Compositions and methods for inhibition of the RAS

Abstract

Provided herein are compounds, or their salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers, as well as pharmaceutical compositions comprising the same.Also provided herein are methods of modulating (e.g., inhibiting) KRAS (e.g., KRAS having G12C mutation) and using them in treating diseases or disorders, such as cancer, in subjects in need thereof.

Description

[Technical Field]

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

[0002] Related Applications This application claims priority to and the benefit of U.S. Patent Application No. 63 / 225,407, filed July 23, 2021, and U.S. Patent Application No. 63 / 329,237, filed April 8, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0003] RAS mutations occur in approximately 20–30% of human cancers, including the majority of pancreatic ductal adenocarcinomas (PDAC), half of colorectal cancers, and one-third of all lung cancers. Given the highest RAS mutation frequency in the top three causes of cancer death in the United States (lung, colorectal, and pancreatic cancers), the development of anti-RAS therapies is a major priority and challenge in cancer research. RAS proteins, apart from the GDP / GTP binding site, were thought to present no suitable pockets for drug binding. Unfortunately, RAS proteins bind these nucleotides with such high (picomolar) affinity that the development of effective nucleotide analogs is virtually impossible. Attempts to block pathways downstream of RAS, in the hope of providing clinical benefit to patients with RAS-driven cancers, have been largely disappointing.

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

[0005] It is estimated that more than 600,000 Americans will die from cancer in 2021, equating to more than 1,600 deaths per day (Cancer Facts and Figures 2021). The leading causes of death are lung, prostate, and colorectal cancer in men, and lung, breast, and colorectal cancer in women. Lung cancer accounts for nearly one-quarter of all cancer deaths, and 82% of these are directly attributable to tobacco smoking. The five-year survival rate for lung cancer patients is only about 20%.

[0006] KRAS is mutationally activated in lung cancer, and glycine-cysteine ​​(G12C) mutations account for the majority of codon 12 mutations associated with tobacco smoking. A significant proportion of colorectal cancers are also driven by KRAS G12C mutations.

[0007] Early clinical data on allele-specific covalent KRAS G12C inhibitors show some efficacy, at least in lung cancer. These KRAS G12C inhibitors (e.g., Amgen Inc.'s sotorasib and Mirati Therapeutics Inc.'s adagrasib) target inactive (GDP)-binding proteins, and their efficacy is enabled by the high intrinsic GTP hydrolysis rate of KRAS G12C mutations (comparable to that of wild-type (WT) KRAS). Clinical data on these drugs show that most patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) experience clinical benefit from selective KRAS G12C inhibition, but patients with colorectal cancer harboring the same mutation rarely respond.

[0008] The limited efficacy of KRAS G12C(GDP) inhibitors in colorectal cancer is being investigated. Unlike NSCLC cell lines, KRAS G12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and respond to growth factor stimulation. In colorectal cancer lines, KRAS G12C inhibition induces a higher phospho-ERK rebound than in NSCLC cells. Furthermore, KRAS G12C-GDP inhibitors have been reported to induce transcription of de novo KRAS G12C in the GTP-bound conformation, which is insensitive to KRAS G12C inactive state inhibitors.

[0009] Therefore, there is a need for improved KRAS G12C inhibitors. Summary of the Invention [Means for solving the problem]

[0010] The present disclosure provides compounds, as well as compositions and kits comprising same, and methods of using same for treating diseases and disorders, such as cancer. In some embodiments, the present disclosure provides KRAS G12C inhibitors that target both active GTP-binding and inactive GDP-binding proteins, and these inhibitors may offer therapeutic advantages over KRAS G12C-GDP inhibitors. In some embodiments, the compounds provided herein have inhibitory activity against KRAS proteins containing a glycine to cysteine ​​mutation at codon 12 (e.g., a G12C mutation) in both their active and inactive conformations. In some embodiments, the compounds provided herein are useful for treating cancers, such as cancers characterized by a KRAS G12C mutation.

