (e.g., —N(R 19 )2) has been replaced.

[0119] In some embodiments, R 4 is H. In some embodiments, R 4 is halogen. In some embodiments, R 4 HA-OR 12 In some embodiments, R 4 is -OCH3.

[0120] In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 (e.g., one or more -OR 12 or —CN). In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is a 3- to 6-membered heterocycle (e.g., a 3- to 6-membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with 5 is unsubstituted or contains one or more R 14In some embodiments, R is a 5- or 6-membered aryl or heteroaryl moiety substituted with 5 is phenyl. In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1~6 In some embodiments, R is a 5-6 membered heteroaryl substituted with alkyl. 5 is pyridyl, furanyl, or imidazolyl, each of which is unsubstituted or contains one or more R 14 (For example, C 1~6 In some embodiments, R 5 is furanyl.

[0121] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is an unsubstituted C such as methyl or ethyl 1~6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1~6 In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH 3 , —CH 2 CH 3 , —CF 2 H, —CF 3 , —CF 2 CH 3 , and —CH 2 CN.

[0122] In some embodiments, R 5 is C 2~6 In some embodiments, R is alkenyl. 5 is C 2~6 Alkynyl (eg, ethynyl).

[0123] In some embodiments, R 5 -OR 12 is selected from, where R 12is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is -OCH3, -OCF3, or -OCF2H.

[0124] In some embodiments, R 5 is -CN.

[0125] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F.

[0126] In some embodiments, R 5 is hydrogen.

[0127] In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 7 -OR 12 where R 12 is H and unsubstituted or one or more R 13 C replaced with 1~6 In some embodiments, R 7 is —OH, —OCH, or —OCHCF. In some embodiments, R 7 is -CN. In some embodiments, R 7 is hydrogen.

[0128] In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R5 , and R 7 are each selected from Cl and F.

[0129] In some embodiments, R 6 is a bicyclic aryl or bicyclic heteroaryl, provided that the aryl or heteroaryl is unsubstituted or contains one or more R 15 In some embodiments, R 6 is a bicyclic aryl or bicyclic heteroaryl, provided that the aryl or heteroaryl is not bound to one or more R 15 is replaced by .

[0130] In some embodiments, R 6 is one or more R 15 In some embodiments, R 6 is one or more R 15 In some embodiments, R 6 teeth, [ka] is selected from.

[0131] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 6 is one or more R 15 In some embodiments, R is a bicyclic heteroaryl substituted with 6 is one or more R 15 In some such embodiments, at least one R is a 9-membered heteroaryl having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with 15 is -N(R 12 )2 (e.g., —NH2). In some embodiments, at least one R 15is halogen (e.g., F). In some embodiments, each R 15 is halogen, -CN, and -N(R 12 )2. In some embodiments, R 6 There are at least two R 15 (e.g., at least halogen and -NH2).

[0132] In some embodiments, R 6 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 15 is replaced by .

[0133] In some embodiments, R 6 teeth, [ka] is selected from.

[0134] In some embodiments, R 6 teeth, [ka] is selected from.

[0135] In some embodiments, R 6 teeth: [ka]

[0136] In some embodiments, R 6 teeth, [ka] is.

[0137] In some embodiments, R 6 is phenyl or heteroaryl, provided that the phenyl or heteroaryl is unsubstituted or contains one or more R 15 is replaced by .

[0138] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some such embodiments, each R 15 is halogen, -OR 12 , -CN, and -N(R 12 )2. In some embodiments, R 6 teeth, [ka] is selected from.

[0139] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some embodiments, R is a monocyclic 5-6 membered heteroaryl substituted with 6 is unsubstituted or contains one or more R 15 In some embodiments, each R 15 is N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 6 teeth, [ka] is.

[0140] In some embodiments, (i) R 2 is C 1~6 selected from alkyl and 3- to 6-membered carbocyclic rings, provided that C 1~6 Alkyl and 3- to 6-membered carbocyclic rings are unsubstituted or have one or more R 13and (ii) R 3 is selected from carbocycles and heterocycles, and the carbocycle or heterocycle is unsubstituted or contains one or more R 10 In some embodiments, R 4 is H. In some embodiments, R 7 is halogen (e.g., F). In some embodiments, R 5 is C 1~6 selected from alkyl, halogen, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 In some embodiments, R 6 is one or more R 15 In some embodiments, R is a bicyclic heteroaryl substituted with 6 teeth, [ka] is.

[0141] In some embodiments, R 1 HA-OR 8 and R 8 is a heterocycle or an alkylheterocycle. In some embodiments, R 1 teeth, [ka] is selected from.

[0142] In some embodiments, R 1 teeth, [ka] is selected from.

[0143] In some embodiments, (i) R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6alkyl (e.g., methyl or ethyl); and (ii) R 3 is unsubstituted or contains one or more R 10 In some embodiments, (i) R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6 alkyl (e.g., methyl or ethyl); and (ii) R 3 is unsubstituted or contains one or more R 10 In some embodiments, (i) R 2 is unsubstituted or contains one or more R 13 (ii) R 3 is unsubstituted or contains one or more R 10 In some embodiments, (i) R 2 is unsubstituted or contains one or more R 13 (ii) R 3 is unsubstituted or contains one or more R 10 and wherein the heterocycle is selected from heterocycles substituted with

[0144] In one aspect, the present disclosure provides a compound represented by formula IA: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 1 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above for Formula I, and are described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides compounds of formula IA, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0145] In some embodiments, the present disclosure provides a compound of formula IA, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8is selected from heterocycle and alkylheterocycle, any of which is unsubstituted or contains one or more R 16 and the alkyl portion of any alkyl heterocycle is C 1~6 alkyl, Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl, and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0146] In some embodiments, R 3is selected from carbocycles and heterocycles, provided that the carbocycle or heterocycle is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 is a 3- to 7-membered heterocycle substituted with

[0147] In some embodiments, R 3 is a carbocyclic ring, which may be unsubstituted or may contain one or more R 10 In some embodiments, R 3 is a polycyclic carbocycle. In some embodiments, R 3 is a monocyclic carbocycle. In some embodiments, R 3 is -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH2.

[0148] In some embodiments, R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is a polycyclic heterocycle. In some embodiments, R 3 is a monocyclic heterocycle. In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is -N(R 19 )2, wherein each R 19 is unsubstituted or substituted C 1~6In some embodiments, R 3 is a heterocycle substituted with -NH2.

[0149] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0150] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0151] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0152] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17 )2, where each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 It is alkyl.

[0153] In some embodiments, R 3 teeth, [ka] is selected from.

[0154] In some embodiments, R 3 comprises an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a component of a heterocycle. In some embodiments, the amino moiety is attached to a carbocycle or heterocycle. In some embodiments, the amino moiety is a primary amine (e.g., -NH). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0155] In some embodiments, R 1 is hydrogen.

[0156] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkyl heterocycle.

[0157] In some embodiments, R 8 is unsubstituted or contains one or more R 16 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle contains 4 to 8 members containing at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, the heterocycle comprises one or more R 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6alkenyl, and H. In some embodiments, at least one R 16 is -OCH3.

[0158] In some embodiments, R 1 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 1 teeth, [ka] is selected from.

[0159] In some embodiments, R 1 teeth, [ka] is selected from.

[0160] In some embodiments, R 1 teeth, [ka] is selected from However, each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, with the proviso that C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 1 teeth, [ka] is selected from.

[0161] In some embodiments, R 1 teeth, [ka] is selected from.

[0162] In some embodiments, R 1 teeth, [ka] is selected from.

[0163] In some embodiments, R 1 teeth, [ka] is selected from.

[0164] In some embodiments, R 1The heterocycle may be unsubstituted or may contain one or more R 16 In some embodiments, R is a 4-6 membered heterocycle containing a nitrogen atom substituted with 1 teeth, [ka] is selected from.

[0165] In some embodiments, R 6 teeth, [ka] is selected from.

[0166] [ka] is selected from.

[0167] In some embodiments, R 6 teeth, [ka] is.

[0168] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0169] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0170] In some embodiments, R 5 is halogen. In some embodiments, R 5is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0171] In some embodiments, (i) R 3 is a 4- or 5-membered heterocyclic ring containing one nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is a heterocycle or alkylheterocycle, and the heterocycle of the heterocycle or alkylheterocycle is a 4-8 membered ring system (e.g., an 8-membered ring system or a 5-membered ring system) containing one nitrogen atom. 4 is hydrogen. In some embodiments, (iv) R 7 is halogen. In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 In some embodiments, R 1 teeth, [ka] is selected from However, each R a and Rb is a halogen, C 1~6 Alkyl, -OR 12 and H. In some embodiments, R 1 teeth, [ka] is selected from.

[0172] In some embodiments, R 7 is F. In some embodiments, R 6 teeth, [ka] is selected from.

[0173] In some embodiments, R 5 is selected from —CF, —Cl, —CHCN, furan, and phenyl. In some embodiments, (i) R 3 is a 4-membered heterocycle containing one nitrogen atom (e.g., azetidine), the heterocycle being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is an alkylheterocycle, the heterocycle being an 8-membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is halogen. In some embodiments, (i) R 3 is a 5-membered heterocycle containing one nitrogen atom (e.g., azetidine), the heterocycle being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is an alkylheterocycle, the heterocycle being an 8-membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is a halogen.

[0174] In some embodiments, (i) R3 is a 4- or 5-membered heterocyclic ring containing one nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is a heterocycle or alkylheterocycle, and the heterocycle of the heterocycle or alkylheterocycle is a 4-8 membered ring system, such as a 5 membered ring system containing one nitrogen atom. 4 is H. In some embodiments, (iv) R 7 is halogen. In some embodiments, R 3 teeth, [ka] is selected from. Any of these may be unsubstituted or may contain one or more R 10 In some embodiments, R 1 teeth, [ka] is selected from However, each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, with the proviso that C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 1 teeth, [ka] is selected from.

[0175] In some embodiments, R 7 is F. In some embodiments, R 6 teeth, [ka] is selected from.

[0176] In some embodiments, R 5 is selected from —CF, —Cl, furan, and phenyl. In some embodiments, (i) R 3 is a 4-membered heterocycle containing one nitrogen atom (e.g., azetidine), the heterocycle being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is an alkylheterocycle, the heterocycle being a five-membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is halogen. In some embodiments, (i) R 3 is a 5-membered heterocycle containing one nitrogen atom (e.g., pyrrolidine), the heterocycle being unsubstituted or containing one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is an alkylheterocycle, the heterocycle being a five-membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is a halogen.

[0177] In some embodiments, (i) R 3 is unsubstituted or contains one or more R 10 (ii) a bridged carbocyclic or heterocyclic ring system substituted with R 1 HA-OR 8 where R 8 is a heterocycle or alkylheterocycle, and the heterocycle of the heterocycle or alkylheterocycle is a 4-8 membered ring system containing one nitrogen atom. 4 is H. In some embodiments, (iv) R 7 is halogen. In some embodiments, (i) R 3 is unsubstituted or contains one or more R 10 and (ii) a heterocyclic ring system substituted with R 1 HA-OR8 where R 8 is a heterocycle or alkylheterocycle, and the heterocycle of the heterocycle or alkylheterocycle is a 4-8 membered ring system containing one nitrogen atom. 3 is unsubstituted or contains one or more R 10 (ii) a carbocyclic ring system substituted with R 1 HA-OR 8 where R 8 is a heterocycle or alkylheterocycle, wherein the heterocycle of the heterocycle or alkylheterocycle is a 4-8 membered ring system containing one nitrogen atom. 3 teeth, [ka] is selected from.

[0178] In some embodiments, R 1 teeth, [ka] is selected from However, each R a and R b is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, with the proviso that C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 1 teeth, [ka] is selected from.

[0179] In some embodiments, R 1 teeth, [ka] is selected from.

[0180] In some embodiments, R 7 is F. In some embodiments, R 5 is -CF3. In some embodiments, R 6 teeth, [ka] is selected from.

[0181] In some embodiments, (i) R 3 is unsubstituted or contains one or more R 10 and (ii) R 1 HA-OR 8 where R 8 is an alkyl heterocycle, the heterocycle being a 4- to 8-membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is a halogen.

[0182] In some embodiments, (i) R 3 is C 1~6 Alkyl-N(R 17 )2, and (ii) R 1 HA-OR 8 where R 8 is an alkylheterocycle, the heterocycle being a 4-8 membered ring system containing one nitrogen atom. In some embodiments, (iii) R 4 is H. In some embodiments, (iv) R 7 is halogen. In some embodiments, R 3 teeth, [ka] is selected from.

[0183] In some embodiments, (i) R 3 is C2 alkyl-N(R 17 )2, and (ii) R 1 HA-OR8 where R 8 is an alkylheterocycle, the heterocycle being a 4-8 membered ring system containing one nitrogen atom; (iii) R 4 is H, and (iv) R 7 is halogen. In some embodiments, R 6 teeth, [ka] is.

[0184] In some embodiments, the present disclosure provides a compound of formula IA1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above for Formula I, and are described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides compounds of formula IA1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0185] In some embodiments, the present disclosure provides a compound according to formula IA1, wherein: R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0186] In some embodiments, R 3 is selected from carbocycles and heterocycles, provided that the carbocycle or heterocycle is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 is a 3- to 7-membered heterocycle substituted with

[0187] In some embodiments, R 3 teeth, [ka] any of which is unsubstituted or has one or more R 10 is replaced by .

[0188] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0189] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0190] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17 )2, where each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 It is alkyl.

[0191] In some embodiments, R 3 teeth, [ka] is selected from.

