Compositions and methods for inhibiting KRAS

Abstract

Provided herein are compounds or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, and pharmaceutical compositions comprising the same. Also provided herein are methods of using the same to modulate (e.g., inhibit) KRAS (e.g., KRAS having a G12D mutation) and treat a disease or condition (such as a cancer) in a subject in need thereof.

Description

[0001] Declaration of rights to inventions made under federally funded research and development

[0002] This invention was made with government support under (1) Contract No. 75N91019D00024 granted by the National Institutes of Health and (2) Contract No. DE-AC52-07NA27344 granted by the U.S. Department of Energy. The government enjoys certain rights in this invention.

[0003] Related applications

[0004] This application claims priority and benefit to U.S. Provisional Application No. 63 / 150,011, filed February 16, 2021, and U.S. Provisional Application No. 63 / 246,181, filed September 20, 2021, the entire contents of each of which are hereby incorporated by reference. Background Technology

[0005] RAS mutations occur in approximately 20-30% of human cancers, including most pancreatic ductal adenocarcinomas (PDAC), half of colorectal cancers, and one-third of all lung cancers. Given the highest RAS mutation frequency observed in the three leading causes of cancer death in the United States (lung, colorectal, and pancreatic cancer), developing anti-RAS therapies is a major priority and significant challenge in cancer research. RAS proteins do not appear to provide a suitable pocket for drugs to bind to besides GDP / GTP binding sites. Unfortunately, RAS proteins bind to these nucleotides with extremely high (picomolar) affinity, making the development of effective nucleotide analogs nearly impossible. Attempts to block downstream RAS pathways in hopes of providing clinical benefit to patients with RAS-driven cancers have generally been disappointing. Recently, allele-specific covalently valent KRAS G12C inhibitors have entered clinical trials, and early clinical data have shown some efficacy, at least in lung cancer.

[0006] 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, these genes mutate differentially and at varying frequencies in cancer. KRAS is the most frequently mutated oncogene in cancer, and KRAS mutations are generally associated with poor prognosis and resistance to therapy. Significant cancer type preferences exist among RAS genes. KRAS mutations are predominant in lung, colorectal, and pancreatic cancers, while NRAS mutations are predominant in cutaneous melanoma and acute myeloid leukemia, and HRAS mutations are found in bladder and head and neck squamous cell carcinomas.

[0007] KRAS is activated by mutations 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. With its incidence continuing to rise, pancreatic cancer is projected to become the second leading cause of cancer death by 2020. Given the lack of biomarkers for early detection, delayed symptoms when the cancer has metastasized, and a 5-year survival rate of 8%, pancreatic cancer is the deadliest cancer in the United States.

[0008] KRAS mutation is the initial genetic step in pancreatic cancer; however, persistent mutation of KRAS function is required to maintain PDAC growth. RNA interference-mediated KRAS inactivation in KRAS G12D-driven PDACs demonstrates rapid regression of tumor growth. These data support the importance of mutant KRAS as a therapeutic target for PDACs. Since 40% of PDACs are driven by KRAS G12D mutants, inhibitors targeting this mutation are in dire need. KRAS G12D mutations also occur frequently in lung and colorectal cancers, making KRAS G12D an ideal therapeutic target for direct G12D allele-specific inhibitors. Summary of the Invention

[0009] In one aspect, this disclosure provides compositions comprising compounds represented by Formula I or Formula II:

[0010]

[0011] Or its salts, esters, tautomers, prodrugs, zwitterionic forms or stereoisomers, wherein R 1 R 2 R 3 R 4 R 5 R 6 and R 7 As provided herein. In some embodiments, the compounds provided herein, or their salts, esters, tautomers, zwitterionic forms, or stereoisomers, can modulate the activity of KRAS proteins, such as KRAS proteins with a G12D mutation.

[0012] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound represented by Formula I or Formula II and a pharmaceutically acceptable carrier.

[0013] In another aspect, this disclosure provides a method for inhibiting KRAS activity in human or animal subjects for treating diseases such as cancer, including pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, and lung cancer.

[0014] In another aspect, this disclosure provides the use of the compounds provided herein, or their salts, esters, tautomers, zwitterionic forms, or stereoisomers, for the manufacture of agents for treating diseases, conditions, or disorders (e.g., cancer) that are improved, treated, suppressed, or alleviated by inhibiting KRAS (including KRAS with a G12D mutation). In some embodiments, the disease, condition, or disorder is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer.

[0015] In another aspect, this disclosure provides compounds, or salts, esters, tautomers, zwitterions, or stereoisomers thereof, as provided herein, for use as pharmaceutical agents. In some embodiments, the pharmaceutical agents are used to treat diseases, conditions, or ailments (e.g., cancer). In some embodiments, the disease, condition, or ailment is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer. Detailed Implementation

[0016] This disclosure provides compounds of Formula I and Formula II, which may have useful KRAS inhibitory activity and can be used to treat or prevent diseases, conditions, or disorders in which KRAS plays an active role. In particular, certain compounds provided herein may have useful inhibitory activity against KRAS with a G12D mutation, the KRAS protein being in an active (GTP-binding) or inactive (GDP-binding) conformation. This disclosure also provides pharmaceutical compositions comprising one or more of the compounds provided herein and a pharmaceutically acceptable carrier, and methods for preparing and using said compounds and compositions. This disclosure further provides methods for inhibiting KRAS (including KRAS with a G12D mutation), the KRAS being in an active or inactive conformation. In one aspect, this disclosure provides a method for treating a condition mediated by KRAS (including KRAS with a G12D mutation) in a subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of a compound or composition provided herein. This document also provides the use of certain compounds provided herein in the manufacture of agents for treating diseases, conditions, or disorders that are improved, treated, suppressed, or alleviated by inhibiting KRAS, including KRAS with the G12D mutation. In some embodiments, the disease, condition, or disorder is cancer.

[0017] When a range of values ​​is disclosed and notation such as “n1...to n2” or “between n1...and n2” (where n1 and n2 are numbers) is used, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range can be an integer or consecutive, between and including the endpoints. For example, the range “2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbon appears in integer units. For example, comparing the range “1 to 3 μM (micromolars)” (which is intended to include 1 μM, 3 μM, and all numbers in between) to any number with significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.) is also meaningful.

[0018] As used herein, “about” is intended to limit the numerical value it modifies, representing a variable within an error limit. When no specific error limit is stated, such as the standard deviation from the average given in a chart or data table, the term “about” should be understood to mean the range that will be covered by the stated value and take into account that significant figures will be rounded to include that number as well.

[0019] As used herein, "acyl" alone or in combination means a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, or any other moiety, wherein the atom attached to the carbonyl group is carbon. An "acetyl" group means a -C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group means an alkyl group attached to a parent molecule moiety via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aromatic acyl groups.

[0020] As used herein, "alkenyl" alone or in combination refers to a straight-chain or branched hydrocarbon group having one or more double bonds and containing 2 to 20 carbon atoms. In some embodiments, the alkenyl group will contain 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system linked at two or more positions, such as vinylene [(-CH=CH-), (-C::C-)]. Suitable examples of alkenyl groups include vinyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, etc. Unless otherwise specified, the term "alkenyl" may include "alkenylene" groups.

[0021] "Alkyne" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond and a specified number of carbon atoms (i.e., C24-C ... 2-6 This refers to two to six carbons. The alkynyl group can include any number of carbons, such as C2, C3, C4, C5, C6, C7, C8, C9 ... 2-3 C 2-4 C 2-5 C 2-6 C 2-7 C 2-8 C 2-9 C2-10 C3, C 3-4 C 3-5 C 3-6 C4, C 4-5 C 4-6 C5, C 5-6 And C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentenynyl, 1,3-pentyrynyl, 1,4-pentyrynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hextriynyl.

[0022] As used herein, "alkoxy" alone or in combination refers to an alkyl ether group, wherein the term alkyl is as described herein. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

[0023] As used herein, "alkyl" alone or in combination refers to a straight-chain or branched alkyl group containing 1 to 20 carbon atoms (e.g., C16, C2 ... 1-20 Alkyl group). In some embodiments, the alkyl group will contain 1 to 10 carbon atoms (e.g., C64 ... 1-10 Alkyl group). In a further embodiment, the alkyl group will contain 1 to 8 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-8 Alkyl group). In a further embodiment, the alkyl group will contain 1 to 6 carbon atoms (e.g., C64 ... 1-6 Alkyl group). In a further embodiment, the alkyl group will contain 1 to 3 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ...60, C60, C60, C60, C60, C60, C6 1-3 Alkyl groups are defined herein as either unsubstituted or substituted. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, etc. As used herein, the term "alkylene" alone or in combination refers to a saturated aliphatic group derived from a straight-chain or branched saturated hydrocarbon connected at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[0024] As used herein, "alkylamino" alone or in combination refers to an alkyl group attached to a parent molecule via an amino group. Suitable alkylamino groups can be monoalkylated or dialkylated to form groups such as N-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-ethylmethylamino.

[0025] As used herein, "alkylthio" alone or in combination refers to an alkyl thioether (RS-) group, wherein the term alkyl is as described herein and wherein sulfur may be oxidized by a single or double oxidation. Examples of suitable alkyl thioether groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, etc.

[0026] As used herein, "acylamino" and "carbamoyl" alone or in combination refer to an amino group as described herein, which is attached to a parent molecule moiety via a carbonyl group, and vice versa. As used herein, an "acylamino" group includes "C-acylamino" and "N-acylamino" groups. As used herein, the term "C-acylamino" alone or in combination refers to a -C(O)N(RR') group, wherein R and R' are as defined herein or by a specifically listed "R" group. In some embodiments, an "acylamino" group includes -C(O)NH2, C 1-4 Alkyl amide and di(C 1-4 Alkyl) amide. As used herein, the term "C" 1-4 "alkylamide" refers to -C(O)NH(C 1-4 Alkyl), wherein C 1-4 Alkyl groups are defined herein. As used herein, the term “N-acylamino” alone or in combination refers to the RC(O)N(R')- group, where R and R' are as defined herein or by a specified enumerated “R” group. As used herein, the term “acylamino” alone or in combination covers an acyl group linked to the parent moiety via an amino group. An example of an “acylamino” group is acetamido(CH3C(O)NH-).

[0027] 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, each of which may be unsubstituted or substituted. Additionally, R and R' may combine to form unsubstituted or substituted heterocycloalkyl groups. The "amino" group may be a primary amine (e.g., -NH2), a secondary amine or a disubstituted amine (e.g., -NHR, where R is not hydrogen), or a tertiary amine or a trisubstituted amine (e.g., -NRR', where neither R nor R' is hydrogen).

[0028] As used herein, "aryl" alone or in combination refers to a carbocyclic aromatic system containing one, two, or three rings, wherein such polycyclic systems are fused together. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracene, and phenanthryl. The aryl moiety may include, for example, 5 to 20 carbon atoms, such as 5 to 12 carbon atoms, such as 5 or 6 carbon atoms.

[0029] As used herein, “aryl-alkenyl” or “aryl-alkenyl” alone or in combination refers to an aryl group that is attached to a parent molecule via an alkenyl group.

[0030] As used herein, “arylalkoxy” or “arylalkoxy” alone or in combination refers to an aryl group attached to the parent molecule via an alkoxy group.

[0031] As used herein, “arylalkyl” or “arylalkyl” alone or in combination refers to an aryl group that is attached to a parent molecule moiety via an alkyl group.

[0032] As used herein, “aryloxy group” alone or in combination refers to an aryl group that is attached to a parent molecule moiety via an oxygen group.

[0033] As used herein, “carbamate” alone or in combination refers to an ester (-NHCOO-) of carbamic acid that can be attached from the nitrogen or acid terminus to the parent molecule moiety and is either unsubstituted or substituted as defined herein.

[0034] As used herein, “O-carbamoyl” alone or in combination refers to the -OC(O)NRR' group, where R and R' are as defined herein.

[0035] As used herein, “N-carbamoyl” alone or in combination refers to the ROC(O)NR'- group, where R and R' are as defined herein.

[0036] As used in this article, “carbonyl” includes formyl group [-C(O)H] when it appears alone and is a -C(O)- group when it appears in combination.

[0037] As used herein, “carboxyl” refers to -C(O)OH or the corresponding “carboxylate” anion, such as in carboxylates. “O-carboxyl” refers to the RC(O)O- group, where R is as defined herein. “C-carboxyl” refers to the -C(O)OR group, where R is as defined herein.

[0038] As used in this article, "cyano" alone or in combination refers to -CN.

[0039] As used herein, "cycloalkyl" alone or in combination, or alternatively "carbocyclic," refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, wherein each cyclic moiety contains 3 to 12 carbon atom ring members and may optionally be a benzo[a]-fused ring system, unsubstituted or substituted as defined herein. The carbocyclic group may comprise bridged ring systems and / or spirocyclic systems (e.g., systems comprising two rings sharing a single carbon atom). The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In some embodiments, the cycloalkyl (or cycloalkenyl) group will comprise 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, dihydroindenyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, etc. As used herein, “bicyclic” and “tricyclic” are intended to include fused ring systems, such as decahydronaphthalene and octahydronaphthalene, as well as polycyclic (multi-center) saturated or partially unsaturated types. The latter type of isomers are generally exemplified as bicyclic [1,1,1]pentane, camphor, adamantane, and bicyclic [3,2,1]octane.

[0040] As used in this article, "ester" alone or in combination refers to the carboxyl group that bridges the two parts connected at the carbon atom.

[0041] As used in this article, “ether” alone or in combination refers to the oxygen group that bridges the two parts connected at the carbon atom.

[0042] As used herein, “halogen” or “halogen” alone or in combination refers to fluorine, chlorine, bromine or iodine.

[0043] As used herein, “haloalkoxy” alone or in combination refers to a haloalkyl group that is attached to a portion of the parent molecule via an oxygen atom.

[0044] As used herein, "haloalkyl" alone or in combination means an alkyl group having the meaning described herein, wherein one or more hydrogen atoms are halogenated. Specifically, it covers monohaloalkyl, dihaloalkyl, and polyhaloalkyl. For example, a monohaloalkyl may have an iodine, bromine, chlorine, or fluorine atom within the group. Dihaloalkyl and polyhaloalkyl may have two or more identical halogen atoms or combinations of different halogen groups. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" means a haloalkyl group linked at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), etc.

[0045] As used herein, "heteroalkyl" alone or in combination refers to a stable straight-chain or branched hydrocarbon chain, fully saturated or containing 1 to 3 degrees of unsaturation, consisting of a specified number of carbon atoms and one to three heteroatoms selected from N, O, and S, wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized. Heteroatoms may be located at any internal position of the heteroalkyl group. At most two heteroatoms may be consecutive, such as -CH2-NH-OCH3.

[0046] 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 system, wherein at least one fused ring is aromatic, and the ring or ring system contains at least one atom selected from N, O, and S. In some embodiments, the heteroaryl group will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heteroaryl group will contain 1 to 2 heteroatoms as ring members. In some embodiments, the heteroaryl group will contain 5 to 7 atoms. The term also covers fused polycyclic groups, wherein the heterocycle is fused to an aryl ring, wherein the heteroaryl ring is fused to another heteroaryl ring, wherein the heteroaryl ring is fused to a heterocyclic alkyl ring, or wherein the heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrroloyl, imidazoyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, furanyl, thiopheneyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazoyl, thiazoyl, isothiazolyl, indolyl, isothizoyl, indolazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxolinyl, quinazolinyl, inzoyl, benzotriazolyl, benzom-dioxacyclopentenyl, benzopyranyl, benzooxazolyl, benzooxadiazolyl, benzothiazoyl, benzothiadiazolyl, benzofuranyl, benzothiaphenyl, crononeyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazopyridazinyl, tetrahydroisoquinolinyl, thiophene-pyridinyl, furan-pyridinyl, pyrrolopyridinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzylinyl, dibenzofuranyl, acridinel, benzylinyl, dibenzopyranyl, etc.

[0047] As used herein, "heterocyclic alkyl" alone or in combination and "heterocycle" interchangeably each 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, wherein each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group will contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocyclic alkyl group will contain 1 to 2 heteroatoms as ring members. In some embodiments, the heterocyclic alkyl group will contain 3 to 8 ring members in each ring. In further embodiments, the heterocyclic alkyl group will contain 3 to 7 ring members in each ring. In even further embodiments, the heterocyclic alkyl group will contain 5 to 6 ring members in each ring. Heterocycles may comprise bridged ring systems and / or spirocyclic systems (e.g., systems comprising two rings sharing a single atom, such as a single carbon atom). The terms “heterocyclic alkyl” and “heterocyclic” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic and benzo-fused ring systems; additionally, both terms also include systems in which a heterocycle is fused to an aryl or additional heterocyclic group as defined herein. Examples of heterocyclic groups include aziridinyl, azirrobutyl, 1,3-benzodioxacyclopentenyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocenolinyl, dihydrobenzodioxacyclohexenyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxalkyl, 1,4-dioxalkyl, 1,3-dioxacyclopentenyl, isoindololinyl, morpholinyl, piperazine, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, etc. Unless specifically prohibited, heterocyclic groups are either unsubstituted or substituted.

[0048] As used in this article, "hydrazine" alone or in combination refers to two amino groups linked by a single bond, namely, -NN-.

[0049] As used in this article, "hydroxyl group" alone or in combination refers to -OH.

[0050] As used herein, “hydroxyalkyl” alone or in combination refers to a hydroxyl group that is attached to a parent molecule portion via an alkyl group.

[0051] As used in this article, “iminohydroxy” alone or in combination refers to =N(OH) and =NO-.

[0052] As used herein, “lower amino” alone or in combination means -NRR’, where R and R’ are independently selected from hydrogen and lower alkyl groups, either unsubstituted or substituted.

[0053] As used herein, “thiol” alone or in combination refers to an RS-group, where R is as defined herein.

[0054] As used in this article, "nitro" alone or in combination refers to -NO2.

[0055] As used in this article, “oxygen group” or “oxo-” alone or in combination refers to -O-.

[0056] As used in this article, “oxo” alone or in combination refers to =O.

[0057] "All-haloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[0058] As used herein, “all-haloalkyl” alone or in combination refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0059] As used herein, the term "ring" or equivalently "cycle" in relation to a chemical structure or part thereof refers to a group in which each atom is a member of a common ring structure. Unless otherwise specified, rings can be saturated or unsaturated, including aromatic rings, and can have 3 to 9 members. If the ring is heterocyclic, it can contain 1 to 4 members selected from B, N, O, S, C(O), and S(O). m The rings contain heteroatoms or heteroatom-containing groups. Unless specifically prohibited, the rings are either unsubstituted or substituted. Two or more rings may be fused together (e.g., they may share a single bond and two common atoms). Two or more rings may be connected in a helical arrangement such that the two rings share only a single atom. Two or more rings may also be configured, or alternatively, in a bridge arrangement such that the two or more rings share three or more atoms.

[0060] As used herein, “sulfonate ester,” “sulfonic acid,” and “sulfonic acid group,” alone or in combination, refer to the -SO3H group and its anion, in which case the sulfonic acid is used for salt formation.

[0061] As used in this article, “thioalkyl” alone or in combination refers to -S-.

[0062] As used in this article, "sulfinyl group" alone or in combination refers to -S(O)-.

[0063] As used in this article, "sulfonyl group" alone or in combination refers to -S(O)2-.

[0064] “N-sulfonamide” refers to the RS(=O)2NR'- group, where R and R' are as defined herein.

[0065] “S-sulfonamide” refers to the -S(=O)2NRR' group, where R and R' are as defined herein.

[0066] As used herein, a "tautomer," alone or in combination, refers to one of two or more isomers that rapidly interconvert. Generally, this interconversion is rapid enough that the individual tautomers do not separate in the absence of the other tautomer. The ratio of the amounts of tautomers can depend on solvent composition, ionic strength, and pH, as well as other solution parameters. The ratio of the amounts of tautomers may vary in a particular solution and in the microenvironment of the biomolecule binding sites within said solution. Examples of tautomers well known in the art include ketone / enol, enamine / imine, and lactam / lactamimide tautomers. Other examples of tautomers well known in the art include 2-hydroxypyridine / 2(1H)-pyridone and 2-aminopyridine / 2(1H)-iminopyridone tautomers.

[0067] As used herein, “thia” and “thio” alone or in combination refer to an -S- group or an ether in which oxygen is replaced by sulfur. Oxidized derivatives of the thio group, namely sulfinyl and sulfonyl groups, are included in the definitions of thia and thio.

[0068] As used in this article, “thiol” alone or in combination refers to the -SH group.

[0069] As used in this article, “thiocarbonyl” includes thioformyl-C(S)H when it appears alone and is a -C(S)- group when it appears in combination.