[0011] In one aspect, the present disclosure provides a compound represented by one of formulas AA (e.g., formula IA, IC, ID, or IE), BB (e.g., formula IB), CC (e.g., formula IIA, IIC, or IID), and DD (e.g., formula IIB), [ka] or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein A, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 23 , R 24 , R 25 , and R 26is as provided herein. In some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can modulate (e.g., inhibit) the activity of a KRAS protein, such as a KRAS protein having a G12C mutation. In some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, comprises an electrophilic moiety E provided herein. In some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can covalently interact with the cysteine ​​at position 12 of a KRAS protein (e.g., a G12C mutation). In some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can bind to a KRAS protein in the active ("GTP-bound") conformation. In some embodiments, the compounds provided herein, or salts, esters, tautomers, zwitterionic forms, or stereoisomers thereof, can bind to KRAS proteins in an inactive ("GDP-bound") conformation.

[0012] In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound represented by one of formulas AA, BB, CC, and DD, or any other formula described herein), or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

[0013] In a further aspect, the present disclosure provides methods of inhibiting KRAS activity in a human or animal subject for the treatment of diseases such as cancer, including pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, and lung cancer, e.g., using a compound provided herein (e.g., a compound represented by one of formulas AA, BB, CC, and DD, or any other formula described herein), or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, or a pharmaceutical composition comprising same.

[0014] In another aspect, the disclosure provides use of a compound provided herein (e.g., a compound represented by one of formulas AA, BB, CC, and DD, or any other formula described herein), or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition (e.g., cancer) that is ameliorated, treated, inhibited, or reduced by inhibition of KRAS, including KRAS having a G12C mutation. In some embodiments, the disease, disorder, or condition is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer.

[0015] In a further aspect, the present disclosure provides a compound provided herein (e.g., a compound represented by one of formulas AA, BB, CC, and DD, or any other formula described herein), or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, for use as a medicament. In some embodiments, the medicament is used in the treatment of a disease, disorder, or condition (e.g., cancer). In some embodiments, the disease, disorder, or condition is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)), colorectal cancer, or lung cancer. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure provides compounds (e.g., compounds of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID) that may have useful KRAS inhibitory activity and may be used to treat or prevent diseases, disorders, or conditions in which KRAS plays an active role. In particular, certain compounds provided herein may have useful inhibitory activity of KRAS with a G12C mutation, whether in the active (GTP-bound) or inactive (GDP-bound) conformation of the KRAS protein. Certain compounds provided herein may be capable of inhibiting both the active and inactive forms of KRAS. The present disclosure also provides pharmaceutical compositions comprising one or more compounds provided herein together with a pharmaceutically acceptable carrier, as well as methods for preparing and using such compounds and compositions. The present disclosure also provides methods for inhibiting KRAS, including KRAS with a G12C mutation, whether in the active or inactive conformation. In one aspect, the present disclosure provides a method for treating a disorder mediated by KRAS, including KRAS with a G12C mutation, in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound or composition provided herein to the subject. Also provided herein is the use of certain compounds provided herein in the manufacture of a medicament for treating a disease, disorder, or condition that is ameliorated, treated, inhibited, or alleviated by inhibiting KRAS, including KRAS with a G12C mutation. In some embodiments, the disease, disorder, or condition is cancer (e.g., as described herein).

[0017] When a range of values ​​is disclosed, where n1 and n2 are numerical values, and the expression "n1... to n2" or "between n1... and n2" is used, the expression is intended to include the numerical values ​​themselves and the range therebetween, unless otherwise specified. The range may be an integer or continuous value between and including the end values. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons, since carbon is an integer unit. As an example, compared to the range "1 to 3 μM (micromolar)," this range is intended to include 1 μM, 3 μM, and all values ​​therebetween, to any significant figure (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0018] As used herein, "about" is intended to qualify the numerical value it modifies, meaning that such value varies within a margin of error. Unless a specific margin of error, such as the standard deviation for the average value shown in a graph or table of data, is stated, the term "about" should be understood to mean not only a range encompassing the stated value, but also a range encompassed by rounding up or down to that numerical value, taking into account significant digits.