[0192] In some embodiments, R 3comprises an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a component of a heterocycle. In some embodiments, the amino moiety is attached to a carbocycle or heterocycle. In some embodiments, the amino moiety is a primary amine (e.g., -NH). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0193] In some embodiments, R 6 teeth, [ka] is selected from.

[0194] In some embodiments, R 6 teeth, [ka] is selected from.

[0195] In some embodiments, R 6 teeth, [ka] is.

[0196] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0197] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0198] In some embodiments, R 5 is halogen. In some embodiments, R5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0199] In some embodiments, the present disclosure provides a compound of formula IA2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are as defined above for Formula I, and are described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides compounds of formula IA2, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0200] In some embodiments, the disclosure provides a compound of formula IA2, wherein: R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19)2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0201] In some embodiments, R 8 is unsubstituted or contains one or more R 16 The present invention includes 3- to 6-membered heterocycles substituted with

[0202] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0203] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0204] In some embodiments, R 3 is selected from carbocycles and heterocycles, provided that the carbocycle or heterocycle is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0205] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0206] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17 In some embodiments, R 3 teeth, [ka] is selected from.

[0207] In some embodiments, R 3 contains an amino moiety (eg, -NRR').

[0208] In some embodiments, R 6 teeth, [ka] is selected from.

[0209] In some embodiments, R 6 teeth, [ka] is selected from.

[0210] In some embodiments, R 6 teeth, [ka] is.

[0211] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0212] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0213] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0214] In another aspect, the present disclosure provides a compound of formula IB: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 1 , R 4 , R 5 , R 6 , and R 7 is as defined above for formula I, and is described herein as a class and subclass, both alone and in combination, and ring A is unsubstituted or contains one or more R 11 In some embodiments, the disclosure provides a compound of formula IB, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0215] In some embodiments, the disclosure provides a compound of formula IB, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl, and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0216] In some embodiments, ring A is unsubstituted or has one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is a 4-6 membered heterocycle substituted with: In some embodiments, ring A contains at least one nitrogen atom. In some embodiments, ring A has the following structure: [ka] Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, ring A has the structure: [ka]

[0217] In some embodiments, ring A has the structure: [ka]

[0218] In some embodiments, ring A is a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0219] In some embodiments, R 1 is hydrogen.

[0220] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkylheterocycle. In some embodiments, the heterocycle or heterocycle of the alkylheterocycle contains 4 to 8 members, including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8 comprises a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, the heterocycle is 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is -OCH3.

[0221] In some embodiments, R 1 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 1 teeth, [ka] is selected from.

[0222] In some embodiments, R 1 teeth, [ka] is selected from.

[0223] In some embodiments, R 1 teeth, [ka] is selected from However, each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, and R a or R c C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 1 teeth, [ka] is selected from.

[0224] In some embodiments, R 1 teeth, [ka] is selected from.

[0225] In some embodiments, R 1 teeth, [ka] is selected from.

[0226] In some embodiments, R 1 teeth, [ka] is selected from.

[0227] In some embodiments, R 1 The heterocycle may be unsubstituted or may contain one or more R 16In some embodiments, R is a 4-6 membered heterocycle containing a nitrogen atom substituted with 1 teeth, [ka] is selected from.

[0228] In some embodiments, R 6 teeth, [ka] is selected from.

[0229] In some embodiments, R 6 teeth, [ka] is selected from.

[0230] In some embodiments, R 6 teeth, [ka] is.

[0231] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0232] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0233] In some embodiments, R 5is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0234] In some embodiments, the present disclosure provides a compound according to formula IB1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 4 , R 5 , R 6 , and R 7 is as defined above for formula I, both alone and in combination, and is described herein as a class and subclass; and ring A is unsubstituted or contains one or more R 11 In some embodiments, the disclosure provides a compound of formula IB1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0235] In some embodiments, the disclosure provides a compound of formula IB1, wherein: Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12, -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0236] In some embodiments, ring A is unsubstituted or has one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A comprises at least one nitrogen atom. In some embodiments, ring A has the following structure: [ka] and Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ). In some embodiments, ring A has the structure: [ka]

[0237] In some embodiments, ring A has the structure: [ka]

[0238] In some embodiments, ring A is a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0239] In some embodiments, R 6 teeth, [ka] is selected from.

[0240] In some embodiments, R 6 teeth, [ka] is selected from.

[0241] In some embodiments, R 6 teeth, [ka] is.

[0242] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0243] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0244] In some embodiments, R5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0245] In some embodiments, (i) ring A is unsubstituted or has one or more R 11 In some embodiments, (ii) R 7 is halogen. In some embodiments, (iii) R 4 is H. In some embodiments, ring A is [ka] is selected from However, each R g is H and C 1~6 alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, at least one R g is C 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, ring A is an unsubstituted piperazine or diazepane. In some embodiments, ring A is [ka] is selected from.

[0246] In some embodiments, R 7 is F. In some embodiments, R 5 is halogen, -CN, C 1~6 alkyl, and 3- to 6-membered carbocyclic rings, 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 6 teeth, [ka] is.

[0247] In some embodiments, ring A is unsubstituted or has one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 It is a diazepane substituted with

[0248] In some embodiments, (i) ring A is unsubstituted or has one or more R 11 In some embodiments, (ii) R 7 is halogen. In some embodiments, (iii) R 4 is H. In some embodiments, ring A is [ka] is selected from (a)R g1 and R g3 or (b) R g2 and R g3 are bonded to each other to form a second ring containing 4 to 6 members, and R is not part of the second ring. g1 , R g2 , R g3 , and R g4 Either H or C 1~6alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, R g1 , R g2 , R g3 , and R g4 At least one of 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, ring A is [ka] is selected from However, R g2 and R g4 are bonded to each other to form a second ring containing 4 to 6 members, and R g1 , R g3 , and R g5 is H and C 1~6 alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, R g1 , R g3 , and R g5 At least one of 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, R h is —C(O)NH 2 . In some embodiments, ring A is [ka] is selected from.

[0249] In some embodiments, R 7 is F. In some embodiments, R 5 is halogen, -CN, C 1~6 alkyl, and 3- to 6-membered carbocyclic rings,1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 6 teeth, [ka] is.

[0250] In some embodiments, (i) ring A is unsubstituted or has one or more R 11 and (ii) R 7 is a halogen, and (iii) R 4 is H.

[0251] In some embodiments, the present disclosure provides a compound according to formula IB2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 4 , R 5 , R 6 , R 7 , and R 8 is as defined above for formula I, and is described herein as a class and subclass, both alone and in combination, and ring A is unsubstituted or contains one or more R 11 In some embodiments, the disclosure provides a compound of formula IB2, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0252] In some embodiments, the disclosure provides a compound of formula IB2, wherein: Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0253] In some embodiments, ring A is unsubstituted or has one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A is unsubstituted or substituted with one or more R 11 In some embodiments, ring A comprises at least one nitrogen atom. In some embodiments, ring A has the following structure: [ka] and Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, ring A is substituted with the following structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, ring A has the following structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, ring A has the structure: [ka]

[0254] In some embodiments, ring A has the structure: [ka]

[0255] In some embodiments, ring A is a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0256] In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkylheterocycle. In some embodiments, the heterocycle or heterocycle of the alkylheterocycle contains 4 to 8 members, including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8 comprises a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, R 8 is unsubstituted or contains one or more R 16 In some embodiments, the heterocycle includes a 3- to 6-membered heterocycle substituted with one or more R 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is -OCH3.

[0257] In some embodiments, -OR 8 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, -OR is alkyl. 8 teeth, [ka] is selected from.

[0258] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0259] In some embodiments, -OR 8 teeth, [ka] is selected from However, each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, and R a or R c C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by . In some embodiments, -OR 8 teeth, [ka] is selected from.

[0260] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0261] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0262] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0263] In some embodiments, R 6 teeth, [ka] is selected from.

[0264] In some embodiments, R 6 teeth, [ka] is selected from.

[0265] In some embodiments, R 6 teeth, [ka] is.

[0266] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0267] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0268] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0269] In some embodiments, (i) ring A is unsubstituted or has one or more R 11 In some embodiments, (ii) R 7 is halogen. In some embodiments, (iii) R 4 is H. In some embodiments, ring A is [ka] is selected from However, each R g is H and C 1~6 alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, at least one R g is C 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, ring A is [ka] is selected from.

[0270] In some embodiments, R 8 is an alkylheterocycle. In some embodiments, -OR 8 teeth, [ka] is selected from.

[0271] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0272] In some embodiments, R 7 is F. In some embodiments, R 5 is halogen, -CN, C 1~6 alkyl, and 3- to 6-membered carbocyclic rings, 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 6 teeth, [ka] is.

[0273] In some embodiments, (i) R 8 is an alkyl heterocycle, and (ii) ring A is unsubstituted or contains one or more R 11 In some embodiments, (i) R 8 is an alkyl heterocycle, and (ii) ring A is unsubstituted or contains one or more R 11 In some embodiments, (i) R 8 is an alkyl heterocycle, and (ii) ring A is an unsubstituted piperazine or diazepane.

[0274] In some embodiments, (i) ring A is unsubstituted or has one or more R 11 In some embodiments, (ii) R 7 is halogen. In some embodiments, (iii) R 4 is H. In some embodiments, ring A is [ka] is selected from (a)R g1 and R g3or (b) R g2 and R g3 are bonded to each other to form a second ring containing 4 to 6 members, and R is not part of the second ring. g1 , R g2 , R g3 , and R g4 Either H or C 1~6 alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, R g1 , R g2 , R g3 , and R g4 At least one of 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, ring A is [ka] is selected from However, R g2 and R g4 are bonded to each other to form a second ring containing 4 to 6 members, and R g1 , R g3 , and R g5 is H and C 1~6 alkyl; R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 In some embodiments, R g1 , R g3 , and R g5 At least one of 1~6 alkyl, for example, C alkyl. In some embodiments, R h is H. In some embodiments, R h is —C(O)NH 2 . In some embodiments, ring A is [ka] is selected from.

[0275] In some embodiments, R 8 is an alkylheterocycle. In some embodiments, -OR 8 teeth, [ka] is selected from.

[0276] In some embodiments, -OR 8 teeth, [ka] is selected from.

[0277] In some embodiments, R 7 is F. In some embodiments, R 5 is halogen, -CN, C 1~6 alkyl, and 3- to 6-membered carbocyclic rings, 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R 6 teeth, [ka] is.

[0278] In some embodiments, (i) R 8 is an alkyl heterocycle, and (ii) ring A is unsubstituted or contains one or more R 11 and (iii) R 7 is a halogen, and (iv) R 4 is H.

[0279] In another aspect, the present disclosure provides a compound of formula IC: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above for Formula I, and are described herein as classes and subclasses, both alone and in combination. In some embodiments, the disclosure provides compounds of formula IC, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0280] In some embodiments, the present disclosure provides a compound of formula IC, wherein: R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl, and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19)NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0281] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0282] In some embodiments, R 3 is a carbocyclic ring, which may be unsubstituted or may contain one or more R 10 In some embodiments, R 3 is a polycyclic carbocycle. In some embodiments, R 3 is a monocyclic carbocycle. In some embodiments, R 3 is -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH2.

[0283] In some embodiments, R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is a polycyclic heterocycle. In some embodiments, R 3is a monocyclic heterocycle. In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is -N(R 19 )2, wherein each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a heterocycle substituted with -NH2.

[0284] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0285] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0286] In some embodiments, R 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 is replaced by .

[0287] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17)2, where each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 It is alkyl.

[0288] In some embodiments, R 3 teeth, [ka] is selected from.

[0289] In some embodiments, R 3 comprises an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a component of a heterocycle. In some embodiments, the amino moiety is attached to a carbocycle or heterocycle. In some embodiments, the amino moiety is a primary amine (e.g., -NH). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0290] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is -N(R 17 )2 substituted C 1~6 alkyl, provided that each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 In some embodiments, R 3 teeth, [ka] is selected from.

[0291] In some embodiments, R 2 or R 3contains an amino moiety (eg, -NRR').

[0292] In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a structure that includes at least one nitrogen atom. In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (Any of these may be unsubstituted or may contain one or more R 11 is replaced by ). In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ). In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0293] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0294] In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0295] In some embodiments, R 6 teeth, [ka] is selected from.

[0296] In some embodiments, R 6 teeth, [ka] is selected from.

[0297] In some embodiments, R 6 teeth, [ka] is.

[0298] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0299] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0300] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7are each selected from Cl and F.

[0301] In another aspect, the disclosure provides a compound according to formula ID or ID': [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 are as defined above for Formula I, both alone and in combination, and are described herein as classes and subclasses; R 23 is -N(R 12 )2 and C 1~6 Alkyl-N(R 12 )2 and R 24 , R 25 , and R 26 is H, halogen, -OR 12 , and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 11 In some embodiments, the disclosure provides a compound of formula ID, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the disclosure provides a compound of formula ID', or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0302] In some embodiments, the disclosure provides a compound of formula ID or ID', wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H and C 1~6 alkyl, R3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H. R 23 is -N(R 12 )2 and C 1~6 Alkyl-N(R 12 )2 is selected. R 24 , R 25, and R 26 is H, halogen, -OR 12 , and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 11 is replaced by .

[0303] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0304] In some embodiments, R 3 is a carbocyclic ring, which may be unsubstituted or may contain one or more R 10 In some embodiments, R 3 is a polycyclic carbocycle. In some embodiments, R 3 is a monocyclic carbocycle. In some embodiments, R 3 is -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH2.

[0305] In some embodiments, R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is a polycyclic heterocycle. In some embodiments, R 3 is a monocyclic heterocycle. In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is -N(R 19 )2, wherein each R 19is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a heterocycle substituted with -NH2.

[0306] In some embodiments, R 3 teeth, [ka] is selected from (Any of these may be unsubstituted or may contain one or more R 10 is replaced by ).