[0070] “N-thiocarbamoyl” refers to the ROC(S)NR'- group, where R and R' are as defined herein.

[0071] “O-thiocarbamoyl” refers to the -OC(S)NRR' group, where R and R' are as defined herein.

[0072] "Cyanthio" refers to the -CNS group.

[0073] Any definition herein may be used in conjunction with any other definition to describe complex structural groups. By convention, the trailing element in any such definition is the element attached to the parent moiety. For example, the complex group alkylamide will represent an alkyl group attached to the parent molecule via an amide, and the term alkoxyalkyl will represent an alkoxy group attached to the parent molecule via an alkyl group.

[0074] As described herein, groups may be substituted or unsubstituted (e.g., “optionally substituted”). Unless otherwise specified, any group may be substituted by one or more substituents, such as the one or more substituents provided herein. Examples of substituents that can replace groups include, but are not limited to, substituents of one or more groups independently selected from, or particularly designated groups, of the following groups, either alone or in combination: alkyl (e.g., C14, C2 ... 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl), ynyl (e.g., C10), alkynyl (e.g., C10), 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 alkynyl), alkanoyl (e.g., C10), alkynyl (e.g., C1 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl), heteroalkyl (e.g., heteroalkyl moiety comprising 1-20 carbon atoms and 1-6 heteroatoms, such as heteroalkyl moiety comprising 1-6 carbon atoms and 1-3 heteroatoms), haloalkyl (e.g., halogenated C... 1-20 Alkyl groups, such as halogenated C4 groups 1-10 alkyl and halogenated C 1-6 Alkyl), haloalkenyl (e.g., halogenated C), 2-20 Alkenyl groups, such as halogenated C groups 2-6 alkenyl), haloynyl (e.g., halogenated C), 2-20 Alkyne groups, such as halogenated C groups 2-6 alkynyl), perhaloalkyl (e.g., C10), 1-20 Perhaloalkyl, such as C 1-6 Perhaloalkyl, such as C 1-3 Perhaloalkyl), perhaloalkoxy (e.g., C10) 1-20 Perhaloalkoxy, such as C 1-6 Perhaloalkoxy), phenyl, aryl (e.g., C10), 5-20 Aryl groups, such as C 5-10 Aryl groups, such as C 5-6 aryl), aryloxy (e.g., C 5-20 Aryloxy groups, such as C 5-10 Aryloxy groups, such as C 5-6 aryloxy groups), alkoxy groups (e.g., C460), and alkoxy groups (e.g. 1-20 Alkoxy groups, such as C 1-10 Alkoxy groups, such as C 1-6 Alkoxy, haloalkoxy (e.g., C 1-20 Haloalkoxy groups, such as C 1-10 Haloalkoxy groups, such as C 1-6 Haloalkoxy), oxo, acyloxy (e.g., including 1-20 carbon atoms, such as 1-10 carbon atoms, such as acyloxy with 1-6 carbon atoms), carbonyl (e.g., C(O) or C=O), carboxyl (e.g., C(O)O), alkyl carbonyl (e.g., C 1-20 Alkyl carbonyl, such as C 1-10 Alkyl carbonyl, such as C 1-6Alkyl carbonyl, such as C 1-3 Alkyl carbonyl), carboxyl ester (e.g., C(O)OR, where R is, for example, an alkyl group (e.g., C... 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 Alkyne group, any of which may be substituted with any group provided herein, carboxylamino group, cyano group (e.g., CN), hydrogen, halogen (e.g., iodine, bromine, chlorine or fluorine), hydroxyl group, amino group (e.g., NR'R" where R' and R" are independently, for example, hydrogen, alkyl group (e.g., C10, C2 ... 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 (alkynyl), wherein any of them may be substituted with any group provided herein, alkylamino (e.g., NR'R", where R' is an alkyl (e.g., C10), 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 Alkyl) and R" is, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 (alkynyl), any of which may be substituted with any group provided herein, arylamino (e.g., NR'R", where R' is an aryl (e.g., C 5-20 Aryl groups, such as C 5-10 Aryl groups, such as C 5-6 Aryl) and R" is, for example, hydrogen, alkyl (e.g., C1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 (alkynyl), wherein any of them may be substituted with any group provided herein, amide (e.g., C(O)NR'R"), wherein R' and R" are independently, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 Alkyne group (any of which may be substituted with any group provided herein), nitro group (e.g., NO2), thiol group (e.g., SH), alkylthio group (e.g., C group substituted with thiol group). 1-20 Alkyl groups, such as C-type alkyl groups substituted with thiol groups 1-10 Alkyl groups, such as C-type alkyl groups substituted with thiol groups 1-6 Alkyl groups, such as C-type alkyl groups substituted with thiol groups 1-3 alkyl), haloalkylthio (e.g., C10), 1-20 Halogenated alkyl thiols, such as C 1-10 Halogenated alkyl thiols, such as C 1-6 Halogenated alkyl thiols, such as C 1-3 Haloalkylthio), perhaloalkylthio (e.g., C 1-20 Perhaloalkylthio groups, such as C 1-10 Perhaloalkylthio groups, such as C 1-6 Perhaloalkylthio groups, such as C 1-3 perhaloalkylthiols), aryl thiols (e.g., C10), 5-20 Aryl thiols, such as C 5-10 Aryl thiols, such as C 5-6 aryl thiols), sulfonates (e.g., S(O)₂OR, where R is, for example, an alkyl group (e.g., C₂). 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 Alkyne group, any of which may be substituted with any group provided herein, sulfonic acid (e.g., S(O)2OH), trisubstituted silyl group (e.g., SiR'R"R*, wherein R', R" and R* are independently selected from, for example, alkyl groups (e.g., C...). 1-20 Alkyl groups, such as C 1-10 Alkyl groups, such as C 1-6 Alkyl groups, such as C 1-3 alkyl), alkenyl (e.g., C10 ...) 2-20 Alkenyl groups, such as C 2-10 Alkenyl groups, such as C 2-6 alkenyl) or ynyl) for example, C 2-20 Alkyne groups, such as C 2-10 Alkyne groups, such as C 2-6 The trisubstituted silyl group may be substituted with any group provided herein; in some cases, the trisubstituted silyl group may be trimethylsilyl, N3, SCH3, C(O)CH3, CO2CH3, CO2H, pyridyl, thiophene, furanyl, carbamate, and urea. Additional groups may also be included. Where structurally feasible, two substituents may be linked together to form a fused five-, six-, or seven-membered carbon ring or heterocycle consisting of zero to three heteroatoms (e.g., N, O, S, etc.), for example, forming a methylenedioxy or ethylenedioxy group. Unsubstituted or substituted groups may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between full and monosubstituted (e.g., -CH2CF3). Where substituents are described without limiting substitution, substituted and unsubstituted forms are included. Where a substituent is defined as "substituted," the substituted form is particularly anticipated. Additionally, different groups of optional substituents for a specific part can be defined as needed; in these cases, the optional substitutions will be defined, usually following the phrase “unsubstituted or substituted”.

[0075] Unless otherwise defined, the terms R, R', R", R*, etc., appearing alone and without numerical 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 unsubstituted or substituted as defined herein. Regardless of whether the R group is numerically designated, each R group, including R, R', and R... n(Where n = (1, 2, 3, ... n)), each substituent and each term should be understood as independent of each other in terms of selection from the group. If any variable, substituent, or term (e.g., aryl, heterocyclic, R, etc.) appears more than once in the formula or general structure, then its definition for each occurrence is independent of its definition for each other occurrence. Those skilled in the art will further recognize that certain groups can be attached to the parent molecule or can occupy a position in the elemental chain from either end of the written structure. For example, an asymmetric group such as -C(O)N(R)- can be attached to the parent moiety at carbon or nitrogen.

[0076] A "bond" refers to a covalent bond between two atoms, or, when the atoms connected by a bond are considered part of a larger substructure, a covalent bond between two parts. Unless otherwise specified, a bond can be a single, double, or triple bond. The dashed line between two atoms in a molecular diagram indicates whether an additional bond may or may not be present at that location.

[0077] The compounds disclosed herein may contain asymmetric centers. These centers are designated by the symbols “R” or “S”, depending on the configuration of the substituents surrounding the chiral carbon atom. It should be understood that this disclosure covers all stereochemical isomer forms, including diastereomers, enantiomers, transisomers, and epimers, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing mixtures of enantiomeric products followed by separation, such as by converting mixtures to diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column, or any other suitable method known in the art. Starting compounds of a particular stereochemistry are commercially available or may be prepared and resolved using techniques known in the art. Additionally, the compounds disclosed herein may exist in geometric isomer forms. This disclosure includes all cis, trans, same-side, reverse-side, opposite-side (E), and same-side (Z) isomers, and suitable mixtures thereof. Additionally, the compounds may exist in tautomer forms; this disclosure provides all tautomers. Furthermore, the compounds provided herein may contain configurational isomers, including groups that can be oriented in a different configuration relative to another moiety. Additionally, the compounds disclosed herein may exist in both unsolvated and solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Generally, the solvated form is considered equivalent to the unsolvated form.

[0078] "Combination therapy" means the administration of two or more therapeutic agents to treat the therapeutic ailment or condition described in this disclosure. Such administration encompasses the combined administration of these therapeutic agents in a substantially simultaneous manner, such as as a single dose unit (e.g., capsule) of the active ingredient in a fixed ratio or as multiple separate dose units (e.g., capsules) for each active ingredient. Additionally, such administration also encompasses the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the ailment or condition described herein.

[0079] In this document, "KRAS inhibitor" refers to an IC50 concentration of no more than about 100 μM and more typically no more than about 50 μM that indicates KRAS activity. 50 Compounds, as measured in the assays generally described herein, such as surface plasmon resonance KRAS-G12D protein binding assays and / or KRAS G12D protein-effect protein interaction disruption assays. "IC 50 "This refers to the inhibitor concentration that reduces the activity of an enzyme (e.g., KRAS) to half its maximum level. Some of the compounds disclosed herein have been found to exhibit inhibition of KRAS. In some embodiments, the compounds will exhibit an IC50 concentration of no more than about 50 μM with respect to KRAS (e.g., KRAS with the G12D mutation). 50 In a further embodiment, the compound will exhibit an IC50 concentration of no more than about 10 μM with respect to KRAS (e.g., KRAS with the G12D mutation). 50 In a further embodiment, the compound will exhibit an IC50 concentration of no more than about 1 μM with respect to KRAS (e.g., KRAS with the G12D mutation). 50 In a further embodiment, the compound will exhibit an IC50 of no more than about 200 nM with respect to KRAS (e.g., KRAS with the G12D mutation). 50 As measured in the KRAS assay described herein. In some embodiments, the compound will exhibit an IC50 of less than about 50 μM, such as less than about 40 μM, 30 μM, 20 μM, 10 μM, 5 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM or less, relative to KRAS (e.g., KRAS with the G12D mutation). 50 In some embodiments, the compound will exhibit an IC50 of less than about 1 μM with respect to KRAS (e.g., KRAS with the G12D mutation). 50In some embodiments, the KRAS inhibitor exhibits greater inhibitory activity against KRAS with the G12D mutation than against KRAS with another mutation, such as G12C, G12R, G12S, G12A, or G12V. For example, in some embodiments, the KRAS inhibitors provided herein exhibit at least two, five, ten, twenty, or higher inhibitory activity against KRAS with the G12D mutation relative to KRAS with another mutation, such as G12C, G12R, G12S, G12A, or G12V, such as the G12C mutation. In some embodiments, the KRAS inhibitors provided herein exhibit greater inhibitory activity against active KRAS with the G12D mutation than against inactive KRAS with the G12D mutation. In some embodiments, the KRAS inhibitors provided herein exhibit less inhibitory activity against active KRAS with the G12D mutation than against inactive KRAS with the G12D mutation. In some embodiments, the KRAS inhibitors provided herein exhibit similar inhibitory activity against active and inactive KRAS with the G12D mutation. In some embodiments, the KRAS inhibitors provided herein exhibit inhibitory activity against K-RAS4a splice variants. In some embodiments, the KRAS inhibitors provided herein exhibit inhibitory activity against K-RAS4b splice variants. In some embodiments, the KRAS inhibitors provided herein exhibit inhibitory activity against both K-RAS4a and K-RAS4b splice variants.

[0080] "Therapeutic effective amount" means the amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease, condition or ailment, or that exhibits detectable therapeutic or inhibitory effects. The exact amount will depend on the therapeutic purpose and will be determined by a person skilled in the art using known techniques (see, for example, 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, edited by Gennaro, Lippincott, Williams & Wilkins).

[0081] The term “therapeutically acceptable” refers to compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for use in contact with patient tissues without excessive toxicity, irritation, or allergic reactions, that are commensurate with a reasonable benefit / risk ratio, and that are effective for their intended use.

[0082] "Treatment," "positive treatment," and "therapeutic approach" refer to any successful indication of treating or improving an injury, ailment, or disorder, including any objective or subjective parameters such as relief; mitigation; reduction of symptoms or making the injury, ailment, or disorder more tolerable for the patient; slowing the rate of deterioration or decline; making the final point of deterioration less debilitating; and / or improving the patient's physical or mental health. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Treatment can also be inherently proactive; that is, it can include prevention of the disease, condition, or disorder; prevention of the onset of one or more symptoms of the disease, condition, or disorder; and / or prevention of the escalation of the disease, condition, or disorder. Prevention of the disease, condition, or disorder can involve complete prevention of the disease and / or prevention of disease progression (e.g., progression to a later stage of the disease, condition, or disorder). For example, prevention of the disease may not mean the complete elimination of any disease-related effects at any level, but may mean prevention of the symptoms of the disease, condition, or disorder to a clinically significant or detectable level.

[0083] "Patient" or "subject" means a living organism that suffers from or is susceptible to a disease, condition, or ailment that can be treated by administration of the compounds or pharmaceutical compositions provided herein. Non-limiting examples include humans, rats, mice, rabbits, hamsters, guinea pigs, cats, dogs, non-human primates (e.g., monkeys), goats, pigs, sheep, cattle, deer, horses, and other non-mammalian animals. Examples of mammals that can be treated by administration of the compounds or pharmaceutical compositions provided herein include, for example, rodents (e.g., rats, mice, squirrels, guinea pigs, hamsters, etc.), rabbits (e.g., rabbits, hares, etc.), primates (e.g., monkeys, apes, etc.), cattle (e.g., cattle), odd-toed ungulates (e.g., horses), even-toed ungulates (e.g., cattle such as cattle, sheep such as sheep, goats such as goats, pigs such as pigs, etc.), and marsupials (e.g., kangaroos, wallabies, large kangaroos, sugar gliders, etc.). In some implementations, the patient or subject is a human. In some implementations, the patient or subject is a companion animal, such as a cat or dog. In some implementations, the patient or subject is a farm animal, such as a goat, sheep, cow, pig, or horse. In some implementations, the patient or subject is an exotic animal, such as a primate (e.g., a monkey), a marsupial (e.g., a kangaroo, wallaby, large kangaroo, sugar glider, etc.), or a non-domesticated or hybrid cat or dog.

[0084] As used herein, “composition” is intended to cover products containing a specified amount of a specified ingredient, and any product produced directly or indirectly from a combination of the specified amounts of the specified ingredients. “Pharmaceutical acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipients.

[0085] "Pharmaceutically acceptable excipients" are substances that facilitate administration of the active agent to a subject and absorption by the subject. Pharmaceutical excipients that can be used in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients can be used in this disclosure.

[0086] The term "prodrug" refers to a compound that is more active in vivo. Some of the compounds disclosed herein can also exist as prodrugs. A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted into the compound in vitro via chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing a suitable enzyme or chemical reagent, it can be slowly converted into the compound. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or the parent drug. For example, a prodrug may have bioavailability when administered orally, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0087] The compounds disclosed herein can exist as therapeutically acceptable salts. This disclosure includes the compounds provided herein in salt form, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts will generally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compounds discussed. Basic addition salts can also be formed and are pharmaceutically acceptable.

[0088] As used herein, the term "therapeutically acceptable salt" refers to the salt or zwitterionic form of the compounds disclosed herein, which are water-soluble or oil-soluble or dispersible and are therapeutically acceptable as defined herein. Salts can be prepared during the final isolation and purification of the compound, or solely by reacting a suitable compound in its free base form with a suitable acid. Representative acid addition salts include acetates, adipates, alginates, L-ascorbic acid salts, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butyrates, camphorates, camphorsulfonates, citrates, disglucose salts, formates, fumarates, gentianates, glutarate, glycerophosphates, glycolates, hemisulfates, heptanates, hexanoates, hippurates, hydrochlorides, hydrobromide salts, hydroiodates, 2-hydroxyethanesulfonate (hydroxyethylsulfonate), lactates, and maleic acid salts. Salts, malonates, DL-mandelates, mesitylenesulfonates, methanesulfonates, naphthalenesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, dihydroxynaphthaleneate, pectinates, persulfates, 3-phenylpropionates, phosphonates, picrates, neopentanoates, propionates, pyroglutamates, succinates, sulfonates, tartrates, L-tartrates, trichloroacetic acid salts, trifluoroacetic acid salts, phosphates, glutamates, bicarbonates, para-toluenesulfonate / p-tosylate, and undecanoates. Furthermore, the basic groups in the compounds disclosed herein can be quaternized using: methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; decyl, lauryl, myristyl, and steroidal chlorides, bromides, and iodides; and benzyl bromide and phenethyl 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 compound with alkali metal or alkaline earth ions. Therefore, this disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein.

[0089] Basic addition salts can be prepared during the final separation and purification of compounds 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 cations for salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, diphenylmethylamine, N,N-diphenylmethylphenethylamine, 1-ephenamine, and N,N'-diphenylmethylethylenediamine. Other representative organic amines that can be used to form basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0090] Salts of compounds can be prepared by reacting a suitable compound in its free base form with a suitable acid.

[0091] "KRAS G12D positive cancer" refers to cancer characterized by KRAS G12D mutation.

[0092] As used herein, “effective amount for combined therapy” means the amount by which the therapeutic agent exhibits (additive, but preferably synergistic) interaction (combined therapeutic effect) when administered alone (in an alternating chronological order, especially in a sequence-specific manner) to a warm-blooded animal, particularly a human being to be treated. Whether this is the case can be determined, in particular, by tracking blood levels that show both compounds present in the blood of the human being to be treated at least during certain time intervals.

[0093] As used herein, “synergistic effect” refers to the action of at least two therapeutic agents: a KRAS G12D inhibitor as defined herein and an adjunct agent, which may be an agent formulated to treat a disease, condition, or disorder or its symptoms. The effect may, for example, be the slowing of the progression of symptoms of a proliferative disease, such as cancer, particularly lung cancer, or its symptoms. Similarly, “synergistically effective amount” refers to the amount required to achieve a synergistic effect.

[0094] When used herein to refer to a group of substituents or a “group of substituents,” the terms “a,” “an,” or “a” mean at least one. For example, in the case where a compound is substituted with “a” alkyl or aryl group, the compound is either unsubstituted or substituted with at least one alkyl and / or at least one aryl group, wherein each alkyl and / or aryl group is optionally distinct. In another example, in the case where a compound is substituted with “a” group of substituents, the compound is substituted with at least one group of substituents, wherein each group of substituents is optionally distinct.

[0095] compound

[0096] In one aspect, this disclosure provides a compound represented by formula I:

[0097]

[0098] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[0099] R 1 Selected from -OR 8 A 4-6 membered heterocycle comprising a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms 16 replace;

[0100] R 2 Selected from H, 3-6 membered carbon rings and C 1-6 Alkyl group, wherein the 3-6 membered carbon ring or the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0101] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0102] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[0103] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0104] R 5 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 3-6 membered carbocyclic rings, 3-6 membered heterocyclic rings, 5-6 membered heteroaryl and phenyl, wherein any C 1-6Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic, heterocyclic, heteroaryl, and phenyl group is unsubstituted or via one or more R groups. 14 replace;

[0105] R 6 It is a phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl group, wherein any phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl group is unsubstituted or has been modified by one or more R groups. 15 replace;

[0106] R 7 Selected from halogens, -OR 12 -CN and H;

[0107] R 8 Selected from H, heterocycles, and alkyl heterocycles, wherein the heterocycle or alkyl heterocycle is unsubstituted or has undergone one or more R... 16 Substitution, wherein the alkyl moiety of any alkyl heterocycle is selected from C 1-6 alkyl;

[0108] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0109] Each R 10 Independently selected from halogens, -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0110] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0111] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0112] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0113] Each R 14 Independently selected from halogens, -OR 12 -CN, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0114] Each R 15 Independently selected from halogens, -OR 12 -CN, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0115] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl, -OR 12 and 3-6 membered heterocycles, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0116] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0117] Each R 18 Independently selected from -OH, -OC 1-6Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0118] Each R 19 Selected independently from C 1-6 Alkyl, 3-6 membered heterocycles and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0119] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl groups, halogens, and 3-6 membered carbon rings;

[0120] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0121] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0122] In some embodiments, this disclosure provides a compound of formula I or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0123] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 8 It is a heterocyclic ring. In some implementations, R 8 It is an alkyl heterocyclic ring. In some embodiments, R 8 It is an alkyl heterocycle, wherein the alkyl portion of the alkyl heterocycle is selected from C10. 1-6 Alkyl group. In some embodiments, R 8 It is -CH2 (heterocyclic). In some embodiments, the heterocyclic or alkyl heterocyclic ring comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S (e.g., 1-2 heteroatoms). In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, the heterocycle or alkyl heterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle or alkyl heterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is via one or more R... 16Replacement. In some implementations, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3. In some implementations, at least one R 16 It is a halogen (e.g., F). In some embodiments, at least one R 16 It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, each R 16 Independently selected from halogens, C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, each R 16 It is independently selected from -F, -CH3, -CH2CH2F, -CH2CHF2, -CH2CH2CN, -OCH3 and -OCHF2.