[0019] As used herein, "acyl," alone or in combination, refers to a carbonyl bound to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom bound to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group bound to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0020] As used herein, "alkenyl," alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can include an "alkenylene" group.

[0021] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least two carbon atoms and at least one triple bond, and having the number of carbon atoms indicated (i.e., C 2-6 (means 2 to 6 carbons). Alkynyl is C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 and C. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, and 1,3,5-hexatriynyl.

[0022] As used herein, "alkoxy," alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined herein. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0023] As used herein, "alkyl," alone or in combination, refers to a straight- or branched-chain alkyl radical containing 1 to 20 carbon atoms (e.g., C 1-20 In certain embodiments, the alkyl refers to a group having 1 to 10 carbon atoms (e.g., C 1-10 In further embodiments, the alkyl may contain 1 to 8 carbon atoms (e.g., C 1-8 In further embodiments, the alkyl may contain 1 to 6 carbon atoms (e.g., C 1-6 In further embodiments, the alkyl may contain 1 to 3 carbon atoms (e.g., C 1-3 The alkyl group may include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, nonyl, and the like. As used herein, the term "alkylene," alone or in combination, means a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon bonded at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" may include an "alkylene" group.

[0024] As used herein, "alkylamino," alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, and the like groups.

[0025] As used herein, "alkylthio," alone or in combination, refers to an alkyl thioether (RS-) radical, where the alkyl term is as defined herein and the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0026] As used herein, "amido" and "carbamoyl," alone or in combination, refer to an amino group, as described herein, attached to the parent molecular moiety through a carbonyl group, or vice versa. As used herein, an "amido" group includes "C-amido" and "N-amido" groups. As used herein, the term "C-amido," alone or in combination, refers to a -C(O)N(RR') group, where R and R' are as defined herein or by the specified specifically recited "R" group. In some embodiments, an "amido" group is -C(O)NH, C 1-4 Alkylamides and di(C 1-4 As used herein, "C alkyl" includes amides. 1-4 The term "alkylamide" refers to -C(O)NH(C 1-4 C 1-4Alkyl is as defined herein. As used herein, the term "N-amido," alone or in combination, refers to the group RC(O)N(R')-, where R and R' are as defined herein or by the specifically recited "R" group specified. As used herein, the term "acylamino," alone or in combination, encompasses an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CHC(O)NH-).

[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, any of which may themselves be unsubstituted or substituted. Additionally, R and R' may combine to form an unsubstituted or substituted heterocycloalkyl. An "amino" group may be a primary amine (e.g., -NH), a secondary or disubstituted amine (e.g., -NHR, where R is not hydrogen), or a tertiary or trisubstituted amine (e.g., -NRR', where neither R nor R' is hydrogen).

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

[0029] The terms "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkenyl group.

[0030] The terms "arylalkoxy" or "araloxy," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkoxy group.

[0031] The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.

[0032] The term "aryloxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxygen.

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

[0034] As used herein, "O-carbamyl," alone or in combination, refers to an --OC(O)NRR' group, with R and R' as defined herein.

[0035] As used herein, "N-carbamyl," alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0036] As used herein, "carbonyl" when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.

[0037] As used herein, "carboxyl" or "carboxy" refers to -C(O)OH or the corresponding "carboxylate" anion, e.g., as in a carboxylic acid salt. An "O-carboxy" group refers to an RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR group, where R is as defined herein.

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

[0039] As used herein, "cycloalkyl" or alternatively "carbocycle," alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, each cyclic moiety containing 3 to 12 carbon atom ring members, and may be a benzo-fused ring system, unsubstituted or substituted as defined herein. Carbocycles can include bridged and / or spirocyclic ring systems (e.g., systems containing two rings that share one carbon atom). The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In certain embodiments, the cycloalkyl (or cycloalkenyl) group contains 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like. As used herein, "bicyclic" and "tricyclic" are intended to include both fused ring systems such as decahydronaphthalene and octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated forms. Examples of the latter type of isomer are generally bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0040] As used herein, "ester," alone or in combination, refers to a carboxy group bridging two moieties joined at a carbon atom.