[0307] In some embodiments, R 3 teeth, [ka] is selected from (Any of these may be unsubstituted or may contain one or more R 10 is replaced by ).

[0308] In some embodiments, R 3 teeth, [ka] is selected from (Any of these may be unsubstituted or may contain one or more R 10 is replaced by ).

[0309] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17 )2, where each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 It is alkyl.

[0310] In some embodiments, R 3 teeth, [ka] is selected from.

[0311] In some embodiments, R 3 comprises an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a component of a heterocycle. In some embodiments, the amino moiety is attached to a carbocycle or heterocycle. In some embodiments, the amino moiety is a primary amine (e.g., -NH). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0312] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is -N(R 17 )2 substituted C 1~6 alkyl, provided that each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH 1~6 In some embodiments, R 3 teeth, [ka] is selected from.

[0313] In some embodiments, R 2 or R 3 contains an amino moiety (eg, -NRR').

[0314] In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a structure that includes at least one nitrogen atom. In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0315] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0316] In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0317] In some embodiments, R 1 is hydrogen.

[0318] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8is an alkylheterocycle. In some embodiments, the heterocycle or heterocycle of the alkylheterocycle contains 4 to 8 members, including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8 comprises a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, R 8 is unsubstituted or contains one or more R 16 In some embodiments, the heterocycle includes a 3- to 6-membered heterocycle substituted with one or more R 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is -OCH3.

[0319] In some embodiments, R 1 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 1 teeth, [ka] is selected from.

[0320] In some embodiments, R 1 teeth, [ka] is selected from.

[0321] In some embodiments, R 1 teeth, [ka] where each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, and R a or R c C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by . In some embodiments, R 1 teeth, [ka] is selected from.

[0322] [ka] is selected from.

[0323] In some embodiments, R 1 teeth, [ka] is selected from.

[0324] In some embodiments, R 1 teeth, [ka] is selected from.

[0325] In some embodiments, R 1 The heterocycle may be unsubstituted or may contain one or more R 16 In some embodiments, R is a 4-6 membered heterocycle containing a nitrogen atom substituted with 1 teeth, [ka] is selected from.

[0326] In some embodiments, R 4 is H. In some embodiments, R 4 is a halogen.

[0327] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0328] In some embodiments, R5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0329] In some embodiments, R 23 is -N(R 12 )2. In some embodiments, R 23 is -NH2.

[0330] In some embodiments, R 24 is halogen. In some embodiments, R 24 is Cl or F. In some embodiments, R 24 is F. In some embodiments, R 24 is H.

[0331] In some embodiments, R 25 and R 26 is H. In some embodiments, R 25 is H. In some embodiments, R 26 is H.

[0332] In one aspect, the present disclosure provides a compound represented by formula IE: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined above for Formula I, both alone and in combination, and are described herein as classes and subclasses; R a and R b is halogen, -OR 12 , C 1~6 alkyl, and H, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 13 In some embodiments, the disclosure provides compounds of formula IE, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0333] In some embodiments, the present disclosure provides a compound of formula IE, wherein: R 2 is H, a 3- to 6-membered carbocyclic ring, and C 1~6 alkyl, provided that the alkyl is a 3- to 6-membered carbocyclic or C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H; R a and R b is halogen, -OR 12 , C 1~6 alkyl, and H; any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 has been replaced by].

[0334] In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, Rb is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a and R b are both halogen. In some embodiments, R a and R b and R are both F. In some embodiments, R a and R b are both unsubstituted or contain one or more R 13 C replaced with 1~6 In some embodiments, R a and R b and R are both methyl. a and R b are both H. In some embodiments, R a Ha-OC 1~6 alkyl, and R b is H.

[0335] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~6 In some embodiments, R 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0336] In some embodiments, R 3 is C 1~6 alkyl, C 1~6 Alkyl is one or more R 9 In some embodiments, R 3 is -N(R 17 )2 substituted C 1~6 alkyl, provided that each R 17 is C 1~6 In some embodiments, R 3 is C substituted with -NH1~6 It is alkyl.

[0337] In some embodiments, R 3 teeth, [ka] is selected from.

[0338] In some embodiments, R 3 comprises an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a component of a heterocycle. In some embodiments, the amino moiety is attached to a carbocycle or heterocycle. In some embodiments, the amino moiety is a primary amine (e.g., -NH). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0339] In some embodiments, R 3 is a carbocyclic ring, which may be unsubstituted or may contain one or more R 10 In some embodiments, R 3 is a polycyclic carbocycle. In some embodiments, R 3 is a monocyclic carbocycle. In some embodiments, R 3 is -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH2.

[0340] In some embodiments, R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is a polycyclic heterocycle. In some embodiments, R 3 is a monocyclic heterocycle. In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is -N(R19 )2, wherein each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a heterocycle substituted with -NH. In some embodiments, R 3 is a bridged heterocyclic ring system. In some embodiments, R 3 is a monocyclic ring. In some embodiments, R 3 is unsubstituted or contains one or more R 10 and azetidine or pyrrolidine substituted with

[0341] In some embodiments, R 3 teeth, [ka] any of which is unsubstituted or has one or more R 10 is replaced by .

[0342] In some embodiments, R 3 teeth, [ka] any of which is unsubstituted or has one or more R 10 is replaced by .

[0343] In some embodiments, R 3 teeth, [ka] any of which is unsubstituted or has one or more R 10 is replaced by .

[0344] In some embodiments, R 2 and R 3means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atoms to which they are attached form a structure containing at least one nitrogen atom. In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0345] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0346] In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-10 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 and together with the atom to which they are attached form a 4-6 membered heterocyclic ring containing at least two nitrogen atoms (e.g., containing an amino moiety (e.g., -NR-)) and / or substituted with a group containing an amino moiety (e.g., -NRR').

[0347] In some embodiments, R 4 is H. In some embodiments, R 4 is halogen. In some embodiments, R 4 HA-OR 12 In some embodiments, R 4 is -OCH3.

[0348] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0349] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is an unsubstituted C such as methyl or ethyl 1~6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1~6 In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 -OR 12 is selected from, where R 12 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is -OCH3, -OCF3, or -OCF2H.

[0350] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0351] In some embodiments, R 6 is one or more R 15 In some embodiments, R 6 teeth, [ka] is selected from.

[0352] In some embodiments, R 6 is one or more R 15 In some embodiments, R is a bicyclic heteroaryl substituted with 6 teeth, [ka] is selected from.

[0353] In some embodiments, R 6 teeth, [ka] is selected from.

[0354] In some embodiments, R 6 teeth, [ka]

[0355] In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 and R 3means that together with the atom to which they are attached (e.g., a nitrogen atom) are unsubstituted or contain one or more R 11 In some embodiments, R 6 teeth, [ka] is selected from.

[0356] In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (Any of these may be unsubstituted or may contain one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (Any of these may be unsubstituted or may contain one or more R 11 is replaced by ). In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0357] In some embodiments, R 4 is H. In some embodiments, R 7 is halogen (e.g., F). In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with2 and R 3 means that together with the atom to which they are attached (e.g., a nitrogen atom) are unsubstituted or contain one or more R 11 In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 and R 3 together with the atom to which they are attached (e.g., a nitrogen atom), form a bridged heterocyclic ring system containing a piperazine ring, and the bridged heterocyclic ring system is unsubstituted or contains one or more R 11 In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 and R 3 means that together with the atom to which they are attached (e.g., a nitrogen atom) are unsubstituted or contain one or more R 11 The piperazine ring is substituted with

[0358] In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 is H, C 1~6 alkyl, and 3- to 6-membered carbocyclic ring, provided that C 1~6 The alkyl or 3- to 6-membered carbocyclic ring may be unsubstituted or may have one or more R 13 and (iii) R 3 is C 1~6 alkyl, C 1~6 Alkyl is one or more R 9 In some embodiments, R 3 is C substituted with -NH 1~6 In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R2 is unsubstituted or contains one or more R 13 It is a 3- to 6-membered carbocyclic ring substituted with

[0359] In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 is H, C 1~6 alkyl, and 3- to 6-membered carbocyclic ring, provided that C 1~6 The alkyl or 3- to 6-membered carbocyclic ring may be unsubstituted or may have one or more R 13 and (iii) R 3 is a carbocyclic ring, which may be unsubstituted or may contain one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a carbocycle substituted with -NH. In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 2 is unsubstituted or contains one or more R 13 It is a 3- to 6-membered carbocyclic ring substituted with

[0360] In some embodiments, (i) R 6 is one or more R 15 (ii) R is a bicyclic heteroaryl substituted with 2 is H, C 1~6 alkyl, and 3- to 6-membered carbocyclic ring, provided that C 1~6The alkyl or 3- to 6-membered carbocyclic ring may be unsubstituted or may have one or more R 13 and (iii) R 3 is a heterocycle, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, the heterocycle contains one or more nitrogen atoms. In some embodiments, R 3 is -N(R 19 )2, wherein each R 19 is unsubstituted or substituted C 1~6 In some embodiments, R 3 is a heterocycle substituted with -NH. In some embodiments, R 3 is a bridged heterocyclic ring system. In some embodiments, R 3 is a monocyclic ring. In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R is an azetidine or pyrrolidine substituted with 3 teeth, [ka] is selected from Any of these may be unsubstituted or may contain one or more R 10 In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 2 is unsubstituted or contains one or more R 13 It is a 3- to 6-membered carbocyclic ring substituted with

[0361] In one aspect, the present disclosure provides a compound represented by formula IF: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, with the proviso that R 1 , R 4 , R 5 , R 6 , and R 7 are as defined above for Formula I, both alone and in combination, and are described herein as classes and subclasses; R g1 , R g2 , R g3 , and R g4 is H and C 1~6 alkyl, or (a) R g1 and R g3 or (b) R g2 and R g3 are bonded to each other to form a second ring containing 4 to 6 members, and R is not part of the second ring. g1 , R g2 , R g3 , and R g4 Either H or C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 alkylNH. In some embodiments, the disclosure provides a compound of formula IF, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0362] In some embodiments, the present disclosure provides a compound of formula IF, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R g1 , R g2 , R g3 , and R g4 is H and C 1~6alkyl, or (a) R g1 and R g3 or (b) R g2 and R g3 are bonded to each other to form a second ring containing 4 to 6 members, and R is not part of the second ring. g1 , R g2 , R g3 , and R g4 Either H or C 1~6 alkyl, any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by R h is H, C 1~6 Alkyl, -C(O)NH2, and -C(O)C 1~6 alkylNH2, R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12, —CN, and H; Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0363] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkylheterocycle. In some embodiments, the heterocycle or heterocycle of the alkylheterocycle contains 4 to 8 members, including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8comprises a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, the heterocycle is 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is -OCH3.

[0364] In some embodiments, R 1 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 and H. In some embodiments, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R a -OC 1~6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R bis F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 1 teeth, [ka] is selected from.

[0365] In some embodiments, R 1 teeth, [ka] is selected from.

[0366] In some embodiments, R 1 teeth, [ka] where each R a is a halogen, C 1~6 Alkyl, -OR 12 R is independently selected from c is C 1~6 alkyl, and R a or R c C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by . In some embodiments, R 1 teeth, [ka] is selected from.

[0367] In some embodiments, R 1 teeth, [ka] is selected from.

[0368] In some embodiments, R 1 teeth, [ka] is selected from.

[0369] In some embodiments, R 1 teeth, [ka] is selected from.

[0370] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is selected from.

[0371] In some embodiments, R 1 is hydrogen.

[0372] In some embodiments, R 4 is H. In some embodiments, R 4 is halogen. In some embodiments, R 4 HA-OR 12 In some embodiments, R 4 is -OCH3.

[0373] In some embodiments, R 5 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 5 is a 3-6 membered heterocycle. In some embodiments, R 5 is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 is a flan.

[0374] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is an unsubstituted C such as methyl or ethyl 1~6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1~6 In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 -OR 12 is selected from, where R 12 is unsubstituted or contains one or more R 13 C replaced with 1~6 In some embodiments, R 5 is -OCH3, -OCF3, or -OCF2H.

[0375] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl or F. In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 5 and R 7 are both halogen. In some embodiments, R 5 and R 7 are both selected from Cl and F. In some embodiments, R 4 , R 5 , and R 7 are each independently halogen. In some embodiments, R 4 , R 5 , and R 7 are each selected from Cl and F.

[0376] In some embodiments, R 6 is one or more R 15 In some embodiments, R 6 teeth, [ka] is selected from.

[0377] In some embodiments, R 6 is one or more R 15 In some embodiments, R is a bicyclic heteroaryl substituted with 6 teeth, [ka] is selected from.

[0378] In some embodiments, R 6 teeth, [ka] is selected from.

[0379] In some embodiments, R 6 teeth, [ka] is selected from.

[0380] In some embodiments, R g1 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g2 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g3 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g4 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl).g1 and R g2 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g1 and R g2 and R are both methyl. g1 and R g3 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g1 and R g3 and R are both methyl. g1 and R g4 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g1 and R g4 and R are both methyl. g2 and R g3 is C 1~6 In some embodiments, R is selected from alkyl (e.g., methyl). g2 and R g3 are both methyl.

[0381] In some embodiments, R g1 and R g3 and are joined together to form a second ring containing 4 to 6 members. In some embodiments, R g2 and R g3 and are joined together to form a second ring containing 4 to 6 members. In some embodiments, R h is H.