[0124] In some implementation schemes, R 1 Selected from:

[0125]

[0126] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a It is methyl. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, Rb It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R b It is methyl. In some embodiments, R 1 Selected from:

[0127]

[0128]

[0129] In some implementation schemes, R 1 Selected from:

[0130]

[0131] In some implementation schemes, R 1 Selected from:

[0132]

[0133] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein R a Or R c C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, an R a Selected from halogens, C 1-6 Alkyl and -OR 12 And other R a It is H. In some implementations, an R a It is a halogen (e.g., F). In some implementations, the two Rs a It is a halogen (e.g., F). In some implementations, an R a Yes - OR 12 (e.g., -OCH3 or -CHF2). In some implementations, an R a It is C 1-6 Alkyl (e.g., methyl). In some embodiments, two R... a It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R c Selected from -CH3, -CH2CH2F, -CH2CHF2, and -CH2CH2CN. In some embodiments, R 1 Selected from:

[0134]

[0135] In some implementation schemes, R 1 Selected from:

[0136]

[0137] In some implementation schemes, R 1 Selected from:

[0138]

[0139]

[0140] In some implementation schemes, R 1 Selected from:

[0141]

[0142] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some such implementations, R 16 Selected from -N(R) 12 2. C 1-6 Alkyl groups and 3-6 membered heterocycles. In some embodiments, R 16 It is -N(C 1-6 Alkyl group 2, for example -N(CH3)2. In some embodiments, R 16 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R 16 It is a bicyclic six-membered heterocycle with one nitrogen atom. In some embodiments, R 1 Selected from:

[0143]

[0144] In some implementation schemes, R 1 It is H.

[0145] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some such embodiments, each R 13 Independently selected from -OR 22 (e.g., -OH) and -CN. In some embodiments, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2Selected from -CH3, -CH2CH3, -CH2CH2OH, -CH2CH2CN, and -CH(CH3)2. In some embodiments, R 2 It is a 3-6 membered carbon ring. In some implementations, R 2 It is cyclopropyl.

[0146] In some implementation schemes, R 3 It is C 1-6 Alkyl, the C 1-6 Alkyl groups via one or more R 9 Replacement. In some implementations, R 3 It is via-N(R) 17 )2 replaced by C 1-6 Alkyl, wherein each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is a C substituted with -NH2, -NH(CH3) or -N(CH3)2 1-6 Alkyl group. In some embodiments, R 3 It is via-N(R) 17 )C(O)C 1-6 Alkyl (e.g., -N(H)C(O)CH3) substituted C 1-6 Alkyl group. In some embodiments, R 3 Is it a scripture-OR 17 (e.g., C-substituted with -OH) 1-6 alkyl.

[0147] In some implementation schemes, R 3 Selected from:

[0148]

[0149] In some implementation schemes, R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a 4-6 membered carbon ring, wherein the carbon ring is unsubstituted or modified by one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic carbon ring (e.g., a 5-6 membered bicyclic carbon ring). In some embodiments, R 3 It is a monocyclic carbon ring (e.g., a 4-6 member monocyclic carbon ring). In some embodiments, R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3It is a carbon ring substituted with -NH2.

[0150] In some implementation schemes, R 3 Selected from:

[0151] In some implementation schemes, R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a 4-8 membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, said heterocycle being unsubstituted or via one or more R atoms. 10 Replacement. In some implementations, R 3 It is a polycyclic heterocyclic ring (e.g., a 6-8 member bicyclic heterocyclic ring). In some embodiments, R 3 It is a monocyclic heterocycle (e.g., a 4-6 membered monocyclic heterocycle). In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is unreplaced or through one or more R 10 Substituted heterocyclic rings, where each R 10 Independently selected from halogens, -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 Replacement. In some implementations, R 3 It is unsubstituted or substituted by one or more of the following: -F, -CH3, -CH2F, -CH2CN, -C(O)CH3, -C(O)CH2NH2, -C(O)NH2 and The heterocycle is substituted with a group. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2.

[0152] In some implementation schemes, R 3 Selected from:

[0153]

[0154] None of them have been replaced or subjected to one or more R10 replace.

[0155] In some implementation schemes, R 3 Selected from:

[0156]

[0157] In some implementation schemes, R 3 Selected from:

[0158]

[0159] None of them have been replaced or subjected to one or more R 10 replace.

[0160] In some implementation schemes, R 2 Or R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, R 2 Or R 3 via the amino moiety (i.e., -N(R)) 17 )2 or -N(R 19 )2) Replace.

[0161] In some implementation schemes, R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms an unsubstituted or R-type atom. 11 Substituted heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 4-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 4-7 membered monocyclic heterocycle having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 7-9 membered bicyclic heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some such implementations, each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 Replacement. In some implementations, each R 11 Independently selected from -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

[0162] In some implementation schemes, R 2 and R 3 Together with the atoms it is attached to, it forms heterocycles selected from the following:

[0163]

[0164] None of them have been replaced or subjected to one or more R 11 replace.

[0165] In some implementation schemes, R 2 and R 3 Together with the atoms it is attached to, it forms heterocycles selected from the following:

[0166]

[0167]

[0168] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0169]

[0170] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0171]

[0172] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0173]

[0174] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0175]

[0176] None of them have been replaced or subjected to one or more R 11 replace.

[0177] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0178]

[0179] In some implementation schemes, R 2 and R 3 Together with the nitrogen atom it is attached to, it forms an unsubstituted or R-atom with one or more R atoms. 11 Substituted heterocycles, said heterocycles comprising an additional nitrogen atom and / or via an amino moiety (e.g., -N(R)). 19 )2) group substitution.

[0180] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is a halogen. In some implementations, R 4 Yes - OR 12 In some implementations, R 4 It is -OCH3.

[0181] In some implementation schemes, R 5 It is unreplaced or through one or more R 14 Replaced 3-6 membered carbon rings. In some implementations, R 5 It is unreplaced or through one or more R 14 (e.g., one or more -OR) 12 Or -CN) replaced 3- or 4-membered carbon rings. In some embodiments, R 5 It is unreplaced or through one or more R 14 Substituted 3-6 membered heterocycles (e.g., 3-6 membered heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 It is unreplaced or through one or more R 14 The substituted 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R5 It is phenyl. In some embodiments, R 5 It is unreplaced or through one or more R 14 (For example, C) 1-6 Alkyl-substituted 5-6-membered heteroaryl groups. In some embodiments, R 5 It is pyridyl, furanyl, or imidazole, each unsubstituted or via one or more R groups. 14 (For example, C) 1-6 Alkyl) substitution. In some embodiments, R 5 It is furanyl.

[0182] In some implementation schemes, R 5 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 Selected from unreplaced C 1-6 Alkyl groups, such as methyl or ethyl. In some embodiments, R 5 Selected from C substituted with one or more halogens or -CN 1-6 Alkyl group. In some embodiments, R 5 Selected from -CF3, -CF2H, and -CH2CN. In some implementations, R 5 Selected from -CH3, -CH2CH3, -CF2H, -CF3, -CF2CH3 and -CH2CN.

[0183] In some implementation schemes, R 5 It is C 2-6 Alkenyl. In some embodiments, R 5 It is C 2-6 Alkyne group (e.g., ethynyl group).

[0184] In some implementation schemes, R 5 Selected from -OR 12 , where R 12 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 It is -OCH3, -OCF3, or -OCF2H.

[0185] In some implementation schemes, R 5 Yes - CN.

[0186] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is either Cl or F.

[0187] In some implementation schemes, R 5It is hydrogen.

[0188] In some implementation schemes, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 7 Yes - OR 12 , where R 12 Selected from H and unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 7 It is -OH, -OCH3, or -OCH2CF3. In some embodiments, R 7 Yes -CN. In some implementations, R 7 It is hydrogen.

[0189] In some implementation schemes, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0190] In some implementation schemes, R 6 It is a bicyclic aryl or bicyclic heteroaryl, wherein the aryl or heteroaryl group is unsubstituted or has been modified by one or more R groups. 15 Replacement. In some implementations, R 6 It is a bicyclic aryl or bicyclic heteroaryl, wherein the aryl or heteroaryl is oxidized by one or more R 15 replace.

[0191] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic aryl group. In some embodiments, R 6 It is through one or more R 15 Substituted naphthyl group. In some embodiments, R 6 Selected from:

[0192]

[0193] In some implementation schemes, R 6 It is a 9-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is unsubstituted or via one or more R atoms. 15Replacement. In some implementations, R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups. In some embodiments, R 6 It has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is derived from one or more R atoms. 15 The substituted 9-membered heteroaryl group. In some such embodiments, at least one R 15 It is -N(R) 12 )2 (e.g., -NH2). In some embodiments, at least one R 15 It is a halogen (e.g., F). In some implementations, each R 15 Independently selected from halogens, -CN and -N(R) 12 )2. In some implementation schemes, R 6 Through at least two R 15 (For example, at least one halogen and -NH2) substitution.

[0194] In some implementation schemes, R 6 Selected from:

[0195]

[0196] None of them have been replaced or subjected to one or more R 15 replace.

[0197] In some implementation schemes, R 6 Selected from:

[0198]

[0199] In some implementation schemes, R 6 Selected from:

[0200]

[0201] In some implementation schemes, R 6 yes:

[0202]

[0203] In some implementation schemes, R 6 yes

[0204] In some implementation schemes, R 6 It is a phenyl or monocyclic heteroaryl group, wherein the phenyl or heteroaryl group is unsubstituted or via one or more R groups. 15 replace.

[0205] In some implementation schemes, R 6 It is unreplaced or through one or more R 15Substituted phenyl groups. In some such embodiments, each R 15 Independently selected from halogens, -OR 12 -CN and -N(R) 12 )2. In some implementation schemes, R 6 Selected from:

[0206]

[0207] In some implementation schemes, R 6 It is unreplaced or through one or more R 15 Substituted monocyclic 5-6 membered heteroaryl groups. In some embodiments, R 6 It is unreplaced or through one or more R 15 Substituted pyridinyl group. In some such embodiments, each R 15 Independently selected from -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 6 yes

[0208] In some implementations, (i)R 2 Selected from C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the C 1-6 Alkyl groups and 3-6 membered carbon rings are unsubstituted or via one or more R groups. 13 Replace; and (ii)R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 4 It is H. In some implementations, R 7 It is a halogen (e.g., F). In some implementations, R 5 Selected from C 1-6 Alkyl, halogen, 3-6 membered carbon rings and 3-6 membered heterocycles, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 Replacement. In some implementations, R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups. In some embodiments, R 6 yes:

[0209]

[0210] In some implementation schemes, R1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring. In some embodiments, R 1 Selected from:

[0211]

[0212] In some implementation schemes, R 1 Selected from:

[0213]

[0214]

[0215] In some implementations, (i)R 2 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl (e.g., methyl or ethyl); and (ii) R 3 Selected from unsubstituted or via one or more R 10 Replaced carbon rings. In some embodiments, (i)R 2 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl (e.g., methyl or ethyl); and (ii) R 3 Selected from unsubstituted or via one or more R 10 Substituted heterocyclic rings. In some implementations, (i)R 2 It is unreplaced or through one or more R 13 Substituted 3-6 membered carbon rings (e.g., cyclopropyl); and (ii) R 3 Selected from unsubstituted or via one or more R 10 Replaced carbon rings. In some embodiments, (i)R 2 It is unreplaced or through one or more R 13 Substituted 3-6 membered carbon rings (e.g., cyclopropyl); and (ii) R 3 Selected from unsubstituted or via one or more R 10 Substituted heterocycles.

[0216] In one aspect, this disclosure provides a compound represented by formula IA:

[0217]

[0218] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 3 R 4 R5 R 6 and R 7 As defined above for Formula I and described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides compounds of Formula IA or salts thereof (e.g., pharmaceutically acceptable salts).

[0219] In some embodiments, this disclosure provides compounds of formula IA, wherein:

[0220] R 1 Selected from -OR 8 A 4-6 membered heterocycle comprising a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms 16 replace;

[0221] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0222] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0223] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0224] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0225] R 7 Selected from halogens, -OR 12 -CN and H;

[0226] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 Substitution, wherein the alkyl moiety of any alkyl heterocycle is selected from C 1-6 alkyl;

[0227] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0228] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0229] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0230] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0231] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0232] Each R 15Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0233] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0234] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0235] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0236] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0237] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0238] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0239] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0240] In some implementation schemes, R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Replaced 3-6 membered carbon rings or heterocycles. In some embodiments, R 3It is unreplaced or through one or more R 10 Replaced 3-7 membered carbon rings. In some embodiments, R 3 It is unreplaced or through one or more R 10 Replaced 3-7 membered heterocycles.

[0241] In some implementation schemes, R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic carbon ring. In some implementations, R 3 It is a monocyclic carbon ring. In some implementations, R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a carbon ring substituted with -NH2.

[0242] In some implementation schemes, R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic heterocyclic ring. In some implementations, R 3 It is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2.

[0243] In some implementation schemes, R 3 Selected from:

[0244]

[0245] None of them have been replaced or subjected to one or more R 10 replace.

[0246] In some implementation schemes, R 3 Selected from:

[0247]

[0248] None of them have been replaced or subjected to one or more R 10 replace.

[0249] In some implementation schemes, R 3 Selected from:

[0250]

[0251]

[0252] None of them have been replaced or subjected to one or more R 10 replace.

[0253] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R) 17 )2, where each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 alkyl.

[0254] In some implementation schemes, R 3 Selected from:

[0255]

[0256] In some implementation schemes, R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a heterocyclic component. In some embodiments, the amino moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amino moiety is a primary amine (e.g., -NH2). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0257] In some implementation schemes, R 1 It is H.

[0258] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 8 It is a heterocyclic ring. In some implementations, R 8 It is an alkyl heterocyclic ring.

[0259] In some implementation schemes, R 8 Contains unsubstituted or via one or more R 16 Substituted 3-6 membered heterocycles. In some embodiments, the heterocycle or alkyl heterocycle comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8It comprises a heterocycle including at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R atoms. 16 Substituents. In some embodiments, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3.

[0260] In some implementation schemes, R 1 Selected from:

[0261]

[0262] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 1 Selected from:

[0263]

[0264] In some implementation schemes, R 1 Selected from:

[0265]

[0266] In some implementation schemes, R 1 Selected from:

[0267]

[0268] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0269]

[0270] In some implementation schemes, R 1 Selected from:

[0271]

[0272] In some implementation schemes, R 1 Selected from:

[0273]

[0274]

[0275] In some implementation schemes, R 1 Selected from:

[0276]

[0277] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some implementations, R 1 Selected from:

[0278]

[0279] In some implementation schemes, R 6 Selected from:

[0280]

[0281] In some implementation schemes, R 6 Selected from:

[0282]

[0283] In some implementation schemes, R 6 yes:

[0284]

[0285] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0286] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0287] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0288] In some implementations, (i)R 3 It is a 4- or 5-membered heterocycle comprising a single nitrogen atom (e.g., azahexacyclic butane), wherein the heterocycle is unsubstituted or via one or more R... 10 Replace; and (ii)R 1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring, wherein the heterocyclic or alkyl heterocyclic ring is a 4-8 membered ring system (e.g., an 8-membered ring system or a 5-membered ring system) containing a single nitrogen atom. In some embodiments, (iii)R 4 It is H. In some implementations, (iv)R 7 It is a halogen. In some implementations, R 3 Selected from:

[0289]

[0290] None of them have been replaced or subjected to one or more R 10 Replacement. In some implementations, R1 Selected from:

[0291]

[0292] Each R a and R b Independently selected from halogens, C 1-6 Alkyl, -OR 12 And H. In some implementations, R 1 Selected from:

[0293]

[0294] In some implementation schemes, R 7 It is F. In some implementations, R 6 Selected from:

[0295]

[0296] In some implementation schemes, R 5 Selected from -CF3, -Cl, -CH2CN, furan, and phenyl. In some embodiments, (i)R 3 It is a 4-membered heterocycle comprising a single nitrogen atom (e.g., azahexacyclic butane), wherein the heterocycle is unsubstituted or via one or more R... 10 Replace; (ii)R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is an 8-membered ring system containing a single nitrogen atom; (iii) R 4 It is H; and (iv)R 7 It is a halogen. In some implementations, (i)R 3 It is a 5-membered heterocycle comprising a single nitrogen atom (e.g., azahexacyclic butane), wherein the heterocycle is unsubstituted or via one or more R... 10 Replace; (ii)R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is an 8-membered ring system containing a single nitrogen atom; (iii) R 4 It is H; and (iv)R 7 It is halogen.

[0297] In some implementations, (i)R 3 It is a 4- or 5-membered heterocycle comprising a single nitrogen atom (e.g., azahexacyclic butane), wherein the heterocycle is unsubstituted or via one or more R... 10 Replace; and (ii)R 1 Yes - OR 8 , where R 8It is a heterocyclic or alkyl heterocyclic ring, wherein the heterocyclic or alkyl heterocyclic ring is a 4-8 membered ring system containing a single nitrogen atom, such as a 5-membered ring system. In some embodiments, (iii)R 4 It is H. In some implementations, (iv)R 7 It is a halogen. In some implementations, R 3 Selected from:

[0298]

[0299] None of them have been replaced or subjected to one or more R 10 Replacement. In some implementations, R 1 Selected from:

[0300]

[0301] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0302]

[0303]

[0304] In some implementation schemes, R 7 It is F. In some implementations, R 6 Selected from:

[0305]

[0306] In some implementation schemes, R 5 Selected from -CF3, -Cl, furan, and phenyl. In some embodiments, (i)R 3 It is a 4-membered heterocycle comprising a single nitrogen atom (e.g., azahexacyclic butane), wherein the heterocycle is unsubstituted or via one or more R... 10 Replace; and (ii)R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is a 5-membered ring system containing a single nitrogen atom; (iii) R 4 It is H; and (iv)R 7 It is a halogen. In some implementations, (i)R 3It is a 5-membered heterocycle comprising a single nitrogen atom (e.g., pyrrolidine), said heterocycle being unsubstituted or via one or more R atoms. 10 Replace; and (ii)R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is a 5-membered ring system containing a single nitrogen atom; (iii) R 4 It is H; and (iv)R 7 It is halogen.

[0307] In some implementations, (i)R 3 It is unreplaced or through one or more R 10 Replacement of bridged carbocyclic or heterocyclic systems; and (ii) R 1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring, wherein the heterocyclic or alkyl heterocyclic ring is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (iii)R 4 It is H. In some implementations, (iv)R 7 It is a halogen. In some implementations, (i)R 3 It is unreplaced or through one or more R 10 Replacement bridge heterocyclic system; and (ii)R 1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring, wherein the heterocyclic or alkyl heterocyclic ring is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (i)R 3 It is unreplaced or through one or more R 10 Replacement bridged carbon ring system; and (ii)R 1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring, wherein the heterocyclic or alkyl heterocyclic ring is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, R 3 Selected from:

[0308]

[0309] In some implementation schemes, R 1 Selected from:

[0310]

[0311] Each R a and R b Independently selected from halogens, C 1-6 Alkyl, -OR 12and H; and where R c Selected from C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0312]

[0313] In some implementation schemes, R 1 Selected from:

[0314]

[0315] In some implementation schemes, R 7 It is F. In some implementations, R 5 Selected from -CF3. In some implementations, R 6 Selected from:

[0316]

[0317] In some implementations, (i)R 3 It is unreplaced or through one or more R 10 Replacement bridge heterocyclic system; (ii) R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is a 4-8 membered ring system containing a single nitrogen atom; (iii)R 4 It is H; and (iv)R 7 It is halogen.