[0041] As used herein, "ether," alone or in combination, refers to an oxy group bridging two moieties joined at a carbon atom.

[0042] As used herein, "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0043] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0044] As used herein, "haloalkyl," alone or in combination, refers to an alkyl radical having the meaning described herein in which one or more hydrogens are replaced by halogen. Specifically included are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. By way of example, a monohaloalkyl radical can have an iodo, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0045] As used herein, "heteroalkyl," alone or in combination, refers to a stable, straight- or branched-chain hydrocarbon chain that is fully saturated or has 1 to 3 degrees of unsaturation, and consists of the specified number of carbon atoms and 1 to 3 selected heteroatoms selected from N, O, and S, where the N and S atoms may be optionally oxidized, and the N heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, for example, -CH-NH-OCH.

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

[0047] As used herein, "heterocycloalkyl" and, interchangeably, "heterocycle," alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic), monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl can contain 1 to 4 heteroatoms as ring members. In further embodiments, the heterocycloalkyl can contain 1 to 2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl can contain 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl can contain 3 to 7 ring members in each ring. In still further embodiments, the heterocycloalkyl can contain 5 to 6 ring members in each ring. Heterocycles can include bridged ring systems and / or spirocyclic systems (e.g., systems containing two rings that share one atom, such as one carbon atom). "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of a tertiary nitrogen ring member, and fused carbocyclic and benzofused ring systems; both terms also include systems in which a heterocycle is fused with an aryl group or an additional heterocyclic group as defined herein. Examples of heterocyclic groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. A heterocycle group may be unsubstituted or substituted, unless specifically prohibited.

[0048] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups joined by a single bond, ie, --NN--.

[0049] As used herein, "hydroxy," alone or in combination, refers to --OH.

[0050] The term "hydroxyalkyl," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an alkyl group.

[0051] As used herein, "iminohydroxy," alone or in combination, refers to =N(OH) and =NO-.

[0052] As used herein, "lower amino," alone or in combination, refers to --NRR', where R and R' are independently selected from hydrogen and lower alkyl, either of which is unsubstituted or substituted.

[0053] As used herein, "mercaptyl," alone or in combination, refers to an RS-group, with R as defined herein.

[0054] As used herein, "nitro," alone or in combination, refers to --NO.sub.2.

[0055] As used herein, "oxy" or "oxa," alone or in combination, refers to --O--.

[0056] As used herein, "oxo," alone or in combination, refers to =O.

[0057] "Perhaloalkoxy" refers to an alkoxy group in which all of the hydrogen atoms are replaced with halogen atoms.

[0058] As used herein, "perhaloalkyl," alone or in combination, refers to an alkyl group in which all of the hydrogen atoms are replaced with halogen atoms.

[0059] As used herein with respect to a chemical structure or portion thereof, "ring" or its equivalent "cycle" means a group in which all atoms are members of a common ring structure. The ring may be saturated or unsaturated (including aromatic) and may have 3 to 9 members, unless otherwise specified. When a ring is heterocyclic, it may contain B, N, O, S, C(O), and S(O). m wherein m is 0, 1, or 2. Unless specifically prohibited, rings are unsubstituted or substituted. Two or more rings may be fused (e.g., two or more rings may share a bond and two common atoms). Two or more rings may be linked to each other in a spiro configuration, such that only one atom is shared between the two rings. Additionally or alternatively, two or more rings may be configured in a bridged configuration, such that three or more atoms are shared between the two or more rings.

[0060] As used herein, "sulfonate," "sulfonic acid," and "sulfonic" alone or in combination refer to the -SO3H group and its anion when sulfonic acid is used in salt formation.

[0061] As used herein, "sulfanyl," alone or in combination, refers to --S--.

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

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

[0064] "N-sulfonamido" refers to an RS(=O)2NR'- group, where R and R' are as defined herein.

[0065] "S-sulfonamido" refers to a -S(=O)2NRR'- group, where R and R' are as defined herein.