[0382] In some embodiments, the compound has the following structure: [ka]

[0383] In some embodiments of the compound according to formula (IF1) or (IF2), R g1 and R g4are each H. In some embodiments of the compound according to formula (IF3) or (IF4), R g2 and R g4 are each H. In some embodiments of the compound according to formula (IF1), (IF2), (IF3), or (IF4), R h is H. In some embodiments of the compound according to formula (IF1), (IF2), (IF3), or (IF4), R 1 teeth, [ka] is selected from However, R a and R b are each independently a halogen, C 1~6 Alkyl, -OR 12 , and H, and any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 In some embodiments of the compound according to formula (IF1), (IF2), (IF3), or (IF4), R 6 teeth, [ka] is selected from.

[0384] In some embodiments of the compound according to formula (IF1), (IF2), (IF3), or (IF4), R 4 is H. In some embodiments of the compound according to formula (IF1), (IF2) (IF3), or (IF4), R 7 is halogen (e.g., F). In some embodiments of the compound according to formula (IF1), (IF2), (IF3), or (IF4), R 5 is halogen, —CN, a 3- to 6-membered carbocyclic ring, a 3- to 6-membered heterocyclic ring, or is unsubstituted or contains one or more R 13 C is replaced by 1~6 It is alkyl.

[0385] In another aspect, the present disclosure provides a compound of formula II: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H, a 3- to 6-membered carbocyclic ring, and C 1~6 alkyl, provided that the alkyl is a 3- to 6-membered carbocyclic or C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, with the proviso that any phenyl, monocyclic heteroaryl, bicyclic aryl, and bicyclic heteroaryl is unsubstituted or contains one or more R 15 is replaced by R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from H, heterocycle, and alkylheterocycle, provided that the heterocycle or alkylheterocycle is unsubstituted or contains one or more R 16 and the alkyl portion of any alkyl heterocycle is C 1~6 alkyl, Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is a halogen, -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is halogen, -OR 12 , -CN, -N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is halogen, -OR 12 , -CN, -N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, C 1~6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18-OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl, 3- to 6-membered heterocycle, and H, with the proviso that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, halogen, and a 3- to 6-membered carbocyclic ring; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0386] In some embodiments, the disclosure provides a compound of Formula II, or a salt thereof (eg, a pharmaceutically acceptable salt):

[0387] In some embodiments, the present disclosure provides a compound of formula II, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is halogen, -OR 12 , -CN, -N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0388] In some embodiments, R 3 is selected from carbocycles and heterocycles, provided that the carbocycle or heterocycle is unsubstituted or contains one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 is a 4- to 6-membered carbocyclic ring, which is unsubstituted or has one or more R 10In some embodiments, R 3 is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 10 In some embodiments, R 3 is unsubstituted or contains one or more R 10 In some embodiments, R 3 teeth, [ka] any of which is unsubstituted or has one or more R 10 is replaced by .

[0389] In some embodiments, R 3 is one or more R 9 C replaced with 1~6 In some embodiments, R 3 is C 1~6 Alkyl-N(R 17 In some embodiments, R 3 is —CH2CH2NH2. In some embodiments, R 3 teeth, [ka] is selected from.

[0390] In some embodiments, R 2 or R 3 contains an amino moiety (e.g., -NRR'). In some embodiments, R 2 or R 3 is an amino moiety (i.e., -N(R 17 )2 or -N(R 19 )2) has been replaced.

[0391] In some embodiments, R 2 and R 3means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom), form a 4-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom), form a 4-7 membered heterocycle having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom) form a piperazine. In some embodiments, R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom), form a 7-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or containing one or more R 11 is replaced by . In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached form a heterocyclic ring having the structure: [ka]

[0392] In some embodiments, R 2 and R 3 means, together with the nitrogen atom to which they are attached, unsubstituted or containing one or more R 11 and forming a heterocycle substituted with a heterocycle containing an additional nitrogen atom (e.g., an amino moiety (e.g., —NR—)) and / or a group containing an amino moiety (e.g., —N(R 19 )2) has been replaced.

[0393] In some embodiments, R 1 is hydrogen.

[0394] In some embodiments, R 1 -OR 8 In some embodiments, R 1 HA-OR 8 and R 8 is a heterocycle or an alkylheterocycle. In some embodiments, R 8 is unsubstituted or contains one or more R 14 In some embodiments, R 8 is a heterocycle. In some embodiments, R 8 is an alkylheterocycle. In some embodiments, R 8 is an alkyl heterocycle, provided that the alkyl portion of the alkyl heterocycle is C 1~6 In some embodiments, R 8 is —CH (heterocycle). In some embodiments, the heterocycle of the heterocycle or alkylheterocycle contains 4 to 8 members, including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 In some embodiments, R 8includes a 4-8 membered heterocycle containing at least one nitrogen atom. In some embodiments, the heterocycle of the heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle of the heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is a 4-6 ... monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is a 4-6 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 16 In some embodiments, at least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H. In some embodiments, at least one R 16 is —OCH. In some embodiments, at least one R 16 is halogen (e.g., F). In some embodiments, at least one R 16 is unsubstituted or contains one or more R 13 C replaced with 1~6 It is alkyl.

[0395] In some embodiments, R 1 teeth, [ka] is selected from.

[0396] In some embodiments, R 1 teeth, [ka] is selected from.

[0397] In some embodiments, R 1 The heterocycle may be unsubstituted or may contain one or more R 16In some such embodiments, R is a 4-6 membered heterocycle containing a nitrogen atom substituted with 16 is -N(R 12 )2, C 1~6 In some embodiments, R 16 is -N(C 1~6 alkyl), e.g., —N(CH). In some embodiments, R 16 is C 1~6 In some embodiments, R 16 is a bicyclic 6-membered heterocycle having one nitrogen atom. In some embodiments, R 1 teeth, [ka] is selected from.

[0398] In some embodiments, R 6 is one or more R 15 In some embodiments, R 6 is one or more R 15 and naphthyl substituted with .

[0399] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 6 is one or more R 15 In some embodiments, R is a bicyclic heteroaryl substituted with 6 is one or more R 15 In some such embodiments, at least one R 15 is -N(R 12 )2 (e.g., —NH2). In some embodiments, at least one R 15is halogen (e.g., F). In some embodiments, each R 15 is halogen, -CN, and -N(R 12 )2. In some embodiments, R 6 There are at least two R 15 (e.g., at least halogen and -NH2).

[0400] In some embodiments, R 6 teeth, [ka] any of which is unsubstituted or has one or more R 15 is replaced by .

[0401] In some embodiments, R 6 teeth, [ka] is selected from.

[0402] In some embodiments, R 6 teeth, [ka] is selected from.

[0403] In some embodiments, R 6 teeth, [ka] is.

[0404] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some such embodiments, each R 15 is halogen, -OR 12, -CN, and -N(R 12 )2 are independently selected.

[0405] In some embodiments, R 6 is unsubstituted or contains one or more R 15 In some embodiments, R is a monocyclic 5-6 membered heteroaryl substituted with 6 is unsubstituted or contains one or more R 15 In some embodiments, each R 15 is N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by .

[0406] In some embodiments, R 4 is H. In some embodiments, R 4 is halogen. In some embodiments, R 4 -OR 12 In some embodiments, R 4 is -OCH3.

[0407] In some embodiments, R 7 is halogen. In some embodiments, R 7 is Cl or F. In some embodiments, R 7 -OR 12 where R 12 is H and unsubstituted or one or more R 13 C replaced with 1~6 In some embodiments, R 7 is —OH, —OCH, or —OCHCF. In some embodiments, R 7 is -CN. In some embodiments, R 7 is hydrogen.

[0408] In some embodiments, R 4 and R7 are both halogen. In some embodiments, R 4 and R 7 are both selected from Cl or F.

[0409] In some embodiments, the compound is represented by a formula included in any of Tables 2-9. In some embodiments, the disclosure provides a compound or salt (e.g., a pharmaceutically acceptable salt thereof) selected from any one of Tables 2, 3, 4, 5, 7, 8, and 9. In some embodiments, the disclosure provides a compound or salt (e.g., a pharmaceutically acceptable salt thereof) selected from any one of Tables 2, 3, 4, 7, 8, and 9.

[0410] Also provided herein is a compound selected from any of Tables 2-9 or any of the Examples set forth herein, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. It will be recognized that the compounds described herein may be provided and / or utilized in any available form (e.g., salt form), and all such forms are contemplated by this disclosure. The disclosure also contemplates forms such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers of the compounds provided herein.

[0411] In some embodiments, provided compounds are provided and / or utilized in the form of a salt (e.g., a pharmaceutically acceptable salt), and reference to a compound provided herein is understood to include reference to the salts thereof, unless otherwise indicated.

[0412] Also provided herein are embodiments in which any embodiment described herein can be combined with any one or more of these embodiments, unless the combinations are mutually exclusive.As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other.For example, an embodiment in which two groups are bonded to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen.Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH.

[0413] composition The present disclosure also provides a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, a provided composition comprises a compound provided herein or a pharmaceutically acceptable salt thereof. For example, the present disclosure comprises a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, together with a pharmaceutically acceptable carrier. In some embodiments, a provided pharmaceutical composition comprises a compound provided herein or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0414] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the oral pharmaceutical formulation is selected from a tablet and a capsule.

[0415] In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration.

[0416] While certain compounds provided herein (e.g., compounds of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, can be administered as the raw chemical, the compounds can also or alternatively be provided in a pharmaceutical formulation. Accordingly, provided herein are pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., compounds of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Suitable formulations will depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as appropriate and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any well-known, suitable manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0417] The pharmaceutical formulations provided herein may be suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and ocular) administration. The most suitable route may depend, for example, on the condition and disorder of the subject to whom the pharmaceutical formulation is to be administered. The pharmaceutical formulations may be provided in unit dosage form. The pharmaceutical formulations may be prepared by any suitable method. A method for preparing a pharmaceutical formulation may include contacting a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient") with one or more pharmaceutically acceptable carriers (e.g., auxiliary ingredients). In general, the formulations are prepared by uniformly and intimately bringing into contact the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0418] The compounds provided herein (e.g., compounds of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II in any available form (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.)) can be provided as discrete units. For example, formulations suitable for oral administration can be provided as capsules, cachets, and / or tablets containing a predetermined amount of the compound (e.g., active ingredient) in any appropriate form, as a solution or suspension in a solvent (e.g., aqueous or non-aqueous solvent), as an emulsion (oil-in-water emulsion or water-in-oil emulsion), or as a powder or granules. Additionally or alternatively, the active ingredient can be provided as a bolus, electuary, or paste.

[0419] Pharmaceutical formulations suitable for oral administration include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be prepared, for example, by compression or molding, optionally with one or more accessory ingredients, such as one or more pharmaceutically acceptable excipients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating surfactant, or dispersing agent. Molded tablets can be prepared by molding, in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent. Tablets may be coated or scored as needed and can be formulated for slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient mixed with one or more fillers, such as lactose, one or more binders, such as starches, and / or one or more lubricants, such as talc or magnesium stearate, and, optionally, one or more stabilizers. In soft capsules, the active compound(s) may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers and other ingredients may also be added. Dragee cores may be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gums, gelling agents, polymers, solvents, or combinations thereof. Dyes or pigments may be added to tablets or dragee coatings for identification purposes or to characterize different combinations of active compound doses.

[0420] Pharmaceutical compositions comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage form, e.g., in ampoules, vials, or in multi-dose containers, to which a preservative may be added. The compositions can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The formulations can also be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, prior to (e.g., immediately before) use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0421] Pharmaceutical compositions containing a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be formulated as an injectable solution, which may be aqueous or non-aqueous (oily) sterile and may contain one or more antioxidants, thickeners, suspending agents, buffers, solutes, and / or bacteriostatic agents. The addition of one or more such additives can make the formulation isotonic with the blood of the intended recipient (e.g., a subject or patient). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0422] In addition to the formulations described elsewhere herein, the compounds provided herein (e.g., compounds of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) can also be formulated as depot preparations in any suitable form (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.). Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., a sparingly soluble salt.

[0423] Pharmaceutical compositions comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) suitable for buccal or sublingual administration can be in the form of a tablet, lozenge, troche, or gel. Such compositions can include the active ingredient in a flavored base such as sucrose and acacia, or tragacanth. Pharmaceutical compositions comprising a compound provided herein or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) suitable for rectal administration can be formulated as a suppository or retention enema and can include a vehicle such as cocoa butter, polyethylene glycol, or other glycerides.

[0424] Certain compounds provided herein (e.g., compounds of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or predetermined forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be formulated for non-systemic administration, such as topical administration. This includes application of a compound disclosed herein, or a predetermined form thereof, to the external surface of the epidermis or buccal cavity, as well as instillation of a compound, or a predetermined form thereof, into the ear, eye, and nose, such that the compound, or a predetermined form thereof, does not enter the bloodstream in significant amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0425] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for administration to the eye, ear, or nose. For topical administration, the active ingredient can comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can comprise 10% w / w. In other embodiments, the active ingredient can comprise less than 5% w / w. In certain embodiments, the active ingredient can comprise 2% to 5% w / w. In other embodiments, the active ingredient can comprise 0.1% to 1% w / w of the formulation.

[0426] For administration by inhalation, a compound (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means of delivering an aerosol spray. Pressurized packs can contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds provided herein can be in the form of a dry powder composition, e.g., a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0427] Preferred unit dosage formulations are those containing an effective dose, as described herein, or an appropriate fraction thereof, of the active ingredient (e.g., a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof).

[0428] It will be understood that, in addition to the ingredients described in detail elsewhere herein, the formulations described herein may include other useful agents having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0429] A compound (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be administered orally or by injection at a dose of 0.1 to 500 mg / kg / day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units can conveniently contain units containing an effective amount of one or more compounds in that dose or multiple thereof, e.g., 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0430] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0431] method The present disclosure also provides a method of modulating KRAS (e.g., KRAS having a G12D mutation), comprising contacting KRAS with a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure can provide a method of altering cell phenotype, cell proliferation, KRAS activity, biochemical output produced by active or inactive KRAS, KRAS expression, and / or KRAS binding to a natural binding partner. Any such characteristic can be monitored and altered by contacting KRAS with a compound provided herein or a predetermined form thereof. The method of modulating KRAS (e.g., KRAS having a G12D mutation) can be a treatment modality for a disease, disorder, or condition (e.g., cancer), a biological assay, a cellular assay, a biochemical assay, or the like.