[0318] In some implementations, (i)R 3 Selected from C 1-6 Alkyl-N(R) 17 )2; and (ii)R 1 Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is a 4-8 membered ring system containing a single nitrogen atom. In some embodiments, (iii)R 4 It is H. In some implementations, (iv)R 7 It is a halogen. In some implementations, R 3 Selected from:

[0319]

[0320] In some implementations, (i)R 3 Selected from C2 alkyl-N(R) 17 )2;(ii)R 1Yes - OR 8 , where R 8 It is an alkyl heterocycle, wherein the heterocycle is a 4-8 membered ring system containing a single nitrogen atom; (iii)R 4 It is H; and (iv)R 7 It is a halogen. In some implementations, R 6 yes:

[0321]

[0322] In some embodiments, this disclosure provides compounds according to formula IA1:

[0323]

[0324] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 3 R 4 R 5 R 6 and R 7 As defined above for Formula I and described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides compounds of Formula IA1 or salts thereof (e.g., pharmaceutically acceptable salts).

[0325] In some embodiments, this disclosure provides compounds according to formula IA1, wherein:

[0326] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0327] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0328] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0329] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0330] R 7 Selected from halogens, -OR 12 -CN and H;

[0331] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0332] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0333] Each R 11 Independently selected from -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, wherein any C 1-6Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0334] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0335] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0336] Each R 14 Independently selected from halogens, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0337] Each R 15 Independently selected from halogens, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0338] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0339] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0340] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0341] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0342] Each R 21 Independently selected from -OH, -OC 1-6Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0343] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0344] In some implementation schemes, R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Replaced 3-6 membered carbon rings or heterocycles. In some embodiments, R 3 It is unreplaced or through one or more R 10 Replaced 3-7 membered carbon rings. In some embodiments, R 3 It is unreplaced or through one or more R 10 Replaced 3-7 membered heterocycles.

[0345] In some implementation schemes, R 3 Selected from:

[0346]

[0347] None of them have been replaced or subjected to one or more R 10 replace.

[0348] In some implementation schemes, R 3 Selected from:

[0349]

[0350] None of them have been replaced or subjected to one or more R 10 replace.

[0351] In some implementation schemes, R 3 Selected from:

[0352]

[0353] None of them have been replaced or subjected to one or more R 10 replace.

[0354] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R) 17 )2, where each R17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 alkyl.

[0355] In some implementation schemes, R 3 Selected from:

[0356]

[0357] In some implementation schemes, R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a heterocyclic component. In some embodiments, the amino moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amino moiety is a primary amine (e.g., -NH2). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0358] In some implementation schemes, R 6 Selected from:

[0359]

[0360] In some implementation schemes, R 6 Selected from:

[0361]

[0362] In some implementation schemes, R 6 yes:

[0363]

[0364] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0365] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0366] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0367] In some embodiments, this disclosure provides compounds according to formula IA2:

[0368]

[0369] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 3 R 4 R 5 R 6 R 7 and R 8 As defined above for Formula I and described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides compounds of Formula IA2 or salts thereof (e.g., pharmaceutically acceptable salts).

[0370] In some embodiments, this disclosure provides compounds of formula IA2, wherein:

[0371] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0372] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0373] R 5 Selected from halogens, -OR 12 -CN,C1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0374] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0375] R 7 Selected from halogens, -OR 12 -CN and H;

[0376] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[0377] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0378] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0379] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0380] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0381] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0382] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0383] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0384] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0385] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0386] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0387] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0388] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0389] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0390] In some implementation schemes, R 8 Contains unsubstituted or via one or more R 16 Replaced 3-6 membered heterocycles.

[0391] In some implementations, -OR 8 Selected from:

[0392]

[0393]

[0394] In some implementations, -OR 8 Selected from:

[0395]

[0396] In some implementation schemes, R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Replaced 3-6 membered carbon rings or heterocycles. In some embodiments, R 3 Selected from:

[0397]

[0398] None of them have been replaced or subjected to one or more R 10 replace.

[0399] In some implementation schemes, R 3 Selected from:

[0400]

[0401] None of them have been replaced or subjected to one or more R 10 replace.

[0402] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R) 17 )2. In some implementation schemes, R 3 Selected from:

[0403]

[0404] In some implementation schemes, R 3 Including amino moiety (e.g., -NRR').

[0405] In some implementation schemes, R 6 Selected from:

[0406]

[0407] In some implementation schemes, R 6 Selected from:

[0408]

[0409] In some implementation schemes, R 6 yes:

[0410]

[0411] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0412] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0413] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0414] In another aspect, this disclosure provides compounds according to formula IB:

[0415]

[0416] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 4 R 5 R 6 and R 7 As defined above for Equation I and described individually and in combination in the categories and subclasses herein; and ring A is unsubstituted or via one or more R... 11 Substituted heterocycles. In some embodiments, this disclosure provides compounds of formula IB or salts thereof (e.g., pharmaceutically acceptable salts).

[0417] In some embodiments, this disclosure provides compounds of formula IB, wherein:

[0418] R 1 Selected from -OR 8 , including a 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R 16 replace;

[0419] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[0420] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0421] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0422] R 6 It is through one or more R 15Substituted bicyclic heteroaryl groups;

[0423] R 7 Selected from halogens, -OR 12 -CN and H;

[0424] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[0425] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0426] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0427] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0428] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0429] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0430] Each R16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0431] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0432] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0433] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0434] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0435] In some implementations, ring A is unsubstituted or via one or more R... 11 Substituted monocyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted polycyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted 4-10 member heterocyclic rings. In some embodiments, ring A is unsubstituted or via one or more R... 11 A substituted 4-6 membered heterocycle. In some embodiments, ring A comprises at least one nitrogen atom. In some embodiments, ring A has the following structure:

[0436]

[0437] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, ring A has the following structure:

[0438]

[0439] The ring was not replaced or passed through one or more R... 11Replacement. In some implementations, ring A has the following structure:

[0440]

[0441] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, ring A has the following structure:

[0442]

[0443] In some implementations, ring A has the following structure:

[0444]

[0445] In some embodiments, ring A is a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0446] In some implementation schemes, R 1 It is H.

[0447] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 8 It is a heterocyclic ring. In some implementations, R 8 It is an alkyl heterocycle. In some embodiments, the heterocycle or alkyl heterocycle comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R atoms. 16 Substituents. In some embodiments, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3.

[0448] In some implementation schemes, R 1 Selected from:

[0449]

[0450] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 1 Selected from:

[0451]

[0452] In some implementation schemes, R 1 Selected from:

[0453]

[0454]

[0455] In some implementation schemes, R 1 Selected from:

[0456]

[0457] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein R a Or R c C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0458]

[0459] In some implementation schemes, R 1 Selected from:

[0460]

[0461] In some implementation schemes, R 1 Selected from:

[0462]

[0463] In some implementation schemes, R 1 Selected from:

[0464]

[0465] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some implementations, R 1 Selected from:

[0466]

[0467] In some implementation schemes, R 6 Selected from:

[0468]

[0469] In some implementation schemes, R 6 Selected from:

[0470] In some implementation schemes, R 6 yes:

[0471]

[0472] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0473] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0474] In some implementation schemes, R 5It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0475] In some embodiments, this disclosure provides compounds according to formula IB1:

[0476]

[0477] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 4 R 5 R 6 and R 7 As defined above for Equation I and described individually and in combination in the categories and subclasses herein; and ring A is unsubstituted or via one or more R... 11 Substituted heterocycles. In some embodiments, this disclosure provides compounds of formula IB1 or salts thereof (e.g., pharmaceutically acceptable salts).

[0478] In some embodiments, this disclosure provides a compound of formula IB1, wherein:

[0479] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[0480] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0481] R 5Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0482] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0483] R 7 Selected from halogens, -OR 12 -CN and H;

[0484] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0485] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0486] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0487] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0488] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0489] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0490] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0491] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0492] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0493] In some implementations, ring A is unsubstituted or via one or more R... 11 Substituted monocyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted polycyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted 4-10 member heterocyclic rings. In some embodiments, ring A is unsubstituted or via one or more R... 11 A substituted 4-6 membered heterocycle. In some embodiments, ring A comprises at least one nitrogen atom. In some embodiments, ring A has the following structure:

[0494]

[0495] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, ring A has the following structure:

[0496]

[0497] The ring was not replaced or passed through one or more R... 11Replacement. In some implementations, ring A has the following structure:

[0498]

[0499] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, ring A has the following structure:

[0500]

[0501] In some implementations, ring A has the following structure:

[0502]

[0503] In some embodiments, ring A is a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0504] In some implementation schemes, R 6 Selected from:

[0505]

[0506] In some implementation schemes, R 6 Selected from:

[0507]

[0508] In some implementation schemes, R 6 yes:

[0509]

[0510] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0511] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0512] In some implementation schemes, R 5 It is a halogen. In some implementations, R5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0513] In some implementations, (i) ring A is unsubstituted or via one or more R... 11 Substituted piperazines or diazacycloheptanes. In some embodiments, (ii)R 7 It is a halogen. In some implementations, (iii)R 4 It is H. In some implementations, ring A is selected from:

[0514]

[0515] Each R g Independently selected from H and C 1-6 Alkyl and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, at least one R g It is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some embodiments, ring A is an unsubstituted piperazine or diazacycloheptane. In some embodiments, ring A is selected from:

[0516]

[0517] In some implementation schemes, R 7 It is F. In some implementations, R 5 Selected from halogens, -CN, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the carbon rings or C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 6 yes:

[0518]

[0519] In some implementations, ring A is unsubstituted or via one or more R... 11 Substituted piperazine. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted diazacycloheptanes.

[0520] In some implementations, (i) ring A is unsubstituted or via one or more R... 11 Replacement of the bridge heterocyclic system. In some implementations, (ii)R 7 It is a halogen. In some implementations, (iii)R 4 It is H. In some implementations, ring A is selected from:

[0521]

[0522] Among them (a)R g1 and R g3 Or (b)R g2 and R g3 They connect together to form a second ring containing 4-6 members, and R that is not part of the second ring... g1 R g2 R g3 and R g4 Either of them is independently selected from H and C. 1-6 Alkyl; and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, R g1 R g2 R g3 and R g4 At least one of them is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some implementations, ring A is selected from:

[0523]

[0524] Where R g2 and R g4 They connect together to form a second ring containing 4-6 members; R g1 R g3 and R g5 Independently selected from H and C 1-6 Alkyl; and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, Rg1 R g3 and R g5 At least one of them is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some implementations, R h It is -C(O)NH2. In some embodiments, ring A is selected from:

[0525]

[0526] In some implementation schemes, R 7 It is F. In some implementations, R 5 Selected from halogens, -CN, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the carbon rings or C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 6 yes:

[0527]

[0528] In some implementations, (i) ring A is unsubstituted or via one or more R... 11 Replacement bridge heterocyclic system; (ii) R 7 It is a halogen; and (iii)R 4 It is H.

[0529] In some embodiments, this disclosure provides compounds according to formula IB2:

[0530]

[0531] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 4 R 5 R 6 R 7 and R 8 As defined above for Equation I and described individually and in combination in the categories and subclasses herein; and ring A is unsubstituted or via one or more R... 11 Substituted heterocycles. In some embodiments, this disclosure provides compounds of formula IB2 or salts thereof (e.g., pharmaceutically acceptable salts).

[0532] In some embodiments, this disclosure provides a compound of formula IB2, wherein:

[0533] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[0534] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0535] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0536] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0537] R 7 Selected from halogens, -OR 12 -CN and H;

[0538] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[0539] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0540] Each R 12 Selected independently from C 1-6Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0541] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0542] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0543] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0544] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0545] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0546] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0547] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0548] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0549] In some implementations, ring A is unsubstituted or via one or more R... 11 Substituted monocyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted polycyclic heterocycles. In some embodiments, ring A is unsubstituted or via one or more R... 11 Substituted 4-10 member heterocyclic rings. In some embodiments, ring A is unsubstituted or via one or more R... 11 A substituted 4-6 membered heterocycle. In some embodiments, ring A comprises at least one nitrogen atom. In some embodiments, ring A has the following structure:

[0550]

[0551] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, ring A has the following structure:

[0552]

[0553] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, ring A has the following structure:

[0554]

[0555] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, ring A has the following structure:

[0556]

[0557] In some implementations, ring A has the following structure:

[0558]

[0559] In some embodiments, ring A is a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, ring A is a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0560] In some implementation schemes, R 8 It is a heterocyclic ring. In some implementations, R 8It is an alkyl heterocycle. In some embodiments, the heterocycle or alkyl heterocycle comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, R 8 Contains unsubstituted or via one or more R 16 Replaced 3-6-membered heterocycles. In some embodiments, the heterocycle contains one or more R... 16 Substituents. In some embodiments, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3.

[0561] In some implementations, -OR 8 Selected from:

[0562]

[0563] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, -OR 8 Selected from:

[0564]

[0565] In some implementations, -OR 8 Selected from:

[0566]

[0567] In some implementations, -OR 8 Selected from:

[0568]

[0569] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein R a Or R c C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, -OR 8 Selected from:

[0570]

[0571]

[0572] In some implementations, -OR 8 Selected from:

[0573]

[0574] In some implementations, -OR 8 Selected from:

[0575]

[0576]

[0577] In some implementations, -OR 8 Selected from:

[0578]

[0579] In some implementation schemes, R 6 Selected from:

[0580]

[0581] In some implementation schemes, R 6 Selected from:

[0582]

[0583] In some implementation schemes, R 6 yes:

[0584]

[0585] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0586] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0587] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0588] In some implementations, (i) ring A is unsubstituted or via one or more R... 11 Substituted piperazines or diazacycloheptanes. In some embodiments, (ii)R 7 It is a halogen. In some implementations, (iii)R 4 It is H. In some implementations, ring A is selected from:

[0589]

[0590] Each R g Independently selected from H and C 1-6 Alkyl and R h Selected from H, C 1-6Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, at least one R g It is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some implementations, ring A is selected from:

[0591]

[0592] In some implementation schemes, R 8 It is an alkyl heterocyclic ring. In some embodiments, -OR 8 Selected from:

[0593]

[0594] In some implementations, -OR 8 Selected from:

[0595]

[0596]

[0597] In some implementation schemes, R 7 It is F. In some implementations, R 5 Selected from halogens, -CN, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the carbon rings or C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 6 yes:

[0598]

[0599] In some implementations, (i)R 8 (ii) is an alkyl heterocycle; and (ii) ring A is unsubstituted or via one or more R 11 Substituted piperazine. In some embodiments, (i)R 8 (ii) is an alkyl heterocycle; and (ii) ring A is unsubstituted or via one or more R 11 Substituted diazacycloheptanes. In some embodiments, (i)R 8 (ii) is an alkyl heterocyclic ring; and (ii) ring A is an unsubstituted piperazine or diazacycloheptane.

[0600] In some implementations, (i) ring A is unsubstituted or via one or more R... 11 Replacement of the bridge heterocyclic system. In some implementations, (ii)R 7 It is a halogen. In some implementations, (iii)R4 It is H. In some implementations, ring A is selected from:

[0601]

[0602] Among them (a)R g1 and R g3 Or (b)R g2 and R g3 They connect together to form a second ring containing 4-6 members, and R that is not part of the second ring... g1 R g2 R g3 and R g4 Either of them is independently selected from H and C. 1-6 Alkyl; and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, R g1 R g2 R g3 and R g4 At least one of them is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some implementations, ring A is selected from:

[0603]

[0604] Where R g2 and R g4 They connect together to form a second ring containing 4-6 members; R g1 R g3 and R g5 Independently selected from H and C 1-6 Alkyl; and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2. In some embodiments, R g1 R g3 and R g5 At least one of them is C 1-6 Alkyl groups, such as C1 alkyl groups. In some embodiments, R h It is H. In some implementations, R h It is -C(O)NH2. In some embodiments, ring A is selected from:

[0605]

[0606] In some implementation schemes, R 8It is an alkyl heterocyclic ring. In some embodiments, -OR 8 Selected from:

[0607]

[0608] In some implementations, -OR 8 Selected from:

[0609]

[0610]

[0611] In some implementation schemes, R 7 It is F. In some implementations, R 5 Selected from halogens, -CN, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the carbon rings or C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 6 yes:

[0612]

[0613] In some implementations, (i)R 8 (ii) is an alkyl heterocycle; (ii) ring A is unsubstituted or via one or more R 11 Replacement bridge heterocyclic system; (iii) R 7 It is a halogen; and (iv)R 4 It is H.

[0614] In another aspect, this disclosure provides compounds according to formula IC:

[0615]

[0616] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 2 R 3 R 4 R 5 R 6 and R 7 As defined above for Formula I and described individually and in combination in the categories and subcategories herein. In some embodiments, this disclosure provides compounds of Formula I or salts thereof (e.g., pharmaceutically acceptable salts).

[0617] In some embodiments, this disclosure provides compounds of formula IC, wherein:

[0618] R 2 Selected from H and C 1-6 alkyl;

[0619] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0620] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[0621] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0622] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0623] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0624] R 7 Selected from halogens, -OR 12 -CN and H;

[0625] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0626] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0627] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0628] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0629] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0630] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0631] Each R15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0632] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0633] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0634] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0635] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0636] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0637] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0638] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2 It is a 3-6 membered carbon ring. In some implementations, R 2 It is cyclopropyl.

[0639] In some implementation schemes, R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic carbon ring. In some implementations, R 3 It is a monocyclic carbon ring. In some implementations, R 3 It is via-N(R)19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a carbon ring substituted with -NH2.

[0640] In some implementation schemes, R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic heterocyclic ring. In some implementations, R 3 It is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2.

[0641] In some implementation schemes, R 3 Selected from:

[0642]

[0643] None of them have been replaced or subjected to one or more R 10 replace.

[0644] In some implementation schemes, R 3 Selected from:

[0645]

[0646] None of them have been replaced or subjected to one or more R 10 replace.

[0647] In some implementation schemes, R 3 Selected from:

[0648]

[0649] None of them have been replaced or subjected to one or more R 10 replace.

[0650] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R)17 )2, where each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 alkyl.

[0651] In some implementation schemes, R 3 Selected from:

[0652]

[0653] In some implementation schemes, R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a heterocyclic component. In some embodiments, the amino moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amino moiety is a primary amine (e.g., -NH2). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0654] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 It is via-N(R) 17 )2 replaced by C 1-6 Alkyl, wherein each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 Alkyl group. In some embodiments, R 3 Selected from:

[0655]

[0656] In some implementation schemes, R 2 Or R 3 Including amino moiety (e.g., -NRR').

[0657] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced monocyclic heterocycles. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced polycyclic heterocyclic rings. In some implementations, R 2 and R 3Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-10 membered heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-6 membered heterocycles. In some implementations, R 2 and R 3 Together with the atoms it is attached to, it forms a structure comprising at least one nitrogen atom. In some embodiments, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0658]

[0659] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0660]

[0661] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0662]

[0663] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0664]

[0665] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0666]

[0667] In some implementation schemes, R 2 and R 3Together with the atoms to which it is attached, it forms a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 Together with the atoms to which they are attached, they form a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0668] In some implementation schemes, R 6 Selected from:

[0669]

[0670] In some implementation schemes, R 6 Selected from:

[0671]

[0672] In some implementation schemes, R 6 yes:

[0673]

[0674] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0675] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0676] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4R 5 and R 7 Each is selected from Cl and F.

[0677] In another aspect, this disclosure provides compounds according to formula ID or ID':

[0678]

[0679] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 2 R 3 R 4 R 5 and R 7 As defined above for Equation I and described individually and in combination in the categories and subclasses of this paper; R 23 Selected from -N(R) 12 )2 and C 1-6 Alkyl-N(R) 12 )2; and R 24 R 25 and R 26 Independently selected from H, halogen, -OR 12 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 11 Alternatives. In some embodiments, this disclosure provides a compound of formula ID or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, this disclosure provides a compound of formula ID' or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0680] In some embodiments, this disclosure provides compounds of formula ID or ID', wherein:

[0681] R 1 Selected from -OR 8 A 4-6 membered heterocycle comprising a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms 16 replace;

[0682] R 2 Selected from H and C 1-6 alkyl;

[0683] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0684] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[0685] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0686] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0687] R 7 Selected from halogens, -OR 12 -CN and H;

[0688] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[0689] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0690] Each R 10 Independently selected from -N(R) 19 )2、-C(O)R 19 -C(O)N(R) 19 )2、-C(O)(C 1-6 Alkyl)N(R 19 )2、-(C1-6 alkyl)C(O)N(R 19 )2、-C(NR 19 )NR 19 CN and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0691] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0692] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0693] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0694] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0695] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0696] Each R 17Selected independently from C 1-6 Alkyl and H;

[0697] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0698] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0699] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0700] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0701] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H;

[0702] R 23 Selected from -N(R) 12 )2 and C 1-6 Alkyl-N(R) 12 )2; and

[0703] R 24 R 25 and R 26 Independently selected from H, halogen, -OR 12 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 11 replace.