[0066] As used herein, "tautomer" refers to one of two or more isomers that rapidly interconvert, alone or in combination. Generally, this interconversion is rapid enough that individual tautomers cannot be isolated in the absence of other tautomers. The ratio of the amounts of tautomers can depend on solvent composition, ionic strength, pH, and other solution parameters. The ratio of the amounts of tautomers can vary in a particular solution and in the microenvironment of a biomolecule binding site within that solution. Examples of tautomers known in the art include keto / enol, enamine / imine, and lactam / lactim tautomers. Examples of tautomers known in the art also include 2-hydroxypyridine / 2(1H)-pyridone and 2-aminopyridine / 2(1H)-iminopyridone tautomers.

[0067] As used herein, "thia" and "thio," alone or in combination, refer to an -S- group or ether where the oxygen is replaced by sulfur. The oxidized derivatives of the thio group, i.e., sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0068] As used herein, "thiol," alone or in combination, refers to a --SH group.

[0069] As used herein, "thiocarbonyl" when alone includes thioformyl-C(S)H and in combination is a -C(S)- group.

[0070] "N-thiocarbamyl" refers to an ROC(S)NR'- group, with R and R' as defined herein.

[0071] "O-thiocarbamyl" refers to an --OC(S)NRR' group, with R and R' as defined herein.

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

[0073] Any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, the last element of such a definition is the element that is attached to the parent moiety. For example, the composite group alkylamido represents an alkyl group attached to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule via an alkyl group.

[0074] As described herein, groups can be substituted or unsubstituted (e.g., "optionally substituted"). Unless otherwise specified, any group can be substituted with one or more substituents, such as one or more of the substituents provided herein. Examples of substituents with which groups may be substituted include, but are not limited to, one or more substituents, alone or in combination, independently selected from the following groups or the set of specifically named groups: alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), alkanoyl (e.g., C 1-20 Alkanoyl, e.g., C 1-10 Alkanoyl, e.g., C 1-6 alkanoyl), heteroalkyl (e.g., heteroalkyl moieties containing 1 to 20 carbon atoms and 1 to 6 heteroatoms, e.g., heteroalkyl moieties containing 1 to 6 carbon atoms and 1 to 3 heteroatoms), haloalkyl (e.g., halo-substituted C 1-20 Alkyl, e.g., halo-substituted C 1-10 Alkyl, halo-substituted C 1-6 alkyl), haloalkenyl (e.g., halo-substituted C 2-20 Alkenyl, e.g., halo-substituted C 2-6alkenyl), haloalkynyl (e.g., halo-substituted C 2-20 Alkynyl, e.g., halo-substituted C 2-6 alkynyl), perhaloalkyl (e.g., C 1-20 Perhaloalkyl, e.g., C 1-6 Perhaloalkyl, e.g., C 1-3 perhaloalkyl), perhaloalkoxy (e.g., C 1-20 Perhaloalkoxy, e.g., C 1-6 perhaloalkoxy), phenyl, aryl (e.g., C 5-20 Aryl, e.g., C 5-10 Aryl, e.g., C 5-6 aryl), aryloxy (e.g., C 5-20 Aryloxy, e.g., C 5-10 Aryloxy, e.g., C 5-6 aryloxy), alkoxy (e.g., C 1-20 Alkoxy, e.g., C 1-10 Alkoxy, e.g., C 1-6 alkoxy), haloalkoxy (e.g., C 1-20 Haloalkoxy, e.g., C 1-10 Haloalkoxy, e.g., C 1-6 haloalkoxy), oxo, acyloxy (e.g., an acyloxy group containing 1 to 20 carbon atoms, e.g., 1 to 10 carbon atoms, e.g., 1 to 6 carbon atoms), carbonyl (e.g., C(O) or C=O), carboxyl (e.g., C(O)O), alkylcarbonyl (e.g., C 1-20 Alkylcarbonyl, e.g., C 1-10 Alkylcarbonyl, e.g., C 1-6 Alkylcarbonyl, e.g., C 1-3 alkylcarbonyl), carboxy ester (e.g., C(O)OR, where R is, for example, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), carboxamido, cyano (e.g., CN), hydrogen, halogen (e.g., iodine, bromine, chlorine, fluorine), hydroxy, amino (e.g., NR'R", where R' and R" are independently, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), alkylamino (e.g., NR'R", where R' is alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), and R" is, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), arylamino (e.g., NR'R", where R' is aryl (e.g., C 5-20 Aryl, e.g., C 5-10Aryl, e.g., C 5-6 aryl), and R" is, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), amido (e.g., C(O)NR'R", where R' and R" are independently, for example, hydrogen, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), nitro (e.g., NO), thiol (e.g., SH), alkylthio (e.g., C substituted with a thiol group). 1-20 Alkyl, e.g., C substituted with a thiol group 1-10 Alkyl, e.g., C substituted with a thiol group 1-6 Alkyl, e.g., C substituted with a thiol group 1-3 alkyl), haloalkylthio (e.g., C 1-20 Haloalkylthio, e.g., C 1-10 Haloalkylthio, e.g., C 1-6 Haloalkylthio, e.g., C 1-3 haloalkylthio), perhaloalkylthio (e.g., C 1-20Perhaloalkylthio, e.g., C 1-10 Perhaloalkylthio, e.g., C 1-6 Perhaloalkylthio, e.g., C 1-3 perhaloalkylthio), arylthiols (e.g., C 5-20 Aryl thiols, such as C 5-10 Aryl thiols, such as C 5-6 arylthiol), sulfonate (e.g., S(O)OR, where R is, for example, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6 alkynyl), any of which may be substituted with any group provided herein), sulfonic acid (e.g., S(O)OH), trisubstituted silyl (e.g., SiR'R"R*, e.g., R', R", and R* are independently, for example, alkyl (e.g., C 1-20 Alkyl, e.g., C 1-10 Alkyl, e.g., C 1-6 Alkyl, e.g., C 1-3 alkyl), alkenyl (e.g., C 2-20 Alkenyl, e.g., C 2-10 Alkenyl, e.g., C 2-6 alkenyl), or alkynyl (e.g., C 2-20 Alkynyl, e.g., C 2-10 Alkynyl, e.g., C 2-6The silyl groups are selected from alkyl, alkynyl, aryl, arylsulfonyl ... Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents for a particular moiety can be defined as needed, and in such cases, the optional substitution is as defined, often immediately following the phrase "unsubstituted or substituted."