[0432] The present disclosure also provides a method of treating a disease, disorder, or condition in a subject in need thereof, using a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure provides a method comprising providing (e.g., administering) an effective amount of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject (e.g., a patient) in need thereof. The present disclosure also provides a method of treating a disease, disorder, or condition in a subject in need thereof, using a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure provides a method comprising providing (e.g., administering) to a subject (e.g., patient) in need thereof a pharmaceutical composition comprising an effective amount of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the subject is known to have (e.g., has previously been diagnosed with) a disease, disorder, or condition, such as cancer. The disease, disorder, or condition can be a KRAS-mediated disease, such as cancer characterized by a G12D mutation in KRAS. In some embodiments, the compound administered to a subject in need thereof according to the methods described herein is a compound described in an embodiment, example, figure, or table herein, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0433] The present disclosure also provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or any of the above-mentioned compounds, and a pharmaceutically acceptable excipient, for use as a medicament, such as a medicament for treating a disease, disorder, or condition (e.g., cancer). The present disclosure also provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or any of the above-mentioned compounds, and a pharmaceutically acceptable excipient, for use in the manufacture of a medicament for treating a disease, disorder, or condition (e.g., cancer) in a subject in need of such treatment.

[0434] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, for treating a disease, disorder, or condition (e.g., cancer) in a subject in need of such treatment.

[0435] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, for use in the manufacture of a medicament for treating a disease, disorder, or condition (e.g., cancer) in a subject in need of such treatment.

[0436] The present disclosure also provides a method of inhibiting KRAS (e.g., KRAS having a G12D mutation) (e.g., in a subject in need of KRAS inhibition), comprising contacting KRAS with a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient.

[0437] The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, for use in inhibiting KRAS (e.g., KRAS having a G12D mutation) (e.g., in a subject in need of inhibition of KRAS). The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, for use in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12D mutation) in a subject in need of KRAS inhibition.

[0438] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, for inhibiting KRAS (e.g., KRAS having a G12D mutation) in a subject in need of KRAS inhibition.

[0439] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising any of the above compounds and a pharmaceutically acceptable excipient, in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12D mutation) in a subject in need of KRAS inhibition.

[0440] The present disclosure also provides methods of administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject (e.g., a patient), thereby alleviating, reducing, eliminating, arresting, or ameliorating one or more symptoms of a disease, disorder, or condition (e.g., cancer) in the subject. In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, slows or prevents tumor growth. In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, results in tumor reduction (e.g., tumor regression).

[0441] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder, or condition is cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer (CRC), endometrial cancer, uterine carcinosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma, Wilms' tumor, retinoblastoma, skin cancer, breast cancer, prostate cancer, head and neck cancer, or ovarian cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung adenocarcinoma), or colorectal cancer (CRC). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). In some embodiments, the cancer is non-small cell lung adenocarcinoma. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is or comprises a solid tumor.

[0442] In some embodiments, the disease, disorder, or condition is associated with KRAS, such as a disorder associated with a mutation in KRAS or a dysregulation of KRAS. In some embodiments, the disease, disorder, or condition is associated with the KRAS gene, such as a disease, disorder, or condition associated with a mutation in the KRAS gene or a dysregulation of the KRAS gene. The mutation or dysregulation of KRAS or KRAS may include a mutation or dysregulation of human K-Ras4a and / or human K-Ras4b. In some embodiments, the disease, disorder, or condition is associated with KRAS (e.g., human K-Ras4a or K-Ras4b) signaling pathway activity, such as a disease, disorder, or condition associated with aberrant KRAS signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with a mutation or dysregulation of human K-Ras4b. In some embodiments, the disease, disorder, or condition is associated with aberrant K-Ras4b signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with a mutation or dysregulation of human K-Ras4a. In some embodiments, the disease, disorder, or condition is associated with aberrant K-Ras4a signaling pathway activity.

[0443] Administration and Combination Therapy The compounds provided herein (e.g., compounds of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) and certain forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), or compositions (e.g., pharmaceutical compositions) comprising them, can be administered in a variety of ways (e.g., orally, topically, or by injection). The amount of active ingredient (e.g., a compound provided herein in any suitable form) administered to a subject (e.g., patient) is the responsibility of the attending physician. The specific dosage level for a particular subject (e.g., patient) will depend on a variety of factors, including, for example, the activity of the active ingredient being administered; the subject's physical attributes (e.g., age, weight, height, BMI, general health, co-morbidities, sex, etc.); other characteristics of the subject (e.g., diet, activity level, country of origin, ethnicity, etc.); time of administration; route of administration; rate of excretion; concomitant medications; the disease, disorder, or condition being treated; and the severity of the disease, disorder, or condition being treated.

[0444] In some embodiments, a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) is administered in combination with an additional agent, such as an additional therapeutic agent. For example, if a subject experiences side effects such as high blood pressure upon administration of a compound provided herein, or a predetermined form thereof, it may be appropriate to administer an additional agent effective in managing the side effects, such as an antihypertensive agent. In another example, the therapeutic effect of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a predetermined form thereof, can be enhanced by administration of an adjuvant, which may itself have only minimal therapeutic effect but, when combined with another therapeutic agent, can provide an enhanced overall therapeutic effect to the subject. In a further example, the therapeutic effect of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a given form thereof, can be enhanced by administering the compound or another form thereof with an additional agent (which may include an additional treatment regimen) that also provides a therapeutic effect. For example, a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a given form thereof, can be administered in combination with an additional agent that may be effective in treating a disease, disorder, or condition, such as cancer. Generally, the combination of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) with one or more additional agents (e.g., therapeutic agents) can enhance the overall effect a subject receives from any of the individual components. In some embodiments, the effect may be additive. In some embodiments, the effect may be synergistic.

[0445] In some embodiments, a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) is administered in combination with an anti-cancer agent (e.g., a chemotherapeutic agent). The anti-cancer agent can be, for example, an alkylating agent, a mitotic inhibitor, a checkpoint inhibitor, an antimetabolite, a plant alkaloid, a terpenoid, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an anti-steroid, an anti-androgen, an mTOR inhibitor, a monoclonal antibody, or a tyrosine kinase inhibitor. The alkylating agent may be, for example, almustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), temozolomide (TEMODAR), thiotepa, or cyclophosphamide (ENDOXAN). The antimetabolite may be, for example, cladribine (LEUSTATIN), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed. The antimitotic agent may be, for example, a taxane, such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL), or a vinca alkaloid, such as vincristine (ONCOVIN), vinblastine, vindesine, or vinorelbine (NAVELBINE).Checkpoint inhibitors can be anti-PD-1 or anti-PD-L1 antibodies such as pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736, or MPDL3280A; the anti-CTLA-4 antibody ipilimumab (YERVOY); or agents targeting LAG3 (lymphocyte activation gene 3 protein), KIR (killer cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (T-cell immunoglobulin and mucin domain-containing-3), or 0X40 (tumor necrosis factor receptor superfamily member 4). Topoisomerase inhibitors can be, for example, camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), or etoposide (EPOSIN). Cytotoxic antibiotics may be, for example, actinomycin D (dactinomycin, COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin. Aromatase inhibitors may be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN). Angiogenesis inhibitors may be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). The antisteroid or antiandrogen may be, for example, aminoglutethimide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). The tyrosine kinase inhibitor may be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA).The mTOR inhibitor can be, for example, everolimus, temsirolimus (TORISEL), or sirolimus. The monoclonal antibody can be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN). Further examples of agents that may be useful in combination with the compounds provided herein or alternative forms thereof include, but are not limited to, amsacrine; Bacillus Calmette-Guerin (BCG) vaccine; buserelin (etilamide); chloroquine (aralen); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridine; dichloroacetate; estramustine; filgrastim (neupogen); fludrocortisone (flourine); goserelin (zoladex); interferon; leucovorin; leuprolide (lupron); levamisole; lonidamine; mesna; metformin; mitotane (o,r'-dd D, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with phototherapy and radiation therapy); suramin; tamoxifen; titanocene dichloride; tretinoin; anabolic steroids such as fluoxymesterone (HALOTESTIN); estrogens such as estradiol, diethylstilbestrol (DES), and dienestrol; progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone.

[0446] Two or more therapeutic agents, one of which is a compound provided herein (e.g., Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or a given form thereof, can be administered in any order or simultaneously. If administered simultaneously, the therapeutic agents can be given in a single, combined form or in multiple forms (e.g., as one pill or as two separate pills). One therapeutic agent can be administered in multiple doses, or both can be administered in multiple doses. If not administered simultaneously, the timing between multiple doses can be any period ranging from a few minutes to four weeks.

[0447] Accordingly, in another aspect, the present disclosure provides a method for treating a disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human or animal subject) in need of such treatment, comprising administering to the subject a predetermined amount of a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), in combination with at least one additional agent for treating the disease, disorder, or condition. In a related aspect, the present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of any one of Formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II), or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), and at least one additional agent for use in treating a disease, disorder, or condition (e.g., cancer).

[0448] In some embodiments, the methods provided herein are used to treat a disease, disorder, or condition (e.g., cancer) and include administering a therapeutically effective amount of a compound of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment for the disease, disorder, or condition, wherein the disease, disorder, or condition is cancer that has acquired resistance to one or more chemotherapeutic agents and / or ionizing radiation. In some embodiments, the methods provided herein are used to treat a disease, disorder, or condition (e.g., cancer) and include administering a therapeutically effective amount of a compound of any one of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II, or a pharmaceutically acceptable salt thereof, in combination with an additional agent, to a subject in need of treatment for the disease, disorder, or condition, wherein the disease, disorder, or condition is cancer that has acquired resistance to one or more chemotherapeutic agents and / or ionizing radiation.

[0449] The compounds, compositions, and methods disclosed herein are useful for treating diseases, disorders, or conditions, such as cancer. In certain embodiments, the disease is one of dysregulated cell proliferation, including cancer. The cancer may be hormone-dependent or hormone-resistant, such as in the case of breast cancer. In certain embodiments, the cancer is or includes a solid tumor. In other embodiments, the cancer is lymphoma or leukemia. In certain embodiments, the cancer is a drug-resistant phenotype of cancer disclosed herein or otherwise known. Tumor invasion, tumor growth, tumor metastasis, and angiogenesis can also be treated using the compositions and methods disclosed herein. In some embodiments, the compounds, compositions, and methods provided herein are also useful for treating precancerous tumors.

[0450] Cancers treatable by the methods disclosed herein include, but are not limited to, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, breast cancer, ovarian cancer, endometrial cancer, lung cancer, and prostate cancer; cancer of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, liver and biliary tract; cancer of the pancreas, bone, connective tissue, skin, cervix, uterus, endometrium, testis, bladder, kidney, and other urinary tissues, including renal cell carcinoma (RCC); cancer of the eye, brain, spinal cord, and other components of the central and peripheral nervous system, and associated structures such as the meninges; and cancer of the thyroid gland and other endocrine glands. The term "cancer" also includes cancers that do not necessarily form solid tumors, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and hematopoietic malignancies, including leukemias (chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia) (CML), acute myeloid leukemia (AML), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas. Additional types of cancer treatable using the compounds and methods provided herein include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, blastoma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial carcinoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary cancer, glioblastoma multiforme, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, liver cancer, Kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, leukemia ... These include: pancreatic cancer, lymphoma, lymphangiosarcoma, lymphangioendothelial sarcoma, medullary thyroid carcinoma, medulloblastoma, meningioma mesothelioma, myeloma, myxosarcoma neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteogenic sarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adrenocortical carcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synovioma, thyroid carcinoma, uveal melanoma, and Wilms' tumor.Additional diseases and disorders treatable by the methods disclosed herein include, but are not limited to, KRAS-related diseases or disorders, such as diseases or disorders associated with KRAS mutations or dysregulation of KRAS, and KRAS gene-related diseases or disorders, such as diseases or disorders associated with KRAS gene mutations or dysregulation of KRAS gene.

[0451] In some embodiments, the compounds, compositions, and methods provided herein are useful for preventing and / or reducing tumor invasion, growth, and / or metastasis.

[0452] The compounds, compositions, and methods provided herein may be useful for the treatment of humans, as well as for the veterinary treatment of non-human animals, including mammals (e.g., as described herein), companion animals, including rodents, exotic animals, and farm animals. For example, the compounds, compositions, and methods provided herein may be useful for the treatment of horses, dogs, or cats.

[0453] Enumeration of Embodiments Embodiment I-1. A compound of formula I: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12)2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0454] Embodiment I-2.R 1 But, -OR 8 The compound of embodiment I-1, wherein

[0455] Embodiment I-3.R 8 The compound of embodiment I-2, wherein is a heterocycle.

[0456] Embodiment I-4.R 8 The compound of embodiment I-3, wherein is an alkylheterocycle.

[0457] Embodiment I-5.R 8 The compound of embodiment I-3 or I-4, wherein comprises a heterocycle containing at least one nitrogen atom.

[0458] Embodiment I-6. The heterocycle is one or R 16 The compound of any one of embodiments I-3 to I-5, comprising a substituent.

[0459] Embodiment I-7. At least one R 16 -OR 12 where R 12 is C 1~6 Alkyl, C 2~6 The compound of embodiment I-6, wherein R is independently selected from alkenyl, and H.