[0704] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2 It is a 3-6 membered carbon ring. In some implementations, R 2 It is cyclopropyl.

[0705] In some implementation schemes, R 3It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic carbon ring. In some implementations, R 3 It is a monocyclic carbon ring. In some implementations, R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a carbon ring substituted with -NH2.

[0706] In some implementation schemes, R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic heterocyclic ring. In some implementations, R 3 It is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2.

[0707] In some implementation schemes, R 3 Selected from:

[0708]

[0709] None of them have been replaced or subjected to one or more R 10 replace.

[0710] In some implementation schemes, R 3 Selected from:

[0711]

[0712] None of them have been replaced or subjected to one or more R 10 replace.

[0713] In some implementation schemes, R 3 Selected from:

[0714]

[0715] None of them have been replaced or subjected to one or more R 10 replace.

[0716] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R) 17 )2, where each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 alkyl.

[0717] In some implementation schemes, R 3 Selected from:

[0718]

[0719] In some implementation schemes, R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a heterocyclic component. In some embodiments, the amino moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amino moiety is a primary amine (e.g., -NH2). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0720] In some implementation schemes, R 3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 It is via-N(R) 17 )2 replaced by C 1-6 Alkyl, wherein each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 Alkyl group. In some embodiments, R 3 Selected from:

[0721]

[0722] In some implementation schemes, R 2 Or R 3 Including amino moiety (e.g., -NRR').

[0723] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced monocyclic heterocycles. In some implementations, R 2and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced polycyclic heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-10 membered heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-6 membered heterocycles. In some implementations, R 2 and R 3 Together with the atoms it is attached to, it forms a structure comprising at least one nitrogen atom. In some embodiments, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0724]

[0725] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0726]

[0727] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0728]

[0729] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0730]

[0731] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0732]

[0733]

[0734] In some implementation schemes, R 2 and R 3 Together with the atoms to which it is attached, it forms a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 Together with the atoms to which they are attached, they form a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0735] In some implementation schemes, R 1 It is H.

[0736] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 8 It is a heterocyclic ring. In some implementations, R 8 It is an alkyl heterocycle. In some embodiments, the heterocycle or alkyl heterocycle comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, R 8 Contains unsubstituted or via one or more R 16 Replaced 3-6-membered heterocycles. In some embodiments, the heterocycle contains one or more R... 16 Substituents. In some embodiments, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3.

[0737] In some implementation schemes, R 1 Selected from:

[0738]

[0739] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 1 Selected from:

[0740]

[0741] In some implementation schemes, R 1 Selected from:

[0742]

[0743] In some implementation schemes, R 1 Selected from:

[0744]

[0745] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein R a Or R c C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0746]

[0747] In some implementation schemes, R 1 Selected from:

[0748]

[0749] In some implementation schemes, R 1 Selected from:

[0750]

[0751]

[0752] In some implementation schemes, R 1 Selected from:

[0753]

[0754] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some implementations, R 1 Selected from:

[0755]

[0756] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is halogen.

[0757] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0758] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0759] In some implementation schemes, R23 It is -N(R) 12 )2. In some implementation schemes, R 23 It is -NH2.

[0760] In some implementation schemes, R 24 It is a halogen. In some implementations, R 24 It is Cl or F. In some implementations, R 24 It is F. In some implementations, R 24 It is H.

[0761] In some implementation schemes, R 25 and R 26 It is H. In some implementations, R 25 It is H. In some implementations, R 26 It is H.

[0762] In one aspect, this disclosure provides a compound represented by the formula IE:

[0763]

[0764] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 2 R 3 R 4 R 5 R 6 and R 7 As defined above for Equation I and described individually and in combination in the categories and subclasses herein; and R a and R b Independently selected from halogens, -OR 12 C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some embodiments, this disclosure provides a compound of formula IE or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0765] In some embodiments, this disclosure provides compounds of formula IE, wherein:

[0766] R 2 Selected from H, 3-6 membered carbon rings and C 1-6 Alkyl group, wherein the 3-6 membered carbon ring or the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0767] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0768] or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[0769] R 4 It is H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0770] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[0771] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0772] R 7 Selected from halogens, -OR 12 -CN and H;

[0773] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0774] Each R 10 Independently selected from -N(R) 19 )2、-C(O)R19 -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0775] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0776] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0777] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0778] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0779] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0780] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0781] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0782] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0783] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0784] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0785] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H; and

[0786] R a and R b Independently selected from halogens, -OR 12 C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace.

[0787] In some implementation schemes, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, Rb It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a and R b They are all halogens. In some implementation schemes, R a and R b Both are F. In some implementations, R a and R b All are unreplaced or processed by one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a and R b Both are methyl groups. In some implementations, R a and R b Both are H. In some implementations, R a Yes - OC 1-6 Alkyl and R b It's H.

[0788] In some implementation schemes, R 2 It is H. In some implementations, R 2 It is C 1-6 Alkyl group. In some embodiments, R 2 It is a 3-6 membered carbon ring. In some implementations, R 2 It is cyclopropyl.

[0789] In some implementation schemes, R 3 It is C 1-6 Alkyl, the C 1-6 Alkyl groups via one or more R 9 Replacement. In some implementations, R 3 It is via-N(R) 17 )2 replaced by C 1-6 Alkyl, wherein each R 17 Selected independently from C 1-6 Alkyl and H. In some embodiments, R 3 It is C substituted with -NH2 1-6 alkyl.

[0790] In some implementation schemes, R 3 Selected from:

[0791]

[0792] In some implementation schemes, R 3Includes an amino moiety (e.g., -NRR'). In some embodiments, the amino moiety is a heterocyclic component. In some embodiments, the amino moiety is attached to a carbocyclic or heterocyclic ring. In some embodiments, the amino moiety is a primary amine (e.g., -NH2). In some embodiments, the amino moiety is a secondary amine (e.g., -NHR).

[0793] In some implementation schemes, R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic carbon ring. In some implementations, R 3 It is a monocyclic carbon ring. In some implementations, R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a carbon ring substituted with -NH2.

[0794] In some implementation schemes, R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is a polycyclic heterocyclic ring. In some implementations, R 3 It is a monocyclic heterocycle. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2. In some embodiments, R 3 It is a bridged heterocyclic system. In some implementations, R 3 It is a single ring. In some implementations, R 3 It is unreplaced or through one or more R 10 Substituted nitrogen-containing heterocyclic butanes or pyrrolidines.

[0795] In some implementation schemes, R 3 Selected from:

[0796]

[0797] None of them have been replaced or subjected to one or more R 10 replace.

[0798] In some implementation schemes, R3 Selected from:

[0799]

[0800] None of them have been replaced or subjected to one or more R 10 replace.

[0801] In some implementation schemes, R 3 Selected from:

[0802]

[0803] None of them have been replaced or subjected to one or more R 10 replace.

[0804] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced monocyclic heterocycles. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced polycyclic heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-10 membered heterocyclic rings. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-6 membered heterocycles. In some implementations, R 2 and R 3 Together with the atoms it is attached to, it forms a structure comprising at least one nitrogen atom. In some embodiments, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0805]

[0806] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0807]

[0808] The ring was not replaced or passed through one or more R... 11Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0809]

[0810] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form a ring with the following structure:

[0811]

[0812] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0813]

[0814] In some implementation schemes, R 2 and R 3 Together with the atoms to which it is attached, it forms a 4-10 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR'). In some embodiments, R 2 and R 3 Together with the atoms to which they are attached, they form a 4-6 membered heterocycle comprising at least two nitrogen atoms (e.g., including an amino moiety (e.g., -NR-)) and / or substituted with a group including an amino moiety (e.g., -NRR').

[0815] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is a halogen. In some implementations, R 4 Yes - OR 12 In some implementations, R 4 It is -OCH3.

[0816] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0817] In some implementation schemes, R 5 Selected from unsubstituted or via one or more R13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 Selected from unreplaced C 1-6 Alkyl groups, such as methyl or ethyl. In some embodiments, R 5 Selected from C substituted with one or more halogens or -CN 1-6 Alkyl group. In some embodiments, R 5 Selected from -CF3, -CF2H, and -CH2CN. In some implementations, R 5 Selected from -OR 12 , where R 12 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 It is -OCH3, -OCF3, or -OCF2H.

[0818] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7 Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0819] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic aryl group. In some embodiments, R 6 Selected from:

[0820]

[0821] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups. In some embodiments, R 6 Selected from:

[0822]

[0823]

[0824] In some implementation schemes, R 6 Selected from:

[0825]

[0826] In some implementation schemes, R 6 Selected from:

[0827]

[0828] In some implementations, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups, and (ii)R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms an unsubstituted or R-type atom. 11 Substituted heterocyclic rings. In some implementations, R 6 Selected from:

[0829]

[0830] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0831]

[0832] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0833]

[0834]

[0835] None of them have been replaced or subjected to one or more R 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0836]

[0837] In some implementation schemes, R 4 It is H. In some implementations, R 7It is a halogen (e.g., F). In some embodiments, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups, and (ii)R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms an unsubstituted or R-type atom. 11 Replacement of the bridge heterocyclic system. In some implementations, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups, and (ii)R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms a bridged heterocyclic system comprising a piperazine ring, the bridged heterocyclic system being unsubstituted or derived from one or more R atoms. 11 Replacement. In some implementations, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups, and (ii)R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms an unsubstituted or R-type atom. 11 Substituted piperazine ring.

[0838] In some implementations, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl; (ii)R 2 Selected from H, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the C 1-6 Alkyl or 3-6 membered carbon rings that are unsubstituted or via one or more R 13 Replacement; and (iii)R 3 It is C 1-6 Alkyl, the C 1-6 Alkyl groups via one or more R 9 Replacement. In some implementations, R 3 It is C substituted with -NH2 1-6 Alkyl group. In some embodiments, R 2 It is H. In some implementations, R 2 It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 2 It is unreplaced or through one or more R 13 Replaced 3-6 membered carbon rings.

[0839] In some implementations, (i)R 6 It is through one or more R 15Substituted bicyclic heteroaryl; (ii)R 2 Selected from H, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the C 1-6 Alkyl or 3-6 membered carbon rings that are unsubstituted or via one or more R 13 Replacement; and (iii)R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Substituted cyclobutyl. In some embodiments, R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a carbon ring substituted with -NH2. In some embodiments, R 2 It is H. In some implementations, R 2 It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 2 It is unreplaced or through one or more R 13 Replaced 3-6 membered carbon rings.

[0840] In some implementations, (i)R 6 It is through one or more R 15 Substituted bicyclic heteroaryl; (ii)R 2 Selected from H, C 1-6 Alkyl groups and 3-6 membered carbon rings, wherein the C 1-6 Alkyl or 3-6 membered carbon rings that are unsubstituted or via one or more R 13 Replacement; and (iii)R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 Substitution. In some embodiments, the heterocycle includes one or more nitrogen atoms. In some embodiments, R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl and H. In some embodiments, R 3 It is a heterocyclic ring substituted with -NH2. In some embodiments, R 3 It is a bridged heterocyclic system. In some implementations, R 3 It is a single ring. In some implementations, R 3It is unreplaced or through one or more R 10 Substituted nitrogen-containing heterocyclic butanes or pyrrolidines. In some embodiments, R 3 Selected from:

[0841]

[0842] None of them have been replaced or subjected to one or more R 10 Replacement. In some implementations, R 2 It is H. In some implementations, R 2 It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 2 It is unreplaced or through one or more R 13 Replaced 3-6 membered carbon rings.

[0843] In one aspect, this disclosure provides a compound represented by the formula IF:

[0844]

[0845] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein R 1 R 4 R 5 R 6 and R 7 As defined above for Equation I and described individually and in combination in the categories and subclasses of this paper; R g1 R g2 R g3 and R g4 Each is independently selected from H and C. 1-6 Alkyl; or (a)R g1 and R g3 Or (b)R g2 and R g3 Connected together, they form a second ring containing 4-6 members, and R is not part of the second ring. g1 R g2 R g3 and R g4 Either of them is independently selected from H and C. 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replace; and R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6Alkyl NH2. In some embodiments, this disclosure provides compounds of formula IF or salts thereof (e.g., pharmaceutically acceptable salts).

[0846] In some embodiments, this disclosure provides compounds of formula IF, wherein:

[0847] R 1 Selected from -OR 8 , comprising a 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R 16 replace;

[0848] R g1 R g2 R g3 and R g4 Each is independently selected from H and C. 1-6 Alkyl; or (a)R g1 and R g3 Or (b)R g2 and R g3 Connected together, they form a second ring containing 4-6 members, and R is not part of the second ring. g1 R g2 R g3 and R g4 Either of them is independently selected from H and C. 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0849] R h Selected from H, C 1-6 Alkyl groups, -C(O)NH2 and -C(O)C 1-6 Alkyl NH2;

[0850] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14 replace;

[0851] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14 replace;

[0852] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0853] R 7 Selected from halogens, -OR 12 -CN and H;

[0854] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0855] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0856] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0857] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replace; and

[0858] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0859] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 8 It is a heterocyclic ring. In some implementations, R... 8It is an alkyl heterocycle. In some embodiments, the heterocycle or alkyl heterocycle comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, the heterocycle comprises one or more R atoms. 16 Substituents. In some embodiments, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3.

[0860] In some implementation schemes, R 1 Selected from:

[0861]

[0862] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 And H. In some implementations, R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R a It is a halogen. In some implementations, R a It is F. In some implementations, R a It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R a Yes - OC 1-6 Alkyl group. In some embodiments, R a It is H. In some implementations, R b It is H. In some implementations, R b It is a halogen. In some implementations, R b It is F. In some implementations, R b It is unreplaced or through one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 1 Selected from:

[0863]

[0864] In some implementation schemes, R 1 Selected from:

[0865]

[0866]

[0867] In some implementation schemes, R 1 Selected from:

[0868]

[0869] Each R a Independently selected from halogens, C 1-6 Alkyl, -OR 12 and H; and where R c Selected from C 1-6 Alkyl, wherein R a Or R c C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Replacement. In some implementations, R 1 Selected from:

[0870]

[0871] In some implementation schemes, R 1 Selected from:

[0872]

[0873] In some implementation schemes, R 1 Selected from:

[0874]

[0875] In some implementation schemes, R 1 Selected from:

[0876]

[0877] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some implementations, R 1 Selected from:

[0878]

[0879] In some implementation schemes, R1 It's H.

[0880] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is a halogen. In some implementations, R 4 Yes - OR 12 In some implementations, R 4 It is -OCH3.

[0881] In some implementation schemes, R 5 It is a 3-6 membered carbon ring. In some implementations, R 5 It is a 3-6 membered heterocyclic ring. In some implementations, R 5 It is a 5- or 6-membered aryl or heteroaryl moiety. In some embodiments, R 5 It's furan.

[0882] In some implementation schemes, R 5 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 Selected from unreplaced C 1-6 Alkyl groups, such as methyl or ethyl. In some embodiments, R 5 Selected from C substituted with one or more halogens or -CN 1-6 Alkyl group. In some embodiments, R 5 Selected from -CF3, -CF2H, and -CH2CN. In some implementations, R 5 Selected from -OR 12 , where R 12 Selected from unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 5 It is -OCH3, -OCF3, or -OCF2H.

[0883] In some implementation schemes, R 5 It is a halogen. In some implementations, R 5 It is Cl or F. In some implementations, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 5 and R 7 They are all halogens. In some implementation schemes, R 5 and R 7 Both are selected from Cl and F. In some implementations, R 4 R 5 and R 7Each is an independent halogen. In some implementations, R 4 R 5 and R 7 Each is selected from Cl and F.

[0884] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic aryl group. In some embodiments, R 6 Selected from:

[0885]

[0886] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups. In some embodiments, R 6 Selected from:

[0887]

[0888] In some implementation schemes, R 6 Selected from:

[0889]

[0890] In some implementation schemes, R 6 Selected from:

[0891]

[0892] In some implementation schemes, R g1 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g2 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g3 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g4 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g1 and R g2 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g1 and R g2 Both are methyl groups. In some implementations, R g1 and R g3 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g1 and R g3 Both are methyl groups. In some implementations, R g1 and Rg4 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g1 and R g4 Both are methyl groups. In some implementations, R g2 and R g3 Selected from C 1-6 Alkyl (e.g., methyl). In some embodiments, R g2 and R g3 They are all methyl groups.

[0893] In some implementation schemes, R g1 and R g3 They connect together to form a second ring containing 4-6 members. In some implementations, R g2 and R g3 They connect together to form a second ring containing 4-6 members. In some implementations, R h It's H.

[0894] In some embodiments, the compound has the following structure:

[0895]

[0896] In some embodiments of the compound according to formula (IF1) or (IF2), R g1 and R g4 Each is H. In some embodiments of the compounds according to formula (IF3) or (IF4), R g2 and R g4 Each is H. In some embodiments of the compounds according to formula (IF1), (IF2), (IF3), or (IF4), R h It is H. In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R 1 Selected from:

[0897]

[0898] Where R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution. In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R 6 Selected from:

[0899]

[0900] In some embodiments of compounds according to formulas (IF1), (IF2), (IF3), or (IF4), R 4 It is H. In some embodiments of compounds according to formula (IF1), (IF2), (IF3) or (IF4), R 7 It is a halogen (e.g., F). In some embodiments of compounds according to formula (IF1), (IF2), (IF3), or (IF4), R 5 It is a halogen, -CN, 3-6 membered carbon ring, 3-6 membered heterocycle, or unsubstituted or via one or more R... 13 Replacement C 1-6 alkyl.

[0901] In another aspect, this disclosure provides compounds according to formula II:

[0902]

[0903] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[0904] R 1 Selected from -OR 8 , comprising a 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R 16 replace;

[0905] R 2 Selected from H, 3-6 membered carbon rings and C 1-6 Alkyl group, wherein the 3-6 membered carbon ring or the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0906] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0907] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[0908] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14 replace;

[0909] R 6 It is a phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl group, wherein any phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl group is unsubstituted or has been modified by one or more R groups. 15 replace;

[0910] R 7 Selected from halogens, -OR 12 -CN and H;

[0911] R 8 Selected from H, heterocycles, and alkyl heterocycles, wherein the heterocycle or alkyl heterocycle is unsubstituted or has undergone one or more R... 16 Substitution, wherein the alkyl moiety of any alkyl heterocycle is selected from C 1-6 alkyl;

[0912] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0913] Each R 10 Independently selected from halogens, -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0914] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0915] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0916] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0917] Each R 14 Independently selected from halogens, -OR 12 -CN, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0918] Each R 15 Independently selected from halogens, -OR 12 -CN, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0919] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl, -OR 12 and 3-6 membered heterocycles, where any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0920] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0921] Each R18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0922] Each R 19 Selected independently from C 1-6 Alkyl, 3-6 membered heterocycles and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0923] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl groups, halogens, and 3-6 membered carbon rings;

[0924] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0925] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0926] In some embodiments, this disclosure provides a compound of formula II or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0927] In some embodiments, this disclosure provides compounds of formula II, wherein:

[0928] R 1 Selected from -OR 8 , including a 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R 16 replace;

[0929] R 2 Selected from H and C 1-6 alkyl;

[0930] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[0931] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms.11 Substituted heterocycles;

[0932] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14 replace;

[0933] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[0934] R 7 Selected from halogens, -OR 12 -CN and H;

[0935] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[0936] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[0937] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0938] Each R 11 Independently selected from -N(R) 19 )2、-C(O)R19 -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[0939] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[0940] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[0941] Each R 14 Independently selected from halogens, -OR 12 -CN, -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0942] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0943] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[0944] Each R 17 Selected independently from C 1-6 Alkyl and H;

[0945] Each R18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0946] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[0947] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[0948] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[0949] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[0950] In some implementation schemes, R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Replaced 3-6 membered carbon rings or heterocycles. In some embodiments, R 3 It is a 4-6 membered carbon ring, wherein the carbon ring is unsubstituted or modified by one or more R... 10 Replacement. In some implementations, R 3 It is a 4-8 membered heterocycle having 1-2 independent heteroatoms selected from nitrogen, oxygen, and sulfur, said heterocycle being unsubstituted or via one or more R atoms. 10 Replacement. In some implementations, R 3 It is unreplaced or through one or more R 10 Substituted nitrogen-containing heterocyclic butanes. In some embodiments, R 3 Selected from:

[0951]

[0952] None of them have been replaced or subjected to one or more R 10 replace.