[0075] Terms such as R, R', R", R*, etc., appearing alone and without a numerical designation, unless otherwise defined, refer to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which are unsubstituted or substituted (e.g., as described herein). Such R and R' groups should be understood as being unsubstituted or substituted as defined herein. Regardless of whether the R group has a numerical designation, R, R', R nAll R groups, including n=(1, 2, 3, ... n), all substituents, and all terms, including n=(1, 2, 3, ... n), should be understood as being independent of each other with respect to selection from a group. When any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or generic structure, its definition at each occurrence is independent of its definition at every other occurrence. Those skilled in the art will further recognize that certain groups may be attached to the parent molecule from either end or occupy a given position in the element chain as depicted. For example, an unsymmetrical group such as -C(O)N(R)- can be attached to the parent moiety at either the carbon or the nitrogen.

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

[0077] Asymmetric centers may exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It is understood that the present disclosure encompasses all stereochemical isomers, including diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as d- and l-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be prepared by synthesis from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomeric products followed by separation, for example, by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Starting compounds of particular stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Furthermore, the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof. Additionally, compounds may exist as tautomers, and all tautomers are provided by the present disclosure. Furthermore, compounds provided herein may include conformational isomers, where the compounds contain groups that can orient in different conformations relative to another moiety. Furthermore, the compounds disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. In general, solvated forms are considered equivalent to unsolvated forms.