[0460] Embodiment I-8. At least one R 16 The compound of embodiment I-7, wherein is —OCH 3 .

[0461] Embodiment I-9.R 1 but, [ka] The compound of embodiment I-1, selected from:

[0462] Embodiment I-10.R 1 but, [ka] The compound of embodiment I-1, selected from:

[0463] Embodiment I-11.R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, and the heterocyclic ring is unsubstituted or contains one or more R 16 The compound of embodiment I-1, substituted with:

[0464] Embodiment I-12.R 1 but, [ka] The compound of embodiment I-11, selected from:

[0465] Embodiment I-13.R 1 The compound of embodiment I-1, wherein is H.

[0466] Embodiment I-14.R 2 The compound of any one of embodiments I-1 to I-13, wherein is H.

[0467] Embodiment I-15.R 2 But C 1~6 The compound of any one of embodiments I-1 to I-13, wherein is alkyl.

[0468] Embodiment I-16.R 3 C 1~6 alkyl, C 1~6 R with one or more alkyl 9 The compound of any one of embodiments I-1 to I-15, substituted with:

[0469] Embodiment I-17.R 3 But -N(R 17 )2 substituted C 1~6 alkyl, provided that each R 17 is C 1~6 The compound of embodiment I-16, wherein R is independently selected from alkyl and H.

[0470] Embodiment I-18.R 3is substituted with -NH2 1~6 The compound of embodiment I-17, wherein is alkyl.

[0471] Embodiment I-19.R 3 but, [ka] The compound of embodiments I-1 to I-15, selected from:

[0472] Embodiment I-20.R 3 is a carbocyclic ring, and said carbocyclic ring is unsubstituted or has one or more R 10 The compound of any one of embodiments I-1 to I-15, substituted with:

[0473] Embodiment I-21.R 3 But -N(R 19 )2, provided that each R 19 is unsubstituted or substituted C 1~6 The compound of embodiment I-20, wherein R is independently selected from alkyl and H.

[0474] Embodiment I-22.R 3 The compound of embodiment I-21, wherein is a carbocycle substituted with -NH2.

[0475] Embodiment I-23.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of any one of embodiments I-1 to I-15, wherein the compound is selected from:

[0476] Embodiment I-24.R 3 is a heterocycle, and the heterocycle is unsubstituted or contains one or more R 10 The compound of any one of embodiments I-1 to I-15, substituted with:

[0477] Embodiment I-25. The compound of Embodiment I-24, wherein said heterocycle contains one or more nitrogen atoms.

[0478] Embodiment I-26.R 3 But -N(R 19 )2, wherein each R 19 is unsubstituted or substituted C 1~6 The compound of embodiment I-24 or I-25, wherein R is independently selected from alkyl and H.

[0479] Embodiment I-27.R 3 The compound of embodiment I-26, wherein is a heterocycle substituted with -NH2.

[0480] Embodiment I-28.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of any one of embodiments I-1 to I-15, substituted with:

[0481] Embodiment I-29.R 2 or R 3 The compound of any one of embodiments I-15 to I-28, wherein comprises an amino moiety.

[0482] Embodiment I-30.R 2 and R 3 and together with the atom to which they are attached (e.g., a nitrogen atom) are unsubstituted or contain one or more R 11 The compound of any one of embodiments I-1 to I-13, wherein the compound forms a heterocycle substituted with

[0483] Embodiment I-31.R 2 and R 3 and the atoms to which they are attached form the following structure: [ka] and forming a heterocycle having the formula 11The compound of embodiment I-30, wherein the compound is substituted with:

[0484] Embodiment I-32.R 2 and R 3 and the atoms to which they are attached form the following structure: [ka] The compound of embodiment I-30, wherein the compound forms a heterocycle having

[0485] Embodiment I-33.R 2 and R 3 and together with the nitrogen atom to which they are attached form a heterocycle that is substituted with a group that (i) contains an additional nitrogen atom or (ii) contains an amino moiety.

[0486] Embodiment I-34.R 4 The compound of any one of embodiments I-1 to I-33, wherein is hydrogen.

[0487] Embodiment I-35.R 4 The compound of any one of embodiments I-1 to I-33, wherein is hydrogen.

[0488] Embodiment I-36.R 5 The compound of any one of embodiments I-1 to I-35, wherein is hydrogen.

[0489] Embodiment I-37.R 7 The compound of any one of embodiments I-1 to I-36, wherein is hydrogen.

[0490] Embodiment I-38.R 6 but, [ka] The compound of any one of embodiments I-1 to I-37, selected from:

[0491] Embodiment I-39.R 6 but, [ka] The compound of embodiment I-38, selected from:

[0492] Embodiment I-40.R 6 but, [ka] The compound of embodiment I-39, selected from:

[0493] Embodiment I-41. A compound of formula IA: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0494] Embodiment I-42.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of embodiment I-41, wherein the compound is substituted with:

[0495] Embodiment I-43.R 3 is unsubstituted or contains one or more R 10 The compound of embodiment I-42, wherein R is a 3- to 6-membered carbocyclic or heterocyclic ring substituted with R.

[0496] Embodiment I-44.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-43, wherein the compound is substituted with:

[0497] Embodiment I-45.R 3 but one or more R 9 C replaced with 1~6 The compound of embodiment I-41, wherein the aryl is selected from alkyl.

[0498] Embodiment I-46.R 3 But C 1~6 Alkyl-N(R 17 The compound of embodiment I-45, wherein the compound is selected from:

[0499] Embodiment I-47.R 3 but, [ka] The compound of embodiment I-45 or I-46, selected from:

[0500] Embodiment I-48.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of embodiment I-45, wherein the compound is selected from:

[0501] Embodiment I-49.R 3 The compound of any one of embodiments I-41 to I-48, wherein comprises an amino moiety.

[0502] Embodiment I-50.R 1 The compound of any one of embodiments I-41 to I-49, wherein is H.

[0503] Embodiment I-51.R 1 -OR 8 The compound of any one of embodiments I-41 to I-50, wherein

[0504] Embodiment I-52.R 8 is unsubstituted or contains one or more R 14 The compound of embodiment I-51, comprising a 3- to 6-membered heterocycle substituted with

[0505] Embodiment I-53.R 1 but, [ka] The compound of embodiment I-51 or I-52, selected from:

[0506] Embodiment I-54.R 1 but, [ka] The compound of embodiment I-51 or I-52, selected from:

[0507] Embodiment I-55.R 1 is unsubstituted or contains one or more R 16 The compound of any one of embodiments I-41 through I-54, wherein R is a 4-6 membered heterocycle containing a nitrogen atom substituted with R.

[0508] Embodiment I-56.R 1 but, [ka] The compound of embodiment I-55, selected from:

[0509] Embodiment I-57.R 6 but, [ka] The compound of any one of embodiments I-41 to I-56, selected from:

[0510] Embodiment I-58.R 6 but, [ka] The compound of embodiment I-57, selected from:

[0511] Embodiment I-59.R 6 but, [ka] The compound of embodiment I-58, selected from:

[0512] Embodiment I-60.R 4 The compound of any one of embodiments I-41 to I-59, wherein is H.

[0513] Embodiment I-61.R 4 The compound of any one of embodiments I-41 through I-59, wherein is halogen.

[0514] Embodiment I-62.R 5 The compound of any one of embodiments I-41 through I-61, wherein is halogen.

[0515] Embodiment I-63.R 7 The compound of any one of embodiments I-41 through I-62, wherein is halogen.

[0516] Embodiment I-64. Compound according to formula IA1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 is H, R 2 is H, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0517] Embodiment I-65.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of embodiment I-64, wherein the compound is substituted with:

[0518] Embodiment I-66.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-65, wherein the compound is substituted with:

[0519] Embodiment I-67.R 3 but one or more R 9 C replaced with 1~6 The compound of embodiment I-64, wherein the alkyl is selected from alkyl.

[0520] Embodiment I-68.R 3 but, [ka] The compound of embodiment I-67, selected from:

[0521] Embodiment I-69.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of embodiment I-64, wherein the compound is selected from:

[0522] Embodiment I-70.R 3 The compound of any one of embodiments I-64 to I-68, wherein comprises an amino moiety.

[0523] Embodiment I-71.R 6 but, [ka] The compound of any one of embodiments I-62 to I-70, selected from:

[0524] Embodiment I-72.R 6 but, [ka] The compound of embodiment I-71, selected from:

[0525] Embodiment I-73.R 6 but, [ka] The compound of embodiment I-72, selected from:

[0526] Embodiment I-74.R 4 The compound of any one of embodiments I-64 to I-73, wherein is H.

[0527] Embodiment I-75.R 4 The compound of any one of embodiments I-64 to I-73, wherein is halogen.

[0528] Embodiment I-76.R 5 The compound of any one of embodiments I-64 to I-75, wherein is halogen.

[0529] Embodiment I-77.R 7 The compound of any one of embodiments I-64 to I-76, wherein is halogen.

[0530] Embodiment I-78. Compound according to formula IA2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1は -OR 8 and; R 2 is H, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0531] Embodiment I-79.R 8 is unsubstituted or contains one or more R 14The compound of embodiment I-78, comprising a 3- to 6-membered heterocycle substituted with:

[0532] Embodiment I-80.R 1 but, [ka] The compound of embodiment I-78, selected from:

[0533] Embodiment I-81.R 1 but, [ka] The compound of embodiment I-78, selected from:

[0534] Embodiment I-82.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of any one of embodiments I-78 to I-81, substituted with:

[0535] Embodiment I-83.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-82, wherein the compound is substituted with:

[0536] Embodiment I-84.R 3 but one or more R 9 C replaced with 1~6 The compound of any one of embodiments I-78 to I-83, wherein the alkyl is selected from:

[0537] Embodiment I-85.R 3 but, [ka] The compound of embodiment I-84, selected from:

[0538] Embodiment I-86.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of any one of embodiments I-78 to I-85, wherein the compound is selected from:

[0539] Embodiment I-87.R 3 The compound of any one of embodiments I-78 to I-86, wherein comprises an amino moiety.

[0540] Embodiment I-88.R 6 but, [ka] The compound of any one of embodiments I-78 to I-87, selected from:

[0541] Embodiment I-89.R 6 but, [ka] The compound of embodiment I-88, selected from:

[0542] Embodiment I-90.R 6 but, [ka] The compound of embodiment I-89, selected from:

[0543] Embodiment I-91.R 4 The compound of any one of embodiments I-78 to I-90, wherein is H.

[0544] Embodiment I-92.R 4 The compound of any one of embodiments I-78 to I-90, wherein is halogen.

[0545] Embodiment I-93.R 5The compound of any one of embodiments I-78 to I-92, wherein is halogen.

[0546] Embodiment I-94.R 7 The compound of any one of embodiments I-78 to I-93, wherein is halogen.

[0547] Embodiment I-95. A compound according to formula IB: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0548] Embodiment I-96. Ring A is unsubstituted or contains one or more R 11 The compound of embodiment I-95, wherein R is a 4-6 membered heterocycle substituted with R.

[0549] Embodiment I-97. The compound of Embodiment I-95, wherein Ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0550] Embodiment I-98. The compound of Embodiment I-95, wherein Ring A has the structure: [ka]

[0551] Embodiment I-99. The compound of any one of Embodiments I-95 through I-98, wherein Ring A contains at least two nitrogen atoms and / or is substituted with a group containing an amino moiety.

[0552] Embodiment I-100.R 1 The compound of any one of embodiments I-95 to I-99, wherein is H.

[0553] Embodiment I-101.R 1 -OR 8 The compound of any one of embodiments I-95 to I-99, wherein

[0554] Embodiment I-102.R 8 is unsubstituted or contains one or more R 14 The compound of embodiment I-101, comprising a 3- to 6-membered heterocycle substituted with

[0555] Embodiment I-103.R 1 but, [ka] The compound of embodiment I-101, selected from:

[0556] Embodiment I-104.R 1 but, [ka] The compound of embodiment I-101, selected from:

[0557] Embodiment I-105.R 1 is unsubstituted or contains one or more R 16 The compound of any one of embodiments I-95 to I-99, wherein R is a 4-6 membered heterocycle containing a nitrogen atom substituted with

[0558] Embodiment I-106.R 1 but, [ka] The compound of embodiment I-105, selected from:

[0559] Embodiment I-107.R 6 but, [ka] The compound of any one of embodiments I-95 to I-106, selected from:

[0560] Embodiment I-108.R 6 but, [ka] The compound of embodiment I-107, selected from:

[0561] Embodiment I-109.R 6 but, [ka] The compound of embodiment I-108, selected from:

[0562] Embodiment I-110.R 4 The compound of any one of embodiments I-95 to I-109, wherein is H.

[0563] Embodiment I-111.R 4 The compound of any one of embodiments I-95 to I-109, wherein is halogen.

[0564] Embodiment I-112.R 5 The compound of any one of embodiments I-95 to I-111, wherein is halogen.

[0565] Embodiment I-113.R 7The compound of any one of embodiments I-95 to I-112, wherein is halogen.

[0566] Embodiment I-114. Compound according to formula IB1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0567] Embodiment I-115. Ring A is unsubstituted or contains one or more R 11 The compound of embodiment I-114, wherein R is a 4-6 membered heterocycle substituted with R.

[0568] Embodiment I-116. The compound of Embodiment I-114, wherein Ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0569] Embodiment I-117. The compound of Embodiment I-114, wherein Ring A has the structure: [ka]

[0570] Embodiment I-118. The compound of any one of Embodiments I-114 through I-117, wherein Ring A contains at least two nitrogen atoms and / or is substituted with a group containing an amino moiety.