[0953] In some implementation schemes, R3 Selected from one or more R 9 Replacement C 1-6 Alkyl group. In some embodiments, R 3 Selected from C 1-6 Alkyl-N(R) 17 2. In some implementation schemes, R 3 It is -CH2CH2NH2. In some implementations, R 3 Selected from:

[0954]

[0955] In some implementation schemes, R 2 Or R 3 Includes an amino moiety (e.g., -NRR'). In some embodiments, R 2 Or R 3 via the amino moiety (i.e., -N(R)) 17 )2 or -N(R 19 )2) Replace.

[0956] In some implementation schemes, R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Replaced 4-6 membered heterocycles. In some implementations, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 4-9 membered heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 4-7 membered monocyclic heterocycle having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms a piperazine. In some embodiments, R 2 and R 3 Together with the atoms to which it is attached (e.g., nitrogen atoms), it forms a 7-9 membered bicyclic heterocycle having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heterocycle is unsubstituted or via one or more R atoms. 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0957]

[0958] The ring was not replaced or passed through one or more R... 11 Replacement. In some implementations, R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[0959]

[0960] In some implementation schemes, R 2 and R 3 Together with the nitrogen atom it is attached to, it forms an unsubstituted or R-atom with one or more R atoms. 11 Substituted heterocycles, said heterocycles comprising an additional nitrogen atom (e.g., an amino moiety (e.g., -NR-)) and / or via a process including an amino moiety (e.g., -N(R)). 19 )2) group substitution.

[0961] In some implementation schemes, R 1 It's H.

[0962] In some implementation schemes, R 1 Yes - OR 8 In some implementations, R 1 Yes - OR 8 , where R 8 It is a heterocyclic or alkyl heterocyclic ring. In some embodiments, R 8 Contains unsubstituted or via one or more R 14 Replaced 3-6 membered heterocyclic rings. In some implementations, R 8 It is a heterocyclic ring. In some implementations, R... 8 It is an alkyl heterocyclic ring. In some embodiments, R 8 It is an alkyl heterocycle, wherein the alkyl portion of the alkyl heterocycle is selected from C10. 1-6 Alkyl group. In some embodiments, R 8 It is -CH2 (heterocyclic). In some embodiments, the heterocyclic or alkyl heterocyclic ring comprises 4-8 members, said members including at least one heteroatom selected from N, O, and S. In some embodiments, R 8 It comprises a heterocycle including at least one nitrogen atom. In some embodiments, R 8 It comprises a 4-8 membered heterocycle including at least one nitrogen atom. In some embodiments, the heterocycle or alkyl heterocycle is a 4-6 monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle or alkyl heterocycle is an 8-membered bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle is via one or more R...16 Replacement. In some implementations, at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H. In some embodiments, at least one R 16 It is -OCH3. In some implementations, at least one R 16 It is a halogen (e.g., F). In some embodiments, at least one R 16 It is unreplaced or through one or more R 13 Replacement C 1-6 alkyl.

[0963] In some implementation schemes, R 1 Selected from:

[0964]

[0965]

[0966] In some implementation schemes, R 1 Selected from:

[0967]

[0968] In some implementation schemes, R 1 It is a 4-6 membered heterocycle including a nitrogen atom, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 Replacement. In some such implementations, R 16 Selected from -N(R) 12 2. C 1-6 Alkyl groups and 3-6 membered heterocycles. In some embodiments, R 16 It is -N(C 1-6 Alkyl group 2, for example -N(CH3)2. In some embodiments, R 16 It is C 1-6 Alkyl (e.g., methyl). In some embodiments, R 16 It is a bicyclic six-membered heterocycle with one nitrogen atom. In some embodiments, R 1 Selected from:

[0969]

[0970] In some implementation schemes, R 6 It is through one or more R 15 Substituted bicyclic aryl group. In some embodiments, R 6 It is through one or more R 15 Substituted naphthyl group.

[0971] In some implementation schemes, R 6 It is a 9-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroaryl group is unsubstituted or via one or more R atoms. 15 Replacement. In some implementations, R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups. In some embodiments, R 6 It has 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is derived from one or more R atoms. 15 The substituted 9-membered heteroaryl group. In some such embodiments, at least one R 15 It is -N(R) 12 )2 (e.g., -NH2). In some embodiments, at least one R 15 It is a halogen (e.g., F). In some implementations, each R 15 Independently selected from halogens, -CN and -N(R) 12 2. In some implementation schemes, R 6 Through at least two R 15 (For example, at least one halogen and -NH2) substitution.

[0972] In some implementation schemes, R 6 Selected from:

[0973]

[0974] None of them have been replaced or subjected to one or more R 15 replace.

[0975] In some implementation schemes, R 6 Selected from:

[0976]

[0977]

[0978] In some implementation schemes, R 6 Selected from:

[0979]

[0980] In some implementation schemes, R 6 yes:

[0981]

[0982] In some implementation schemes, R 6 It is unreplaced or through one or more R 15 Substituted phenyl groups. In some such embodiments, each R15 Independently selected from halogens, -OR 12 -CN and -N(R) 12 )2.

[0983] In some implementation schemes, R 6 It is unreplaced or through one or more R 15 Substituted monocyclic 5-6 membered heteroaryl groups. In some embodiments, R 6 It is unreplaced or through one or more R 15 Substituted pyridinyl group. In some such embodiments, each R 15 Independently selected from -N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace.

[0984] In some implementation schemes, R 4 It is H. In some implementations, R 4 It is a halogen. In some implementations, R 4 Yes - OR 12 In some implementations, R 4 It is -OCH3.

[0985] In some implementation schemes, R 7 It is a halogen. In some implementations, R 7 It is Cl or F. In some implementations, R 7 Yes - OR 12 , where R 12 Selected from H and unsubstituted or via one or more R 13 Replacement C 1-6 Alkyl group. In some embodiments, R 7 It is -OH, -OCH3, or -OCH2CF3. In some embodiments, R 7 Yes -CN. In some implementations, R 7 It is hydrogen.

[0986] In some implementation schemes, R 4 and R 7 They are all halogens. In some implementation schemes, R 4 and R 7 Both are selected from Cl and F.

[0987] In some embodiments, the compound is represented by a formula included in any of Tables 2-9. In some embodiments, this disclosure provides compounds selected from any of Tables 2, 3, 4, 5, 7, 8, and 9, or salts thereof (e.g., pharmaceutically acceptable salts thereof). In some embodiments, this disclosure provides compounds selected from any of Tables 2, 3, 4, 7, 8, and 9, or salts thereof (e.g., pharmaceutically acceptable salts thereof).

[0988] This document also provides compounds selected from any of Tables 2 through 9 or any of the examples provided herein, or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers. It should be understood 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 in this disclosure. This disclosure also contemplates the forms of the compounds provided herein, such as esters, tautomers, prodrugs, zwitterionic forms, and stereoisomers.

[0989] In some embodiments, the provided compounds are provided and / or utilized in salt form (e.g., pharmaceutically acceptable salt form). Unless otherwise indicated, references to compounds provided herein should be understood to include references to their salts.

[0990] This document also provides embodiments in which any of the embodiments described herein can be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive. As used herein, two embodiments are “mutually exclusive” when one embodiment is defined differently from another. For example, an embodiment in which two groups combine 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.

[0991] Composition

[0992] This disclosure also provides a composition (e.g., a pharmaceutical composition) comprising a compound provided herein (e.g., a compound of any one of 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, the provided composition comprises a compound provided herein or a pharmaceutically acceptable salt thereof. For example, this disclosure provides a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of 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, and a pharmaceutically acceptable carrier. In some embodiments, the provided pharmaceutical composition comprises a compound provided herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0993] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the oral pharmaceutical formulation is selected from tablets and capsules.

[0994] 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.

[0995] While certain compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers may be administered as original chemicals, these compounds may be provided, alternatively or in the form of pharmaceutical formulations. Therefore, pharmaceutical formulations are provided herein comprising one or more of the compounds disclosed herein (e.g., compounds of any of Formula 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, along with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier must be “acceptable” in the sense of compatibility with the other components of the formulation and harmlessness to the recipient. Appropriate formulation depends on the chosen route of administration. Well-known techniques, carriers, and excipients may be used where appropriate and as understood in the art. The pharmaceutical compositions disclosed herein can be manufactured in any known suitable manner, for example by means of conventional mixing, dissolving, granulation, pill making, grinding, emulsification, encapsulation, embedding or compression processes.

[0996] The pharmaceutical formulations provided herein are suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including transdermal, buccal, sublingual, and intraocular) administration. The most suitable route may depend, for example, on the disease and condition of the subject to whom the pharmaceutical formulation will be administered. The pharmaceutical formulation may be provided in unit dosage form. The pharmaceutical formulation may be prepared by any suitable method. Methods for preparing a pharmaceutical formulation may include contacting the compounds provided herein (e.g., formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their pharmaceutically acceptable salts, esters, amides, prodrugs, or solvates (“active ingredient”) with one or more pharmaceutically acceptable carriers (e.g., excipients). Generally, formulations are prepared by homogenizing and tightly associating the active ingredient with a liquid carrier or a finely fragmented solid carrier, or both, and then shaping the product into the desired formulation if necessary.

[0997] Pharmaceutical formulations of the compounds provided herein (e.g., compounds of any of the following 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.)) may be provided as discrete units. For example, formulations suitable for oral administration may be provided as capsules, tablets, and / or tablets containing a predetermined amount of any suitable form of the compound (e.g., the active ingredient); as a solution or suspension in a solvent (e.g., an aqueous or non-aqueous solvent); as an emulsion (e.g., an oil-in-water liquid emulsion or a water-in-oil liquid emulsion); or as a powder or granules. The active ingredient may additionally or alternatively be provided as a pellet, granule, or paste.

[0998] Pharmaceutical formulations suitable for oral administration include tablets, push-in capsules made of gelatin, and soft-seal capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Tablets can be prepared, for example, by compression or molding, optionally with one or more excipients, such as one or more pharmaceutically acceptable excipients. Compressed tablets can be prepared, for example, by compression of the active ingredient (such as powder or granules) in a suitable machine, optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant. Molded tablets can be prepared, for example, by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. All formulations for oral administration should be in the dosage suitable for such administration. Push-in capsules may contain the active ingredient mixed with, for example, one or more fillers, such as lactose; one or more binders, such as one or more 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 can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Stabilizers and other elements may also be added. The core of the sugar-coated pill has a suitable coating. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum, gelling agent, polymer, solvent, or a combination thereof. Dyes or pigments may be added to the coating of the tablet or sugar-coated pill for identification or characterization of different combinations of active compound dosages.

[0999] Pharmaceutical compositions comprising 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) or in their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) may be formulated for parenteral administration by injection, such as by rapid bolus or continuous infusion. Injectable formulations may be available in unit dosage forms, such as ampoules, vials, or multi-dose containers, with added preservatives. Compositions may be in the form of suspensions, solutions, or emulsions, such as in oily or aqueous media, and may contain formulations such as suspending agents, stabilizers, and / or dispersants. Formulations may be available in unit or multi-dose containers, such as sealed ampoules and vials, and may be in powder form or stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, just before use (e.g., immediately before use). Temporary injection solutions and suspensions can be prepared from the previously described types of sterile powders, granules, and tablets.

[1000] Pharmaceutical compositions comprising the compounds provided herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or in their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be formulated into solutions for injection. These solutions can be aqueous or non-aqueous (oil-based) sterile solutions and may contain one or more antioxidants, thickeners, suspending agents, buffers, solutes, and / or antibacterial agents. The addition of one or more such additives can promote isotonicity of the formulation with the blood of the intended recipient (e.g., a subject or patient). Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[1001] In addition to the formulations described elsewhere herein, compounds provided herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) in any suitable form (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can also be formulated into reservoir formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, such as slightly soluble salts.

[1002] Pharmaceutical compositions suitable for buccal or sublingual administration containing compounds described herein (e.g., compounds of any one of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or in their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) may be in the form of tablets, lozenges, soft lozenges, or gels. Such compositions may contain a flavoring matrix, such as sucrose and active ingredients in gum arabic or tragacanth. Pharmaceutical compositions suitable for rectal administration containing compounds described herein or in their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) may be formulated as suppositories or retention enemas and may contain a medium, such as cocoa butter, polyethylene glycol, or other glycerides.

[1003] Certain compounds described herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be formulated for non-systemic administration, such as topical administration. This includes external application of the compounds or their forms disclosed herein to the epidermis or buccal cavity, and instillation of such compounds or their forms into the ear, eye, and nose such that the compounds or their forms do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[1004] Formulations suitable for topical application include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for application to the eyes, ears, or nose. The active ingredient for topical application may, for example, comprise 0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, the active ingredient may comprise less than 5% w / w. In some embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, the active ingredient may comprise 0.1% to 1% w / w of the formulation.

[1005] For administration by inhalation, compounds (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) can be conveniently delivered from an inhaler, a pressurized nebulizer pack, or other convenient delivery aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver a measured amount. Alternatively, for administration by inhalation or inhalation, the compounds described herein can be in the form of dry powder compositions, for example, mixtures of the compound with a suitable powder matrix, such as lactose or starch powder. The powder compositions can be present in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or inhaler.

[1006] Preferred unit-dose formulations are those containing an effective dose or appropriate portion of an active ingredient (e.g., a compound provided herein (e.g., a compound of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or its salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer) as described herein.

[1007] It should be understood that, in addition to the ingredients specifically described elsewhere herein, the formulations described herein may include other useful agents relevant to the type of formulation discussed, such as flavoring agents, those suitable for oral administration.

[1008] The compound (e.g., a compound of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or its form (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) may be administered orally or by injection at doses ranging from 0.1 to 500 mg / kg per day. The dosage range for adults is generally 5 mg to 2 g per day. Tablets or other forms provided in discrete units may conveniently contain an amount of one or more compounds that are effective at such doses or as multiple such doses, for example, units containing 5 mg to 500 mg, typically about 10 mg to 200 mg.

[1009] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host being treated and the specific administration method.

[1010] method

[1011] This disclosure also provides a method for modulating KRAS (e.g., KRAS with a G12D mutation), the method comprising contacting KRAS with a compound provided herein (e.g., a compound of any one of 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. For example, this disclosure may provide a method for altering cell phenotype, cell proliferation, KRAS activity, biochemical output from active or inactive KRAS, KRAS expression, and / or binding of KRAS to a natural binding partner. Any such characteristic can be monitored and can be altered after contact of KRAS with a compound provided herein or its form. Methods for modulating KRAS (e.g., KRAS with a G12D mutation) may be modulotherapy for diseases, symptoms, or disorders (e.g., cancer), bioassays, cellular assays, biochemical assays, etc.

[1012] This disclosure also provides methods for treating a disease, condition, or ailment of a subject in need with a compound provided herein (e.g., a compound of any one of 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. For example, this disclosure provides a method comprising providing (e.g., administering) to a subject in need (e.g., a patient) an effective amount of a compound provided herein (e.g., a compound of any one of 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. This disclosure also provides methods for treating a disease, condition, or disorder in a subject in need using a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of 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. For example, this disclosure provides a method comprising providing (e.g., administering) to a subject in need (e.g., a patient) a pharmaceutical composition comprising an effective amount of a compound provided herein (e.g., a compound of any one of 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, the subject is known to have (e.g., has been previously diagnosed with) a disease, condition, or disorder, such as cancer. The disease, condition, or disorder may be a KRAS-mediated disease, such as cancer characterized by a G12D mutation in KRAS. In some implementations, the compound administered to the subject in need according to the methods described herein is the compound or its stereoisomer or pharmaceutically acceptable salt described in the implementations, examples, figures or tables herein.

[1013] This disclosure also provides pharmaceutical compositions comprising compounds as provided herein (e.g., compounds of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for use as pharmaceutical agents, such as agents for treating diseases, conditions, or disorders (e.g., cancer). This disclosure also provides pharmaceutical compositions comprising compounds as provided herein (e.g., compounds of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for use in manufacturing pharmaceutical agents for treating diseases, conditions, or disorders (e.g., cancer) in a subject of need.

[1014] This disclosure also provides for the use of 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) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or pharmaceutical compositions comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for the treatment of a disease, condition, or ailment (e.g., cancer) in a subject of need.

[1015] This disclosure also provides the use of 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) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or pharmaceutical compositions comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for the manufacture of an agent for treating a disease, condition, or ailment (e.g., cancer) in a subject in need.

[1016] This disclosure also provides a method for inhibiting KRAS (e.g., KRAS with a G12D mutation) (e.g., in a subject in need), the method comprising reacting KRAS with a compound as provided herein (e.g., a compound of any one of 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, or a pharmaceutical composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.

[1017] This disclosure also provides pharmaceutical compositions comprising compounds as provided herein (e.g., compounds of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or comprising any one of the foregoing compounds and a pharmaceutically acceptable excipient, for use in inhibiting KRAS (e.g., KRAS with a G12D mutation) (e.g., in subjects in need). This disclosure also provides pharmaceutical compositions comprising compounds as provided herein (e.g., compounds of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or comprising any one of the foregoing compounds and a pharmaceutically acceptable excipient, for use in manufacturing an agent for inhibiting KRAS (e.g., KRAS with a G12D mutation) in subjects in need.

[1018] This disclosure also provides for the use of 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) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or pharmaceutical compositions comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for the inhibition of KRAS (e.g., KRAS with a G12D mutation) in a subject of need.

[1019] This disclosure also provides the use of 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) or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, or pharmaceutical compositions comprising any of the foregoing compounds and pharmaceutically acceptable excipients, for the manufacture of an agent for inhibiting KRAS (e.g., KRAS with a G12D mutation) in a subject of need.

[1020] This disclosure also provides a method comprising administering to a subject (e.g., a patient) a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of 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, thereby alleviating, reducing, eliminating, stopping, or improving one or more symptoms of said subject, such as one or more symptoms of a disease, symptom, or disorder (e.g., cancer). In some embodiments, administration of a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of 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 may slow or prevent tumor growth. In some embodiments, administration of a therapeutically effective amount of the compound provided herein (e.g., a compound of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or its salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer causes tumor shrinkage (e.g., tumor regression).

[1021] In some embodiments of any of the methods, uses, and pharmaceutical agents provided herein, the disease, symptom, or ailment is cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic duct adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer (CRC), endometrial cancer, uterine carcinosarcoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma, Wilm 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 duct adenocarcinoma), lung cancer (e.g., non-small cell lung cancer adenocarcinoma), or colorectal cancer (CRC). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic duct adenocarcinoma). In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer adenocarcinoma). In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is a solid tumor or contains a solid tumor.

[1022] In some embodiments, the disease, condition, or disorder is related to KRAS, such as conditions associated with KRAS mutations or KRAS dysregulation. In some embodiments, the disease, condition, or disorder is related to the KRAS gene, such as diseases, conditions, or disorders associated with KRAS gene mutations or KRAS gene dysregulation. KRAS or KRAS mutations or dysregulations may include mutations or dysregulations of human K-Ras4a and / or human K-Ras4b. In some embodiments, the disease, condition, or disorder is related to KRAS (e.g., human K-Ras4a or K-Ras4b) signaling pathway activity, such as diseases, conditions, or disorders associated with abnormal KRAS signaling pathway activity. In some embodiments, the disease, condition, or disorder is related to mutations or dysregulations of human K-Ras4b. In some embodiments, the disease, condition, or disorder is related to abnormal K-Ras4b signaling pathway activity. In some embodiments, the disease, condition, or disorder is related to mutations or dysregulations of human K-Ras4a. In some implementations, the disease, symptom, or ailment is associated with abnormal K-Ras4a signaling pathway activity.

[1023] Application and combination therapy

[1024] The compounds described herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) and their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) or compositions comprising them (e.g., pharmaceutical compositions) may be administered in various modes (e.g., orally, topically, or by injection). The amount of active ingredient (e.g., any suitable form of the compounds described herein) administered to a subject (e.g., a patient) is the responsibility of the healthcare provider. The specific dose level administered to a given subject (e.g., a patient) will depend on a number of factors, including, for example, the activity of the active ingredient administered; the subject's physical condition (e.g., age, weight, height, body mass index, general health status, comorbidities, sex, etc.); other characteristics of the subject (e.g., diet, exercise level, ethnicity, race, etc.); the time of administration; the route of administration; the rate of excretion; the combination of drugs; the disease, condition, or disorder being treated; and the severity of the disease, condition, or disorder being treated.