[0571] Embodiment I-119.R 6 but, [ka] The compound of any one of embodiments I-114 to I-118, selected from:

[0572] Embodiment I-120.R 6but, [ka] The compound of embodiment I-119, selected from:

[0573] Embodiment I-121.R 6 but, [ka] The compound of embodiment I-120, selected from:

[0574] Embodiment I-122.R 4 The compound of any one of embodiments I-114 to I-121, wherein is H.

[0575] Embodiment I-123.R 4 The compound of any one of embodiments I-114 to I-121, wherein is halogen.

[0576] Embodiment I-124.R 5 The compound of any one of embodiments I-114 to I-123, wherein is halogen.

[0577] Embodiment I-125.R 7 The compound of any one of embodiments I-114 to I-124, wherein is halogen.

[0578] Embodiment I-126. A compound according to formula IB2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 HA-OR 8 and; Ring A is unsubstituted or contains one or more R 11 is a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0579] Embodiment I-127. Ring A is unsubstituted or contains one or more R 11 The compound of embodiment I-126, wherein R is a 4-6 membered heterocycle substituted with R.

[0580] Embodiment I-128. The compound of Embodiment I-126, wherein Ring A has the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0581] Embodiment I-129. The compound of Embodiment I-126, wherein Ring A has the structure: [ka]

[0582] Embodiment I-130. The compound of any one of Embodiments I-126 through I-129, wherein Ring A contains at least two nitrogen atoms and / or is substituted with a group containing an amino moiety.

[0583] Embodiment I-131.R 8 is unsubstituted or contains one or more R 14 The compound of any one of embodiments I-126 to I-130, comprising a 3-6 membered heterocycle substituted with

[0584] Embodiment I-132.R 1 but, [ka] The compound of any one of embodiments I-126 to I-131, selected from:

[0585] Embodiment I-133.R 1 but, [ka] The compound of any one of embodiments I-126 to I-131, selected from:

[0586] Embodiment I-134.R 6 but, [ka] The compound of any one of embodiments I-126 to I-133, selected from:

[0587] Embodiment I-135.R 6 but, [ka] The compound of embodiment I-134, selected from:

[0588] Embodiment I-136.R 6 but, [ka] The compound of embodiment I-135, selected from:

[0589] Embodiment I-137.R 4 The compound of any one of embodiments I-126 to I-136, wherein is H.

[0590] Embodiment I-138.R 4 The compound of any one of embodiments I-126 to I-136, wherein is halogen.

[0591] Embodiment I-139.R 5 The compound of any one of embodiments I-126 through I-138, wherein is halogen.

[0592] Embodiment I-140.R 7The compound of any one of embodiments I-126 to I-139, wherein is halogen.

[0593] Embodiment I-141. A compound according to formula IC: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is halogen, -OR 12 , —CN, and H; Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl, and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0594] Embodiment I-142.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of embodiment I-141, wherein the compound is substituted with:

[0595] Embodiment I-143.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-141, wherein the compound is substituted with:

[0596] Embodiment I-144.R 3 but one or more R 9 C replaced with 1~6 The compound of any one of embodiments I-141 to I-143, wherein the alkyl is selected from:

[0597] Embodiment I-145.R 3 but, [ka] The compound of embodiment I-144, selected from:

[0598] Embodiment I-146.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of any one of embodiments I-141 to I-145, wherein the compound is selected from:

[0599] Embodiment I-147.R 3 The compound of any one of embodiments I-141 to I-146, wherein comprises an amino moiety.

[0600] Embodiment I-148.R 2 and R 3 and together with the atoms to which they are attached are unsubstituted or contain one or more R 11 The compound of embodiment I-141, wherein the compound forms a 4-6 membered heterocycle substituted with

[0601] Embodiment I-149.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0602] Embodiment I-150.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka]

[0603] Embodiment I-151.R 2 and R 3 and together with the atom to which they are attached form a heterocycle that is substituted with a group that (i) contains an additional nitrogen atom or (ii) contains an amino moiety.

[0604] Embodiment I-152.R 6 but, [ka] The compound of any one of embodiments I-141 to I-151, selected from:

[0605] Embodiment I-153.R 6 but, [ka] The compound of embodiment I-152, selected from:

[0606] Embodiment I-154.R 6 but, [ka] The compound of embodiment I-153, selected from:

[0607] Embodiment I-155.R 4 The compound of any one of embodiments I-141 to I-154, wherein is H.

[0608] Embodiment I-156.R 4 The compound of any one of embodiments I-141 to I-154, wherein is halogen.

[0609] Embodiment I-157.R 5 The compound of any one of embodiments I-141 to I-156, wherein is halogen.

[0610] Embodiment I-158.R 7 The compound of any one of embodiments I-141 to I-157, wherein is halogen.

[0611] Embodiment I-159. A compound according to formula ID: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 5 is halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 7 is halogen, -OR 12 , —CN, and H; R 8is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C 2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H. R 23 is -N(R 12 )2 and C 1~6 Alkyl-N(R 12 )2 is selected, R 24 , R 25 , and R 26 is H, halogen, -OR 12 , and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 11 is replaced by Each R 27 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 alkyl, and halogen].

[0612] Embodiment I-160.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of embodiment I-159, wherein the compound is substituted with:

[0613] Embodiment I-161.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-159, wherein the compound is substituted with:

[0614] Embodiment I-162.R 3 but one or more R 9 C replaced with 1~6The compound of embodiment I-159, wherein the alkyl is selected from:

[0615] Embodiment I-163.R 3 but, [ka] The compound of embodiment I-162, selected from:

[0616] Embodiment I-164.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of embodiment I-159, wherein the compound is selected from:

[0617] Embodiment I-165.R 3 The compound of any one of embodiments I-159 to I-164, wherein comprises an amino moiety.

[0618] Embodiment I-166.R 2 and R 3 and together with the atoms to which they are attached are unsubstituted or contain one or more R 11 The compound of embodiment I-159, wherein the compound forms a 4-6 membered heterocycle substituted with

[0619] Embodiment I-167.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0620] Embodiment I-168.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka]

[0621] Embodiment I-169.R 2 and R 3 and together with the atom to which they are attached form a heterocycle that (i) contains an additional nitrogen atom, or (ii) is substituted with a group that contains an amino moiety.

[0622] Embodiment I-170.R 1 The compound of any one of embodiments I-159 to I-169, wherein is H.

[0623] Embodiment I-171.R 1 -OR 8 The compound of any one of embodiments I-159 to I-169, wherein

[0624] Embodiment I-172.R 8 is unsubstituted or contains one or more R 14 The compound of embodiment I-171, comprising a 3- to 6-membered heterocycle substituted with

[0625] Embodiment I-173.R 1 but, [ka] The compound of any one of embodiments I-159 to I-169, selected from:

[0626] Embodiment I-174.R 1 but, [ka] The compound of any one of embodiments I-159 to I-169, selected from:

[0627] Embodiment I-175.R 1 is unsubstituted or contains one or more R 16The compound of any one of embodiments I-159 to I-169, wherein R is a 4-6 membered heterocycle containing a nitrogen atom substituted with

[0628] Embodiment I-176.R 1 but, [ka] The compound of embodiment I-175, selected from:

[0629] Embodiment I-177.R 4 The compound of any one of embodiments I-159 to I-176, wherein is H.

[0630] Embodiment I-178.R 4 The compound of any one of embodiments I-159 to I-176, wherein is halogen.

[0631] Embodiment I-179.R 5 The compound of any one of embodiments I-159 to I-178, wherein is halogen.

[0632] Embodiment I-180.R 7 The compound of any one of embodiments I-159 to I-179, wherein is halogen.

[0633] Embodiment I-181.R 23 But -N(R 12 The compound of any one of embodiments I-159 to I-180, wherein R 1 is 1 or 2;

[0634] Embodiment I-182.R 23 The compound of embodiment I-181, wherein is -NH2.

[0635] Embodiment I-183.R 24 The compound of any one of embodiments I-159 to I-182, wherein is hydrogen.

[0636] Embodiment I-184.R 25 and R 26The compound of any one of embodiments I-159 to I-183, wherein is H.

[0637] Embodiment I-185. A compound according to formula II: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 is H and C 1~6 alkyl, R 3 is C 1~6 selected from alkyl, carbocycle, and heterocycle, provided that any C 1~6 Alkyl is one or more R 9 and the carbocyclic or heterocyclic ring is unsubstituted or is substituted with one or more R 10 is replaced by Or, R 2 and R 3 means, together with the atom to which they are attached, unsubstituted or containing one or more R 11 forming a heterocycle substituted with R 4 is H, halogen, -OR 12 , -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, 3- to 6-membered carbocyclic ring, and 3- to 6-membered heterocyclic ring, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 and any carbocyclic and heterocyclic ring is unsubstituted or substituted with one or more R 14 is replaced by R 6 is one or more R 15 is a bicyclic heteroaryl substituted with R7 is halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, either of which is unsubstituted or contains one or more R 16 is replaced by Each R 9 is -N(R 17 )2, -N(R 17 )C(O)C 1~6 Alkyl, and -OR 17 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 18 is replaced by Each R 10 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 11 is -N(R 19 )2, -C(O)R 19 , -C(O)N(R 19 )2, -C(O)(C 1~6 alkyl)N(R 19 )2, -(C 1~6 alkyl)C(O)N(R 19 )2, -C(NR 19 )NR 19 CN and C 1~6 alkyl, provided that any C 1~6 Alkyl is unsubstituted or has one or more R 20 is replaced by Each R 12 is C 1~6 Alkyl, C2~6 alkenyl, and H, provided that any C 1~6 Alkyl or C 2~6 Alkenyl is unsubstituted or has one or more R 13 is replaced by Each R 13 -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 15 is a halogen, N(R 12 )2, and C 1~6 alkyl, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 13 is replaced by Each R 16 is a halogen, -N(R 12 )2, and C 1~6 Alkyl, and -OR 12 are independently selected from any C 1~6 Alkyl is unsubstituted or has one or more R 13 is replaced by Each R 17 is C 1~6 independently selected from alkyl and H; Each R 18 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 19 is C 1~6 independently selected from alkyl and H, provided that any C 1~6 The alkyl may be unsubstituted or may have one or more R 21 is replaced by Each R 20 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6 independently selected from alkyl, and halogen; Each R 21 -OH, -OC 1~6 Alkyl, -CN, -NH2, -NHC 1~6independently selected from alkyl, and halogen; Each R 22 is C 1~6 Alkyl, C 2~6 alkenyl, and H.

[0638] Embodiment I-186.R 3 is selected from carbocycles and heterocycles, provided that said carbocycles or heterocycles are unsubstituted or contain one or more R 10 The compound of embodiment I-185, wherein the compound is substituted with:

[0639] Embodiment I-187.R 3 but, [ka] any of which is unsubstituted or has one or more R 10 The compound of embodiment I-186, wherein the compound is substituted with:

[0640] Embodiment I-188.R 3 but one or more R 9 C replaced with 1~6 The compound of embodiment I-185, wherein the alkyl is selected from alkyl.

[0641] Embodiment I-189.R 3 but, [ka] The compound of embodiment I-188, selected from:

[0642] Embodiment I-190.R 3 But C 1~6 Alkyl-N(R 17 )C(O)C 1~6 AlkylN(R 17 The compound of embodiment I-185, wherein the compound is selected from:

[0643] Embodiment I-191.R 3The compound of any one of embodiments I-185 to I-190, wherein comprises an amino moiety.

[0644] Embodiment I-192.R 2 and R 3 and together with the atoms to which they are attached are unsubstituted or contain one or more R 11 The compound of embodiment I-185, wherein the compound forms a 4-6 membered heterocycle substituted with

[0645] Embodiment I-193.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka] (The ring may be unsubstituted or may have one or more R 11 is replaced by ).

[0646] Embodiment I-194.R 2 and R 3 and, together with the atoms to which they are attached, form a heterocycle having the structure: [ka]

[0647] Embodiment I-195.R 2 and R 3 and together with the atom to which they are attached form a heterocycle substituted with a group that (i) contains an additional nitrogen atom and / or (ii) contains an amino moiety.

[0648] Embodiment I-196.R 1 The compound of any one of embodiments I-185 to I-195, wherein is H.

[0649] Embodiment I-197.R 1 -OR 8The compound of any one of embodiments I-185 to I-195, wherein

[0650] Embodiment I-198.R 8 is unsubstituted or contains one or more R 14 The compound of embodiment I-197, comprising a 3- to 6-membered heterocycle substituted with

[0651] Embodiment I-199.R 1 but, [ka] The compound of any one of embodiments I-185 to I-195, selected from:

[0652] Embodiment I-200.R 1 but, [ka] The compound of any one of embodiments I-185 to I-195, selected from:

[0653] Embodiment I-201.R 1 is unsubstituted or contains one or more R 16 The compound of any one of embodiments I-185 to I-195, wherein R is a 4-6 membered heterocycle containing a nitrogen atom substituted with

[0654] Embodiment I-202.R 1 but, [ka] The compound of embodiment I-201, selected from:

[0655] Embodiment I-203.R 6 but, [ka] The compound of any one of embodiments I-185 to I-202, selected from:

[0656] Embodiment I-204.R 6 but, [ka] The compound of embodiment I-203, selected from:

[0657] Embodiment I-205.R 6 but, [ka] The compound of embodiment I-204, selected from:

[0658] Embodiment I-206.R 4 The compound of any one of embodiments I-185 to I-205, wherein is H.

[0659] Embodiment I-207.R 4 The compound of any one of embodiments I-185 to I-205, wherein is halogen.

[0660] Embodiment I-208.R 7 The compound of any one of embodiments I-185 to I-207, wherein is halogen.

[0661] Embodiment I-209. A compound set forth in any one of Tables 2-4, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof.

[0662] Embodiment I-210. The compound of embodiment I-209 as shown in Table 2.

[0663] Embodiment I-211. The compound of embodiment I-209 as shown in Table 3.

[0664] Embodiment I-212. The compound of embodiment I-209 as shown in Table 4.

[0665] Embodiment I-213. A pharmaceutical composition comprising the compound of any one of embodiments I-1 through I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0666] Embodiment I-214. The compound of any one of embodiments I-1 to I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, for use as a medicament.

[0667] Embodiment I-215. The compound of embodiment I-214, wherein said agent is useful for the prevention or treatment of a disease, disorder, or condition ameliorated by inhibition of KRAS with a G12D mutation.

[0668] Embodiment I-216. The compound of embodiment I-214 or I-215, wherein said agent is useful for the prevention or treatment of cancer.

[0669] Embodiment I-217. The compound of embodiment I-216, wherein said cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0670] Embodiment I-218. The compound of any one of embodiments I-1 through I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, for use in treating a disease, disorder, or condition.

[0671] Embodiment I-219. The compound of embodiment I-218, wherein said disease, disorder, or condition is cancer.

[0672] Embodiment I-220. The compound of embodiment I-219, wherein said cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0673] Embodiment I-221. The compound of any one of embodiments I-218 through I-220 for use in treating a disease, disorder, or condition in a subject in need of such treatment.

[0674] Embodiment I-222. The compound of any one of embodiments I-1 through I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, for use in the manufacture of a medicament.

[0675] Embodiment I-223. The compound of embodiment I-222, wherein said agent is useful for the prevention or treatment of a disease, disorder, or condition ameliorated by inhibition of KRAS with a G12D mutation.

[0676] Embodiment I-224. The compound of embodiment I-222 or I-223, wherein said agent is useful in the treatment of cancer.

[0677] Embodiment I-225. The compound of embodiment I-224, wherein said cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0678] Embodiment I-226. A method comprising administering a therapeutically effective amount of the compound of any one of embodiments I-1 through I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject in need thereof.

[0679] Embodiment I-227. The compound of embodiment I-226, wherein said subject has a disease, disorder, or condition that is ameliorated by inhibition of KRAS with a G12D mutation.

[0680] Embodiment I-228. The method of embodiment I-226 or I-227, wherein the subject has cancer.

[0681] Embodiment I-229. The method of embodiment I-228, wherein said subject has been previously diagnosed with said cancer.

[0682] Embodiment I-230. The method of embodiment I-228, wherein said subject has previously undergone a treatment regimen for said cancer.

[0683] Embodiment I-231. The method of embodiment I-228, wherein the subject has previously been in remission of said cancer.

[0684] Embodiment I-232. The compound of any one of Embodiments I-228 to I-230, wherein said cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

[0685] Embodiment I-233. The method of any one of Embodiments I-226 to I-232, wherein the compound, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, is administered in combination with an additional therapeutic agent.

[0686] Embodiment I-234. Use of the compound of any one of embodiments I-1 to I-212, or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, for the manufacture of a medicament for the treatment of cancer.

[0687] Embodiment I-235. The use of embodiment I-234, wherein the cancer...

Claims

1. A compound represented by formula ID': 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, R １ is -OR ８ , a 4-6 membered heterocycle containing a nitrogen atom, and H, provided that the heterocycle is unsubstituted or is selected from one or more R １６ is replaced by R2 and R ３ means, together with the atom to which they are attached, unsubstituted or one or more R １１ forming a 4- to 6-membered heterocycle substituted with R ４ is H, halogen, -OR １２ , -C.N., C. １～６ Alkyl, C ２～６ Alkenyl, C ２～６ alkynyl, 3- to 6-membered carbocycle, and 3- to 6-membered heterocycle, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ and any carbocyclic and heterocyclic rings are unsubstituted or substituted with one or more R １４ is replaced by R ５ is halogen, -OR １２ , -C.N., C. １～６ Alkyl, C ２～６ Alkenyl, C ２～６ alkynyl, 3- to 6-membered carbocycle, and 3- to 6-membered heterocycle, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ and any carbocycle or heterocycle is unsubstituted or substituted with one or more R １４ is replaced by R ７ is halogen, -OR １２ , —CN, and H; R ８ is selected from heterocycle and alkylheterocycle, any of which is unsubstituted or substituted with one or more R １６ is replaced by Each R １１ is -N(R １９ ) ２ , -C(O)R １９ , -C(O)N(R １９ ) ２ , -C(O)(C １～６ alkyl)N(R １９ ) ２ , -(C １～６ alkyl)C(O)N(R １９ ) ２ , -C(NR １９ ) N.R. １９ C.N. and C. １～６ alkyl, provided that any C １～６ Alkyl is unsubstituted or has one or more R ２０ and each R １２ is C １～６ Alkyl, C ２～６ alkenyl, and H, with the proviso that any C １～６ Alkyl or C ２～６ Alkenyl is unsubstituted or has one or more R １３ is replaced by Each R １３ is -OR ２２ , -CN, -N(R ２２ ) ２ and halogen; Each R １４ is halogen, -OR １２ , -N(R １２ ) ２ , and C １～６ alkyl, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ is replaced by Each R １６ is halogen, -N(R １２ ) ２ , C １～６ alkyl, and —OR 12 , provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ is replaced by Each R １７ is C １～６ independently selected from alkyl and H; Each R １８ is -OH, -OC １～６ Alkyl, -CN, -NH ２ , -NHC １～６ independently selected from alkyl, alkyl, and halogen; Each R １９ is C １～６ alkyl, and H, with the proviso that any C １～６ Alkyl is unsubstituted or has one or more R ２１ is replaced by Each R ２０ is -OH, -OC １～６ Alkyl, -CN, -NH ２ , -NHC １～６ independently selected from alkyl, alkyl, and halogen; Each R ２１ is -OH, -OC １～６ Alkyl, -CN, -NH ２ , -NHC １～６ independently selected from alkyl, alkyl, and halogen; Each R ２２ is C １～６ Alkyl, C ２～６ alkenyl, and H; R 23 is selected from -N(R 12 ) 2 and C 1-6 alkyl-N(R 12 ) 2 ; R 24 , R 25 , and R 26 are independently selected from H, halogen, —OR 12 , and C 1-6 alkyl, provided that any C 1-6 alkyl is unsubstituted or substituted with one or more R 11 .

2. R １ But, -OR ８ 2. The compound of claim 1,

3. R ８ is a heterocycle, said heterocycle being unsubstituted or containing one or more R １６ 3. The compound of claim 1 or 2, substituted with

4. R ８ is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, the heterocycle being unsubstituted or having one or more R １６ The compound according to any one of claims 1 to 3, substituted with

5. R ８ is an alkylheterocycle, said alkylheterocycle being unsubstituted or having one or more R １６ 3. The compound of claim 1 or 2, substituted with

6. The alkyl heterocycle is -CH ２ (heterocycle), wherein the heterocycle is unsubstituted or has one or more R １６ 6. The compound of claim 5 , substituted with

7. The heterocycle of the alkylheterocycle is a 4-8 membered heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heterocycle is unsubstituted or is substituted with one or more R １６ 7. The compound of claim 5 or 6, substituted with

8. R ８ However, one or more R １６ The compound according to any one of claims 1 to 7, substituted with

9. Each R １６ But halogen, C １～６ Alkyl and -OR １２ Independently selected from any C １～６ Alkyl is unsubstituted or has one or more R １３ The compound according to any one of claims 1 to 8, which is substituted with

10. -OR ８ but, 【Chemistry 2】 and However, R ａ and R ｂ Each independently represents a halogen, C １～６ Alkyl, -OR １２ , and H; any C １～６ Alkyl is unsubstituted or has one or more R １３ The compound according to any one of claims 1, 2, and 5 to 9, which is substituted with

11. -OR ８ but, 【Chemistry 3】 is selected from however, Each R ａ is halogen, C １～６ Alkyl, -OR １２ and H, R ｃ is C １～６ alkyl, However, R ａ Or R ｃ C １～６ Alkyl is unsubstituted or has one or more R １３ The compound according to any one of claims 1 to 9, substituted with

12. One R ａ But halogen, C １～６ Alkyl, and -OR １２ and other R ａ The compound of claim 11 , wherein

13. -OR ８ but, 【Chemistry 4】 2. The compound of claim 1 , selected from:

14. R １ is a 4- to 6-membered heterocycle containing a nitrogen atom, the heterocycle being unsubstituted or having one or more R １６ 2. The compound of claim 1 , substituted with:

15. Each R １６ But -N(R １２ ) ２ , and C １～６ 15. The compound of claim 1 or 14, independently selected from alkyl.

16. R １ but, 【Chemistry 5】 16. The compound according to any one of claims 1, 14, and 15, selected from:

17. R １ The compound of claim 1 , wherein

18. R ２ and R ３ and together with the atom to which they are attached form a 4-6 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, said heterocycle being unsubstituted or having one or more R １１ 2. The compound of claim 1 , substituted with:

19. Each R １１ But -N(R １９ ) ２ , -C(O)R １９ , -C(O)N(R １９ ) ２ , -C(O)(C １～６ alkyl)N(R １９ ) ２ , and C １～６ alkyl, provided that any C １～６ Alkyl is unsubstituted or has one or more R ２０ 20. The compound of claim 1 or 18, substituted with:

20. R ２ and R ３ and, together with the atoms to which they are bound, 【Chemistry 6】 20. The compound according to claim 1 or 18, which forms a heterocycle selected from:

21. R ６ but, 【Chemistry 7】 2. The compound of claim 1,

22. R ４ The compound according to any one of claims 1 to 20, wherein is H.

23. R ４ But, -OR １２ The compound according to any one of claims 1 to 20,

24. R ５ is H, halogen, -OR １２ , -C.N., C. １～６ Alkyl, C ２～６ alkynyl, and 3- to 6-membered carbocyclic ring, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ and any carbocycle is unsubstituted or substituted with one or more R １４ The compound according to any one of claims 1 to 23, substituted with

25. R ５ 25. The compound of claim 24, wherein is a halogen.

26. R ５ is unsubstituted or has one or more R １３ C substituted with １～６ 25. The compound of claim 24, which is alkyl.

27. R ５ is selected from 3- to 6-membered carbocycles, and 3- to 6-membered heterocycles, with the proviso that any carbocycle and 3- to 6-membered heterocycle is unsubstituted or is substituted with one or more R １４ 25. The compound of claim 24 substituted with:

28. R ７ The compound according to any one of claims 1 to 27, wherein is halogen.

29. R ７ The compound according to any one of claims 1 to 27, wherein is -CN.

30. R5 is halogen, -OR １２ , -C.N., C. １～６ Alkyl, C ２～６ Alkenyl, C ２～６ alkynyl, 3- to 6-membered carbocycle, and 3- to 6-membered heterocycle, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ and any carbocyclic and heterocyclic rings are unsubstituted or substituted with one or more R １４ is replaced by R 8 is selected from heterocycle and alkylheterocycle, any of which is unsubstituted or contains one or more R １６ is replaced by Each R １４ is halogen, N(R １２ ) ２ , and C １～６ alkyl, provided that any C １～６ Alkyl is unsubstituted or has one or more R １３ is replaced by Each R １６ is halogen, -N(R １２ ) ２ , and C １～６ Alkyl, and -OR １２ Independently selected from any C １～６ Alkyl is unsubstituted or has one or more R １３ is replaced by Each R １９ But, C １～６ independently selected from alkyl and H, provided that any C １～６ Alkyl is unsubstituted or has one or more R ２１ is replaced by Each R ２０ However, -OH, -OC １～６ Alkyl, -CN, -NH ２ , -NHC １～６ 30. The compound of any one of claims 1 to 29, wherein the radicals are independently selected from alkyl, and halogen.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

32. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, for use as a medicament.

33. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, for use in the manufacture of a medicament.

34. 34. The composition of claim 32 or 33, wherein the agent is useful for the treatment of a disease, disorder, or condition that is ameliorated by inhibition of KRAS having a G12D mutation.

35. The composition of any one of claims 32 to 34, wherein the medicament is useful for the treatment of cancer.

36. 31. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition.

37. 37. The composition of claim 36, wherein the disease, disorder, or condition is cancer.

38. 38. The composition of claim 35 or 37, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

39. A composition comprising administering a pharmaceutical composition containing a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof.

40. 40. The composition of claim 39, wherein the subject has a disease, disorder, or condition that is ameliorated by inhibition of KRAS having a G12D mutation.

41. The composition of claim 39 or 40, wherein the subject has cancer.

42. 42. The composition of claim 41, wherein the subject has previously been diagnosed with said cancer.

43. 42. The composition of claim 41, wherein the subject has previously undergone a treatment regimen for the cancer.

44. 42. The composition of claim 41, wherein the subject has previously been in remission of the cancer.

45. The composition of any one of claims 41 to 44, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

46. The composition of any one of claims 41 to 45, wherein the compound or a pharma- ceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.

47. 31. Use of a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament.

48. 48. The use of claim 47, wherein the medicament is for treating cancer.

49. 49. The use of claim 48, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

50. A composition comprising a compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, for use in a method comprising contacting a KRAS protein with the compound, or a pharma- ceutically acceptable salt thereof.

51. 51. The composition of claim 50, wherein contacting the KRAS protein with the compound modulates KRAS.

52. 52. The composition of claim 50 or 51, wherein the KRAS protein has a G12D mutation.

53. The composition of any one of claims 50 to 52, wherein the KRAS protein is in an active state.

54. The composition of any one of claims 50 to 52, wherein the KRAS protein is in an inactive state.

55. A compound selected from the structures set forth in the following table, or a pharma- ceutically acceptable salt thereof: 【Table 1】 【Table 2】

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