[1025] In some embodiments, the compounds provided herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) are administered in combination with an adjuvant (such as an additional therapeutic agent). For example, if a subject experiences side effects such as hypertension after receiving a compound or its form provided herein, it may be appropriate to administer an adjuvant that effectively controls the side effects, such as an antihypertensive agent. In another instance, the therapeutic efficacy of the compounds provided herein (e.g., compounds of any of formulas I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms can be enhanced by administering an adjuvant that may have only minimal therapeutic benefit on its own, but which, in combination with another therapeutic agent, can provide the subject with enhanced overall therapeutic benefit. In yet another instance, the therapeutic benefits of the compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms can be enhanced by administration of said compounds or their alternative forms, along with additional agents that also provide therapeutic benefits (which may comprise additional treatment regimens). For example, the compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms can be administered in combination with additional agents that are effective in treating diseases, conditions, or disorders (such as cancer). Generally, the combination of the compounds provided herein (e.g., compounds of any of Formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or their forms with one or more additional agents (e.g., therapeutic agents) can enhance the overall benefit experienced by a subject after individually receiving any one component. In some embodiments, the effects may be additive. In some embodiments, the effects may be synergistic.

[1026] In some embodiments, 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) or their forms (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.) are administered in combination with an anticancer agent (e.g., a chemotherapeutic agent). The anticancer agent may be, for example, an alkylating agent, an antimitotic agent, a checkpoint inhibitor, an antimetabolite, a plant alkaloid, a terpene, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an antisteroid, an androgen, an mTOR inhibitor, a monoclonal antibody, or a tyrosine kinase inhibitor. Alkylating agents can be, for example, amustine, 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). Antimetabolites can be, for example, cladribine (LEUSTATIN), purine, thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), leucovorin (FUSILEY), methotrexate (RHEUMATREX), or raltitrexed.Antimitotic agents can be, for example, taxanes such as docetaxel (TAXITERE) or paclitaxel (ABRAXANE, TAXOL); or vinca alkaloids 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; anti-CTLA-4 antibody ipilimumab (YERVOY); or agents targeting LAG3 (lymphocyte activation gene 3 protein), KIR (cytotoxic cell immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3 (containing T cell immunoglobulin and mucin domain-3), or OX40 (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 can be, for example, actinomycin D (COSMEGEN), bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), fludarabine (FLUDARA), idarubicin, mitomycin (MITOSOL), mitoxantrone (NOYANTRONE), or plicamycin. Aromatase inhibitors can be, for example, aminoglutethimide, anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (RIYIZOR), or exemestane (AROMASIN).Angiogenesis inhibitors can be, for example, genistein, sunitinib (SUTENT), or bevacizumab (AYASTIN). Antisteroids or antiandrogens can be, for example, cytamide (CYTADREN), bicalutamide (CASODEX), cyproterone, flutamide (EULEXIN), or nilutamide (NILANDRON). Tyrosine kinase inhibitors can be, for example, imatinib (GLEEVEC), erlotinib (TARCEVA), afatinib (GILOTRIF), lapatinib (TYKERB), sorafenib (NEXAVAR), or axitinib (INLYTA). mTOR inhibitors can be, for example, everolimus, temsirolimus (TORISEL), or sirolimus. Monoclonal antibodies can be, for example, trastuzumab (HERCEPTIN) or rituximab (RITUXAN).Additional examples of agents that can be used in combination with the compounds or their alternative forms provided herein include, but are not limited to, amsacrine; Bacillus subtilis. Calmette-Guerin (BCG) vaccine; buserelin (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate, and other bisphosphonates; colchicine; demethoxyviridin; dichloroacetate; estramustine; filgrastim (NEUPOGEN); fludrocortisone (FLORINEF); goserelin (ZOLADEX); interferon; leuprolide (LUPRON); levamisole; lonidamine; mesna; metformin (metformin); mitotane (o,r'-DDD, LYSODREN); nocodazole; octreotide (SANDOSTATIN); perifosine; porfimer (especially in combination with phototherapy and radiotherapy); suramin; tamoxifen; titanocenedichloride; 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.

[1027] Two or more therapeutic agents, one of which is 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 in any form thereof, may be administered in any order or simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single uniform form or in multiple forms (e.g., as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given in multiple doses. If not administered simultaneously, the time between multiple doses may be any duration ranging from several minutes to four weeks.

[1028] Therefore, in another aspect, this disclosure provides a method for treating a disease, condition, or ailment (e.g., cancer) in a subject (e.g., a human or animal subject) with a therapeutic need, the method comprising administering to the subject an amount of a compound provided herein (e.g., a compound of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or in a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), combined with at least one additional agent for treating the disease, condition, or ailment. In a related aspect, this disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound provided herein (e.g., a compound of any one of formula I, IA, IA1, IA2, IB, IB1, IB2, IC, ID, ID', IE, IF, or II) or in a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), and at least one additional agent for treating the disease, condition, or ailment (e.g., cancer).

[1029] In some embodiments, the methods provided herein are used to treat a disease, condition, or ailment (e.g., cancer), the methods comprising administering to a subject in need 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 adjuvant, wherein the disease, condition, or ailment is cancer resistant to one or more chemotherapeutic agents and / or ionizing radiation.

[1030] The compounds, compositions, and methods disclosed herein can be used to treat diseases, conditions, or disorders, such as cancer. In some embodiments, the disease is one of the cell proliferation disorders, including cancer. Cancer can be hormone-dependent or hormone-resistant, such as in the case of breast cancer. In some embodiments, the cancer is a solid tumor or contains a solid tumor. In other embodiments, the cancer is lymphoma or leukemia. In some embodiments, the cancer is a drug-resistant phenotype of the cancer disclosed herein or otherwise known. The compositions and methods disclosed herein can also be used to treat tumor invasion, tumor growth, tumor metastasis, and angiogenesis. In some embodiments, the compounds, compositions, and methods provided herein can also be used to treat precancerous tumor formation.

[1031] Cancers that can be treated using 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; cancers of the oral cavity and pharynx (lips, tongue, mouth, larynx, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, liver, and biliary tract; cancers of the pancreas, bones, connective tissue, skin, cervix, uterus, endometrial body, testes, bladder, kidneys, and other urinary tissues, including renal cell carcinoma (RCC); cancers of the eye, brain, spinal cord, and other components and related structures of the central and peripheral nervous systems (such as the meninges); and cancers of the thyroid and other endocrine glands. The term "cancer" also encompasses cancers that do not necessarily form solid tumors, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and hematopoietic malignancies, including leukemia (chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML)), and lymphomas, including lymphocytic, granulocytic, and monocytic lymphomas. Additional types of cancer that can be treated using the compounds and methods provided herein include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, degenerative astrocytoma, basal cell carcinoma, glioma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonal carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric cancer, genitourinary tract cancer, multimorphic glioma, head and neck cancer, hemangioblastoma, hepatocellular carcinoma, liver cancer, and Kaposi's sarcoma. Sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphatic system carcinoma, lymphoma, lymphangiosarcoma, lymphangioendothelial sarcoma, medullary thyroid carcinoma, myeloblastoma, meningioma, mesothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, osteosarcoma, epithelial ovarian cancer, papillary carcinoma, papillary adenocarcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pineal tumor, 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, synovial tumor, thyroid cancer, uveal melanoma, and Wilm's tumor. Additional diseases and conditions that can be treated by the methods disclosed herein include, but are not limited to, diseases or conditions related to KRAS, such as those related to KRAS mutations or KRAS dysregulation, and diseases or conditions related to the KRAS gene, such as those related to KRAS gene mutations or KRAS gene dysregulation.

[1032] In some embodiments, the compounds, compositions and methods provided herein can be used to prevent and / or reduce tumor invasion, growth and / or metastasis.

[1033] The compounds, compositions, and methods provided herein can be used to treat humans and non-human animals, including companion animals, exotic animals, and farm animals (e.g., those described herein), including mammals, rodents, etc. For example, the compounds, compositions, and methods provided herein can be used to treat horses, dogs, or cats.

[1034] List of implementation plans

[1035] Implementation Scheme I-1. A compound represented by Formula I:

[1036]

[1037] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1038] R 1 Selected from -OR 8 A 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 replace;

[1039] R 2 Selected from H and C 1-6 alkyl;

[1040] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[1041] Or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[1042] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14replace;

[1043] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbon rings and heterocycles therein are unsubstituted or derived from one or more R... 14 replace;

[1044] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1045] R 7 Selected from halogens, -OR 12 -CN and H;

[1046] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[1047] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[1048] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1049] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1050] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1051] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1052] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1053] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1054] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1055] Each R 17 Selected independently from C 1-6 Alkyl and H;

[1056] Each R 18 Independently selected from -OH, -OC 1-6Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1057] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1058] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1059] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1060] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1061] Implementation Scheme I-2. The compound of Implementation Scheme I-1, wherein R 1 Yes - OR 8 .

[1062] Implementation Scheme I-3. The compound of Implementation Scheme I-2, wherein R 8 It is a heterocyclic ring.

[1063] Implementation Scheme I-4. The compound of Implementation Scheme I-3, wherein R 8 It is an alkyl heterocyclic ring.

[1064] Implementation Scheme I-5. The compound of Implementation Scheme I-3 or I-4, wherein R 8 It contains a heterocycle that includes at least one nitrogen atom.

[1065] Implementation Scheme I-6. The compound of any one of Implementation Schemes I-3 to I-5, wherein the heterocycle comprises one or more R 16 Substituents.

[1066] Implementation Scheme I-7. The compound of Implementation Scheme I-6, wherein at least one R 16 Yes - OR 12 , where R 12 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1067] Implementation Scheme I-8. The compound of Implementation Scheme I-7, wherein at least one R 16 It is -OCH3.

[1068] Implementation Scheme I-9. The compound of Implementation Scheme I-1, wherein R 1 Selected from:

[1069]

[1070] Implementation Scheme I-10. The compound of Implementation Scheme I-1, wherein R 1 Selected from:

[1071]

[1072] Implementation Scheme I-11. The compound of Implementation Scheme I-1, wherein R 1 It is a 4-6 membered heterocycle containing a nitrogen atom, said heterocycle being unsubstituted or via one or more R atoms. 16 replace.

[1073] Implementation Scheme I-12. The compound of Implementation Scheme I-11, wherein R 1 Selected from:

[1074]

[1075] Implementation Scheme I-13. The compound of Implementation Scheme I-1, wherein R 1 It's H.

[1076] Implementation Scheme I-14. A compound of any one of Implementation Schemes I-1 to I-13, wherein R 2 It's H.

[1077] Implementation Scheme I-15. A compound of any one of Implementation Schemes I-1 to I-13, wherein R 2 It is C 1-6 alkyl.

[1078] Implementation Scheme I-16. A compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 It is C 1-6 Alkyl, the C 1-6 Alkyl groups via one or more R 9 replace.

[1079] Implementation Scheme I-17. The compound of Implementation Scheme I-16, wherein R 3 It is via-N(R) 17 )2 replaced by C 1-6 Alkyl, wherein each R 17 Selected independently from C 1-6 Alkyl groups and H.

[1080] Implementation Scheme I-18. The compound of Implementation Scheme I-17, wherein R 3 It is C substituted with -NH2 1-6 alkyl.

[1081] Implementation Scheme I-19. A compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 Selected from:

[1082]

[1083] Implementation Scheme I-20. A compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 It is a carbon ring, which is unsubstituted or derived from one or more R... 10 replace.

[1084] Implementation Scheme I-21. The compound of Implementation Scheme I-20, wherein R 3 It is via-N(R) 19 )2-substituted carbon rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl groups and H.

[1085] Implementation Scheme I-22. The compound of Implementation Scheme I-21, wherein R 3 It is a carbon ring substituted with -NH2.

[1086] Implementation Scheme I-23. The compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 Selected from C 1-6 Alkyl-N(R) 17 )C(O)C 1-6 Alkyl N(R) 17 )2.

[1087] Implementation Scheme I-24. The compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 It is a heterocyclic ring, which is unsubstituted or derived from one or more R... 10 replace.

[1088] Implementation Scheme I-25. The compound of Implementation Scheme I-24, wherein the heterocycle comprises one or more nitrogen atoms.

[1089] Implementation Scheme I-26. The compound of Implementation Scheme I-24 or I-25, wherein R 3 It is via-N(R) 19 )2-substituted heterocyclic rings, wherein each R 19 Independently selected from unsubstituted or substituted C 1-6 Alkyl groups and H.

[1090] Implementation Scheme I-27. The compound of Implementation Scheme I-26, wherein R 3 It is a heterocyclic ring substituted with -NH2.

[1091] Implementation Scheme I-28. A compound of any one of Implementation Schemes I-1 to I-15, wherein R 3 Selected from:

[1092]

[1093] None of them have been replaced or subjected to one or more R 10 replace.

[1094] Implementation Scheme I-29. The compound of any one of Implementation Schemes I-15 to I-28, wherein R 2 Or R 3 It contains an amino group.

[1095] Implementation Scheme I-30. A compound of any one of Implementation Schemes I-1 to I-13, wherein R 2 and R 3 Together with the atoms it is attached to (e.g., nitrogen atoms), it forms an unsubstituted or R-type atom. 11 Substituted heterocycles.

[1096] Implementation Scheme I-31. The compound of Implementation Scheme I-30, wherein R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[1097]

[1098] None of them have been replaced or subjected to one or more R 11 replace.

[1099] Implementation Scheme I-32. The compound of Implementation Scheme I-30, wherein R 2 and R 3 Together with the atoms they are attached to, they form heterocycles with the following structure:

[1100]

[1101] Implementation Scheme I-33. The compound of any one of Implementation Schemes I-30 to I-32, wherein R 2 and R 3 Together with the nitrogen atom to which it is attached, a heterocycle is formed, which (i) contains an additional nitrogen atom or (ii) is substituted by a group containing an amino moiety.

[1102] Implementation Scheme I-34. The compound of any one of Implementation Schemes I-1 to I-33, wherein R4 It is hydrogen.

[1103] Implementation Scheme I-35. A compound of any one of Implementation Schemes I-1 to I-33, wherein R 4 It is halogen.

[1104] Implementation Scheme I-36. The compound of any one of Implementation Schemes I-1 to I-35, wherein R 5 It is halogen.

[1105] Implementation Scheme I-37. The compound of any one of Implementation Schemes I-1 to I-36, wherein R 7 It is halogen.

[1106] Implementation Scheme I-38. A compound of any one of Implementation Schemes I-1 to I-37, wherein R 6 Selected from:

[1107]

[1108] Implementation Scheme I-39. The compound of Implementation Scheme I-38, wherein R 6 Selected from:

[1109]

[1110] Implementation scheme I-40. Compounds of implementation scheme I-39, wherein R 6 yes:

[1111]

[1112] Implementation Scheme I-41. A compound represented by formula IA:

[1113]

[1114] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1115] R 1 Selected from -OR 8 A 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 replace;

[1116] R 2 It is H;

[1117] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[1118] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1119] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1120] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1121] R 7 Selected from halogens, -OR 12 -CN and H;

[1122] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[1123] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[1124] Each R 10 Independently selected from -N(R) 19 )2、-C(O)R 19 -C(O)N(R) 19 )2、-C(O)(C 1-6Alkyl)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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1125] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1126] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1127] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1128] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1129] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1130] Each R 17 Selected independently from C 1-6 Alkyl and H;

[1131] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1132] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1133] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1134] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1135] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1136] Implementation Scheme I-42. The compound of Implementation Scheme I-41, wherein R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace.

[1137] Implementation Scheme I-43. The compound of Implementation Scheme I-42, wherein R 3 It is unreplaced or through one or more R 10 Substituted 3-6 membered carbon rings or heterocycles.

[1138] Implementation Scheme I-44. The compound of Implementation Scheme I-43, wherein R 3 Selected from:

[1139]

[1140] None of them have been replaced or subjected to one or more R 10 replace.

[1141] Implementation Scheme I-45. The compound of Implementation Scheme I-41, wherein R 3 Selected from one or more R 9 Replacement C 1-6 alkyl.

[1142] Implementation Scheme I-46. The compound of Implementation Scheme I-45, wherein R 3 Selected from C 1-6 Alkyl-N(R) 17 )2.

[1143] Implementation Scheme I-47. The compound of Implementation Scheme I-45 or I-46, wherein R 3 Selected from:

[1144]

[1145] Implementation Scheme I-48. The compound of Implementation Scheme I-45, wherein R 3 Selected from C 1-6 Alkyl-N(R) 17 )C(O)C 1-6 Alkyl N(R) 17 )2.

[1146] Implementation Scheme I-49. The compound of any one of Implementation Schemes I-41 to I-48, wherein R 3 It contains an amino group.

[1147] Implementation scheme I-50. The compound of any one of implementation schemes I-41 to I-49, wherein R 1 It is H.

[1148] Implementation Scheme I-51. The compound of any one of Implementation Schemes I-41 to I-50, wherein R 1 Yes - OR 8 .

[1149] Implementation Scheme I-52. The compound of Implementation Scheme I-51, wherein R 8 Contains unsubstituted or via one or more R 14 Replaced 3-6 membered heterocycles.

[1150] Implementation Scheme I-53. The compound of Implementation Scheme I-51 or I-52, wherein R 1 Selected from:

[1151]

[1152] Implementation Scheme I-54. The compound of Implementation Scheme I-51 or I-52, wherein R 1 Selected from:

[1153]

[1154] Implementation Scheme I-55. The compound of any one of Implementation Schemes I-41 to I-54, wherein R 1 It is a 4-6 membered heterocycle containing a nitrogen atom, said heterocycle being unsubstituted or via one or more R atoms. 16 replace.

[1155] Implementation scheme I-56. The compound of implementation scheme I-55, wherein R 1 Selected from:

[1156]

[1157] Implementation Scheme I-57. The compound of any one of Implementation Schemes I-41 to I-56, wherein R 6 Selected from:

[1158]

[1159] Implementation scheme I-58. The compound of implementation scheme I-57, wherein R 6 Selected from:

[1160]

[1161] Implementation scheme I-59. The compound of implementation scheme I-58, wherein R 6 yes:

[1162]

[1163] Implementation scheme I-60. The compound of any one of implementation schemes I-41 to I-59, wherein R 4 It is H.

[1164] Implementation Scheme I-61. The compound of any one of Implementation Schemes I-41 to I-59, wherein R 4 It is halogen.

[1165] Implementation Scheme I-62. The compound of any one of Implementation Schemes I-41 to I-61, wherein R 5 It is halogen.

[1166] Implementation Scheme I-63. The compound of any one of Implementation Schemes I-41 to I-62, wherein R 7 It is halogen.

[1167] Implementation Scheme I-64. A compound according to Formula IA1:

[1168]

[1169] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1170] R 1 It is H;

[1171] R 2 It is H;

[1172] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[1173] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1174] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1175] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1176] R 7 Selected from halogens, -OR 12 -CN and H;

[1177] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR 17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[1178] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1179] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1180] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1181] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1182] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1183] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1184] Each R 17 Selected independently from C 1-6 Alkyl and H;

[1185] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1186] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1187] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1188] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1189] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1190] Implementation Scheme I-65. The compound of Implementation Scheme I-64, wherein R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace.

[1191] Implementation Scheme I-66. The compound of Implementation Scheme I-65, wherein R 3 Selected from:

[1192]

[1193] None of them have been replaced or subjected to one or more R 10 replace.

[1194] Implementation Scheme I-67. The compound of Implementation Scheme I-64, wherein R 3 Selected from one or more R 9 Replacement C 1-6 alkyl.

[1195] Implementation Scheme I-68. The compound of Implementation Scheme I-67, wherein R 3 Selected from:

[1196]

[1197] Implementation Scheme I-69. The compound of Implementation Scheme I-64, wherein R 3 Selected from C 1-6 Alkyl-N(R) 17 )C(O)C 1-6 Alkyl N(R) 17 )2.

[1198] Implementation scheme I-70. The compound of any one of implementation schemes I-64 to I-68, wherein R 3 It contains an amino group.

[1199] Implementation Scheme I-71. The compound of any one of Implementation Schemes I-62 to I-70, wherein R 6 Selected from:

[1200]

[1201] Implementation Scheme I-72. The compound of Implementation Scheme I-71, wherein R 6 Selected from:

[1202]

[1203] Implementation Scheme I-73. The compound of Implementation Scheme I-72, wherein R 6 yes:

[1204]

[1205] Implementation Scheme I-74. The compound of any one of Implementation Schemes I-64 to I-73, wherein R 4 It is H.

[1206] Implementation Scheme I-75. The compound of any one of Implementation Schemes I-64 to I-73, wherein R 4 It is halogen.

[1207] Implementation Scheme I-76. The compound of any one of Implementation Schemes I-64 to I-75, wherein R 5 It is halogen.

[1208] Implementation Scheme I-77. The compound of any one of Implementation Schemes I-64 to I-76, wherein R 7 It is halogen.

[1209] Implementation scheme I-78. A compound according to formula IA2:

[1210]

[1211] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1212] R 1 Yes - OR 8 ;

[1213] R 2 It is H;

[1214] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[1215] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1216] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1217] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1218] R 7 Selected from halogens, -OR 12 -CN and H;

[1219] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[1220] Each R 9 Independently selected from -N(R) 17 )2、-N(R 17 )C(O)C 1-6 Alkyl and -OR17 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 18 replace;

[1221] Each R 10 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1222] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1223] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1224] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1225] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1226] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups13 replace;

[1227] Each R 17 Selected independently from C 1-6 Alkyl and H;

[1228] Each R 18 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1229] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1230] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1231] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1232] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1233] Implementation Scheme I-79. The compound of Implementation Scheme I-78, wherein R 8 Contains unsubstituted or via one or more R 14 Replaced 3-6 membered heterocycles.

[1234] Implementation scheme I-80. Compounds of implementation scheme I-78, wherein R 1 Selected from:

[1235]

[1236] Implementation scheme I-81. The compound of implementation scheme I-78, wherein R 1 Selected from:

[1237]

[1238] Implementation Scheme I-82. The compound of any one of Implementation Schemes I-78 to I-81, wherein R 3 Selected from carbocyclic and heterocyclic rings, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R...10 replace.

[1239] Implementation Scheme I-83. The compound of Implementation Scheme I-82, wherein R 3 Selected from:

[1240]

[1241] None of them have been replaced or subjected to one or more R 10 replace.

[1242] Implementation Scheme I-84. The compound of any one of Implementation Schemes I-78 to I-83, wherein R 3 Selected from one or more R 9 Replacement C 1-6 alkyl.

[1243] Implementation Scheme I-85. The compound of Implementation Scheme I-84, wherein R 3 Selected from:

[1244]

[1245] Implementation scheme I-86. The compound of any one of implementation schemes I-78 to I-85, wherein R 3 Selected from C 1-6 Alkyl-N(R) 17 )C(O)C 1-6 Alkyl N(R) 17 )2.

[1246] Implementation scheme I-87. The compound of any one of implementation schemes I-78 to I-86, wherein R 3 It contains an amino group.

[1247] Implementation scheme I-88. The compound of any one of implementation schemes I-78 to I-87, wherein R 6 Selected from:

[1248]

[1249] Implementation Scheme I-89. The compound of Implementation Scheme I-88, wherein R 6 Selected from:

[1250]

[1251] Implementation scheme I-90. Compounds of implementation scheme I-89, wherein R 6 yes:

[1252]

[1253] Implementation Scheme I-91. The compound of any one of Implementation Schemes I-78 to I-90, wherein R 4 It is H.

[1254] Implementation Scheme I-92. The compound of any one of Implementation Schemes I-78 to I-90, wherein R 4 It is halogen.

[1255] Implementation scheme I-93. The compound of any one of implementation schemes I-78 to I-92, wherein R 5 It is halogen.

[1256] Implementation scheme I-94. The compound of any one of implementation schemes I-78 to I-93, wherein R 7 It is halogen.

[1257] Implementation scheme I-95. A compound according to formula IB:

[1258]

[1259] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1260] R 1 Selected from -OR 8 A 4-6 membered heterocycle containing a nitrogen atom and H, wherein the heterocycle is unsubstituted or via one or more R atoms. 16 replace;

[1261] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[1262] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1263] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1264] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1265] R 7 Selected from halogens, -OR 12 -CN and H;

[1266] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[1267] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1268] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1269] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1270] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1271] Each R 15 Independently selected from halogens, N(R) 12)2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1272] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1273] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1274] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1275] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1276] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1277] Implementation Scheme I-96. Compounds of Implementation Scheme I-95, wherein ring A is unsubstituted or via one or more R 11 Replaced 4-6 membered heterocycles.

[1278] Implementation Scheme I-97. The compound of Implementation Scheme I-95, wherein ring A has the following structure:

[1279]

[1280] The ring was not replaced or passed through one or more R... 11 replace.

[1281] Implementation Scheme I-98. The compound of Implementation Scheme I-95, wherein ring A has the following structure:

[1282]

[1283] Implementation Scheme I-99. The compound of any one of Implementation Schemes I-95 to I-98, wherein ring A comprises at least two nitrogen atoms and / or is substituted by a group including an amino moiety.

[1284] Implementation scheme I-100. The compound of any one of implementation schemes I-95 to I-99, wherein R 1 It is H.

[1285] Implementation Scheme I-101. The compound of any one of Implementation Schemes I-95 to I-99, wherein R 1 Yes - OR 8 .

[1286] Implementation Scheme I-102. The compound of Implementation Scheme I-101, wherein R 8 Contains unsubstituted or via one or more R 14 Replaced 3-6 membered heterocycles.

[1287] Implementation Scheme I-103. The compound of Implementation Scheme I-101, wherein R 1 Selected from:

[1288]

[1289] Implementation Scheme I-104. The compound of Implementation Scheme I-101, wherein R 1 Selected from:

[1290]

[1291] Implementation scheme I-105. The compound of any one of implementation schemes I-95 to I-99, wherein R 1 It is a 4-6 membered heterocycle containing a nitrogen atom, said heterocycle being unsubstituted or via one or more R atoms. 16 replace.

[1292] Implementation Scheme I-106. The compound of Implementation Scheme I-105, wherein R 1 Selected from:

[1293]

[1294] Implementation Scheme I-107. The compound of any one of Implementation Schemes I-95 to I-106, wherein R 6 Selected from:

[1295]

[1296] Implementation Scheme I-108. The compound of Implementation Scheme I-107, wherein R 6 Selected from:

[1297]

[1298] Implementation Scheme I-109. The compound of Implementation Scheme I-108, wherein R 6 yes:

[1299]

[1300] Implementation scheme I-110. The compound of any one of implementation schemes I-95 to I-109, wherein R 4 It is H.

[1301] Implementation Scheme I-111. The compound of any one of Implementation Schemes I-95 to I-109, wherein R 4 It is halogen.

[1302] Implementation Scheme I-112. The compound of any one of Implementation Schemes I-95 to I-111, wherein R 5 It is halogen.

[1303] Implementation Scheme I-113. The compound of any one of Implementation Schemes I-95 to I-112, wherein R 7 It is halogen.

[1304] Implementation Scheme I-114. A compound according to Formula IB1:

[1305]

[1306] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1307] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[1308] R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1309] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1310] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1311] R 7 Selected from halogens, -OR 12 -CN and H;

[1312] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1313] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1314] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1315] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1316] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1317] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1318] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1319] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1320] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1321] Implementation Scheme I-115. The compound of Implementation Scheme I-114, wherein ring A is unsubstituted or via one or more R 11 Replaced 4-6 membered heterocycles.

[1322] Implementation Scheme I-116. The compound of Implementation Scheme I-114, wherein ring A has the following structure:

[1323]

[1324] The ring was not replaced or passed through one or more R... 11 replace.

[1325] Implementation Scheme I-117. The compound of Implementation Scheme I-114, wherein ring A has the following structure:

[1326]

[1327] Implementation Scheme I-118. A compound of any one of Implementation Schemes I-114 to I-117, wherein ring A comprises at least two nitrogen atoms and / or is substituted by a group comprising an amino moiety.

[1328] Implementation Scheme I-119. The compound of any one of Implementation Schemes I-114 to I-118, wherein R 6 Selected from:

[1329]

[1330] Implementation scheme I-120. Compounds of implementation scheme I-119, wherein R 6 Selected from:

[1331]

[1332] Implementation Scheme I-121. The compound of Implementation Scheme I-120, wherein R 6 yes:

[1333]

[1334] Implementation scheme I-122. The compound of any one of implementation schemes I-114 to I-121, wherein R 4 It is H.

[1335] Implementation scheme I-123. The compound of any one of implementation schemes I-114 to I-121, wherein R 4 It is halogen.

[1336] Implementation scheme I-124. The compound of any one of implementation schemes I-114 to I-123, wherein R 5 It is halogen.

[1337] Implementation Scheme I-125. A compound of any one of Implementation Schemes I-114 to I-124, wherein R 7 It is halogen.

[1338] Implementation scheme I-126. A compound according to formula IB2:

[1339]

[1340] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1341] R 1 Yes - OR 8 ;

[1342] Ring A is unsubstituted or via one or more R 11 Substituted heterocycles;

[1343] R 4 It is H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R...14 replace;

[1344] R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein any carbocyclic and heterocyclic rings are unsubstituted or derived from one or more R... 14 replace;

[1345] R 6 It is through one or more R 15 Substituted bicyclic heteroaryl groups;

[1346] R 7 Selected from halogens, -OR 12 -CN and H;

[1347] R 8 Selected from heterocyclic and alkyl heterocyclic compounds, wherein either one is unsubstituted or has undergone one or more R... 16 replace;

[1348] Each R 11 Independently selected from -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, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace;

[1349] Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, where any C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace;

[1350] Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens;

[1351] Each R 14 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1352] Each R 15 Independently selected from halogens, N(R) 12 )2 and C 1-6 Alkyl, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1353] Each R 16 Independently selected from halogens, -N(R) 12 2. C 1-6 Alkyl and -OR 12 , of which any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace;

[1354] Each R 19 Selected independently from C 1-6 Alkyl and H, wherein any C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace;

[1355] Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen;

[1356] Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; and

[1357] Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 Alkenyl and H.

[1358] Implementation Scheme I-127. Compounds of Implementation Scheme I-126, wherein ring A is unsubstituted or via one or more R 11 Replaced 4-6 membered heterocycles.

[1359] Implementation Scheme I-128. The compound of Implementation Scheme I-126, wherein ring A has the following structure:

[1360]

[1361] The ring was not replaced or passed through one or more R... 11 replace.

[1362] Implementation Scheme I-129. The compound of Implementation Scheme I-126, wherein ring A has the following structure:

[1363]

[1364] Implementation scheme I-130. The compound of any one of implementation schemes I-126 to I-129, wherein ring A comprises at least two nitrogen atoms and / or is substituted by a group including an amino moiety.

[1365] Implementation Scheme I-131. The compound of any one of Implementation Schemes I-126 to I-130, wherein R 8 Contains unsubstituted or via one or more R 14 Replaced 3-6 membered heterocycles.

[1366] Implementation scheme I-132. The compound of any one of implementation schemes I-126 to I-131, wherein R 1 Selected from:

[1367]

[1368] Implementation scheme I-133. The compound of any one of implementation schemes I-126 to I-131, wherein R 1 Selected from:

[1369]

[1370] Implementation scheme I-134. The compound of any one of implementation schemes I-126 to I-133, wherein R 6 Selected from:

[1371]

[1372] Implementation Scheme I-135. The compound of Implementation Scheme I-134, wherein R 6 Selected from:

[1373]

[1374] Implementation Scheme I-136. The compound of Implementation Scheme I-135, wherein R 6 yes:

[1375]

[1376] Implementation scheme I-137. The compound of any one of implementation schemes I-126 to I-136, wherein R 4It is H.

[1377] Implementation scheme I-138. A compound of any one of implementation schemes I-126 to I-136, wherein R 4 It is halogen.

[1378] Implementation scheme I-139. The compound of any one of implementation schemes I-126 to I-138, wherein R 5 It is halogen.

[1379] Implementation scheme I-140. The compound of any one of implementation schemes I-126 to I-139, wherein R 7 It is halogen.

[1380] Implementation scheme I-141. A compound according to formula IC:

[1381]

[1382] Or its salts (e.g., pharmaceutically acceptable salts), esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, wherein:

[1383] R 2 Selected from H and C 1-6 alkyl;

[1384] R 3 Selected from C 1-6 Alkyl, carbocyclic, and heterocyclic compounds, wherein any C 1-6 Alkyl groups via one or more R 9 Substitution, wherein the carbocyclic or heterocyclic ring is unsubstituted or derived from one or more R... 10 replace;

[1385] or R 2 and R 3 Together with the atoms they are attached to, they form unsubstituted or substituted forms via one or more R atoms. 11 Substituted heterocycles;

[1386] R 4 It i...

Claims

1. A compound represented by the formula ID': (ID’) Or its pharmaceutically acceptable salt, wherein: R 1 yes ; R 2 and R 3 Together with the atoms they are attached to, they form 4-6 membered heterocycles selected from the following: , , , , , , , , , , , , , , , , , , , , and ; R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein the carbon rings and heterocycles are unsubstituted or derived from one or more R... 14 replace; R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein the carbon rings and heterocycles are unsubstituted or derived from one or more R... 14 replace; R 7 Selected from halogens, -OR 12 -CN and H; Each R 11 Independently selected from -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, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace; Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, wherein the C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace; Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens; Each R 14 Independently selected from halogens, -OR 12 -N(R) 12 )2 and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace; Each R 19 Selected independently from C 1-6 Alkyl and H, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace; Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H; R 23 Selected from -N(R) 12 )2 and C 1-6 Alkyl-N(R) 12 )2; R 24 R 25 and R 26 Independently selected from H, halogen, -OR 12 and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 11 Replace; and R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, wherein C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace.

2. The compound of claim 1, wherein R 1 Selected from: , , , and .

3. The compound of claim 1, wherein R 1 yes .

4. The compound of claim 1, wherein each R 11 Independently selected from -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, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace.

5. The compound of claim 1, wherein R 2 and R 3 Together with the atoms they are attached to, they form 4-6 membered heterocycles selected from the following: , , , , , , , , and .

6. The compound of claim 1, wherein R 2 and R 3 Together with the atoms they are attached to, they form 4-6 membered heterocycles selected from the following: , , , and .

7. The compound of claim 1, wherein R 2 and R 3 It forms together with the atoms it is attached to. .

8. The compound of claim 1, wherein... yes .

9. The compound of claim 1, wherein R 4 It's H.

10. The compound of claim 1, wherein R 4 Yes - OR 12 .

11. The compound of claim 1, wherein R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 Alkyne group and 3-6 membered carbide ring, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, and wherein the carbon ring is unsubstituted or via one or more R 14 replace.

12. The compound of claim 1, wherein R 5 It is halogen.

13. The compound of claim 1, wherein R 5 It is unreplaced or through one or more R 13 Replacement C 1-6 alkyl.

14. The compound of claim 1, wherein R 5 It is a C substituted with one or more halogens. 1-6 alkyl.

15. The compound of claim 1, wherein R 5 It is a 3-6 membered carbon ring, wherein the carbon ring is unsubstituted or derived from one or more R... 14 replace.

16. The compound of claim 1, wherein R 7 It is halogen.

17. The compound of claim 1, wherein R 7 Yes - CN.

18. A compound represented by the formula ID': (ID’) Or its pharmaceutically acceptable salt, wherein: R 1 yes ; yes ; R 2 and R 3 Together with the atoms it is attached to, it forms heterocycles selected from the following: , , , and ; R 4 It is H; R 5 It is a halogen or a C substituted with one or more halogens. 1-6 alkyl; R 7 It is halogen; and R a and R b Each is independently selected from halogens, C 1-6 Alkyl groups and H.

19. The compound of claim 18, wherein R 1 Selected from: , , and .

20. The compound of claim 19, wherein R 1 yes .

21. The compound of claim 18, wherein R 2 and R 3 It forms together with the atoms it is attached to. .

22. The compound of claim 18, wherein R 5 It is a C substituted with one or more halogens. 1-6 alkyl.

23. The compound of claim 18, wherein R 7 It is halogen.

24. A compound having the following structure Or its pharmaceutically acceptable salt.

25. A compound represented by the formula ID': (ID’) Or its pharmaceutically acceptable salt, wherein: R 1 yes ; R 2 Selected from H; R 3 It is selected from the following heterocycles: , , , , , , , , , , , , , , , , , and ; R 4 Selected from H, halogen, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein the carbon rings and heterocycles are unsubstituted or derived from one or more R... 14 replace; R 5 Selected from halogens, -OR 12 -CN,C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, 3-6 membered carbon ring and 3-6 membered heterocycle, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 Substitution, wherein the carbon rings and heterocycles are unsubstituted or derived from one or more R... 14 replace; R 7 Selected from halogens, -OR 12 -CN and H; Each R 11 Independently selected from -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, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 20 replace; Each R 12 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H, wherein the C 1-6 Alkyl or C 2-6 Alkenes that are unsubstituted or derived from one or more R groups 13 replace; Each R 13 Independently selected from -OR 22 -CN, -N(R) 22 )2 and halogens; Each R 14 Independently selected from halogens, -OR 12 -N(R) 12 )2 and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace; Each R 19 Selected independently from C 1-6 Alkyl and H, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 21 replace; Each R 20 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; Each R 21 Independently selected from -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 Alkyl and halogen; Each R 22 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl and H; R 23 Selected from -N(R) 12 )2 and C 1-6 Alkyl-N(R) 12 )2; R 24 R 25 and R 26 Independently selected from H, halogen, -OR 12 and C 1-6 Alkyl, wherein the C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 11 Replace; and R a and R b Each is independently selected from halogens, C 1-6 Alkyl, -OR 12 and H, wherein C 1-6 Alkyl groups that are unsubstituted or derived from one or more R groups 13 replace.

26. The compound of claim 25, wherein R 1 Selected from: , , , and .

27. The compound of claim 25, wherein R 1 yes .

28. The compound of claim 25, wherein R 3 Selected from: , , , , , , , and .

29. The compound of claim 25, wherein... yes .

30. The compound of claim 25, wherein R 4 It's H.

31. The compound of claim 25, wherein R 5 Yes - CN.

32. The compound of claim 25, wherein R 5 It is halogen.

33. The compound of claim 25, wherein R 5 It is a C substituted with one or more halogens. 1-6 alkyl.

34. The compound of claim 25, wherein R 7 It is halogen.

35. The compound of claim 25, wherein R 7 It's H.

36. A compound represented by the formula ID': (ID’) Or its pharmaceutically acceptable salt, wherein: R 1 yes ; yes ; R 2 It is C 1-6 alkyl; R 3 Selected from: , , , , , , , and ; R 4 It is H; R 5 It is CN, halogen, or C substituted with one or more halogens. 1-6 alkyl; R 7 It is H or halogen; and R a and R b Each is independently selected from halogens, C 1-6 Alkyl groups and H.

37. The compound of claim 36, wherein R 1 Selected from: , , and .

38. The compound of claim 36, wherein R 1 yes .

39. The compound of claim 36, wherein R 3 yes .

40. The compound of claim 36, wherein R 5 It is a C substituted with one or more halogens. 1-6 alkyl.

41. The compound of claim 36, wherein R 7 It is halogen.

42. A compound selected from the following table or a pharmaceutically acceptable salt thereof: 。 43. A pharmaceutical composition comprising a compound as described in any one of claims 1-42 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

44. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-42, used as a pharmaceutical agent.

45. The compound of any one of claims 1-42 or a pharmaceutically acceptable salt thereof, used in the manufacture of a pharmaceutical preparation.

46. ​​The compound of claim 44, wherein the agent is used to treat a disease, condition or disorder that is improved by inhibiting KRAS with a G12D mutation.

47. The compound of claim 45, wherein the agent is used to treat a disease, condition or disorder that is improved by inhibiting KRAS with a G12D mutation.

48. The compound of claim 44, wherein the agent can be used to treat cancer.

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

50. The compound of claim 45, wherein the agent is used to treat cancer.

51. The compound of claim 50, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

52. The compound of claim 46, wherein the disease, symptom, or ailment is cancer.

53. The compound of claim 52, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

54. The compound of claim 47, wherein the disease, symptom, or ailment is cancer.

55. The compound of claim 54, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

56. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-42, for the treatment of diseases, symptoms or ailments.

57. The compound of claim 56, wherein the disease, symptom, or ailment is cancer.

58. The compound of claim 57, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

59. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-42 in the manufacture of a pharmaceutical preparation.

60. The use as claimed in claim 59, wherein the agent is used to treat a disease, condition, or disorder that is improved by inhibiting KRAS with a G12D mutation.

61. The use as described in claim 59, wherein the agent is used to treat cancer.

62. The use as described in claim 60, wherein the agent is used to treat cancer.

63. The use as claimed in claim 61, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

64. The use as described in claim 62, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer.

65. An in vitro method comprising contacting a KRAS protein with a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-42.

66. The method of claim 65, wherein contacting the KRAS protein with the compound modulates KRAS.

67. The method of claim 65, wherein the KRAS protein has a G12D mutation.

68. The method of claim 66, wherein the KRAS protein has a G12D mutation.

69. The method of claim 65, wherein the KRAS protein is in an active state.

70. The method of claim 66, wherein the KRAS protein is in an active state.

71. The method of claim 67, wherein the KRAS protein is in an active state.

72. The method of claim 68, wherein the KRAS protein is in an active state.

73. The method of claim 65, wherein the KRAS protein is in an inactive state.

74. The method of claim 66, wherein the KRAS protein is in an inactive state.

75. The method of claim 67, wherein the KRAS protein is in an inactive state.

76. The method of claim 68, wherein the KRAS protein is in an inactive state.

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