[0078] "Combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents substantially simultaneously, e.g., in a single dosage unit (e.g., capsule) having a fixed ratio of active ingredients, or in multiple separate dosage units (e.g., capsules) for each active ingredient. Furthermore, such administration also includes the sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0079] A "KRAS inhibitor" has an IC of about 100 μM or less, more typically about 50 μM or less, with respect to KRAS activity, as measured by assays generally described herein, such as a matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS) assay and / or the level of covalent modification with Cys12 in KRAS G12C, as measured using a KRAS G12C protein-effector protein interaction disruption assay. 50 "IC" is used herein to refer to compounds that exhibit 50 " is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., KRAS) to half of its maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibitory activity against KRAS. In certain embodiments, a compound has an IC of about 50 μM or less against KRAS (e.g., KRAS with a G12C mutation) as measured in the KRAS assay described herein. 50 and in a further embodiment, the compound exhibits an IC of about 10 μM or less against KRAS (e.g., KRAS with a G12C mutation). 50 and in still further embodiments, the compound exhibits an IC of about 1 μM or less against KRAS (e.g., KRAS with a G12C mutation). 50 and in still further embodiments, the compound has an IC of about 200 nanomolar (nM) or less against KRAS (e.g., KRAS with a G12C mutation). 50In some embodiments, the compound exhibits an IC of less than about 50 μM, e.g., less than about 40 μM, 30 μM, 20 μM, 10 μM, 9 μM, 8 μM, 7 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2 μM, 1 μM, 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or less, against KRAS (e.g., KRAS having a G12C mutation). 50 In certain embodiments, the compound exhibits an IC of less than about 1 μM, e.g., less than about 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, or less, against KRAS (e.g., KRAS with a G12C mutation). 50In some embodiments, the KRAS inhibitors have inhibitory activity against KRAS with a G12C mutation that exceeds the inhibitory activity against KRAS with another mutation, such as a G12D, G12R, G12S, G12A, or G12V mutation. For example, in some embodiments, the KRAS inhibitors provided herein have at least 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, or more inhibitory activity against KRAS with a G12C mutation compared to KRAS with another mutation, such as a G12D, G12R, G12S, G12A, or G12V mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against KRAS with a G12C mutation than against KRAS with a G12D mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against KRAS with a G12C mutation than against KRAS with a G12R mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12S mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12A mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against KRAS having a G12C mutation than against KRAS having a G12V mutation. In some embodiments, the KRAS inhibitors provided herein have greater inhibitory activity against active KRAS having a G12C mutation ("GTP-bound") than against inactive ("GDP-bound") KRAS having a G12C mutation. In some embodiments, the KRAS inhibitors provided herein have less inhibitory activity against active KRAS having a G12C mutation ("GTP-bound") than against inactive ("GDP-bound") KRAS having a G12C mutation. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against both active ("GTP-bound") and inactive ("GDP-bound") KRAS with a G12C mutation.In some embodiments, the KRAS inhibitors provided herein have similar inhibitory activity against active ("GTP-bound") and inactive ("GDP-bound") KRAS with a G12C mutation. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against the K-RAS4a splice variant. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against the K-RAS4b splice variant. In some embodiments, the KRAS inhibitors provided herein have inhibitory activity against both the K-RAS4a and K-RAS4b splice variants.

[0080] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a specified disease, disorder, or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, 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, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0081] The term "therapeutically acceptable" refers to a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient, that is free from excessive toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use.

[0082] "Treate," "treating," and "treatment" refer to any indicator of success in treating or ameliorating an injury, pathology, disease, disorder, or condition, including any objective or subjective parameter, such as remission, remission, relief of symptoms, or making the injury, pathology, disease, disorder, or condition more tolerable to the patient, slowing the rate of degeneration or decline, reducing the ultimate point of degeneration, and / or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. Treatment may be preemptive in nature, i.e., can include prevention of the disease, disorder, or condition, prevention of the onset of one or more symptoms of the disease, disorder, or condition, and / or prevention of the worsening of the disease, disorder, or condition. Prevention of a disease, disorder, or condition can include complete protection from the disease and / or prevention of the progression of the disease (e.g., to a later stage of the disease, disorder, or condition). For example, preventing a disease may mean preventing the symptoms of a disease, disorder, or condition to a clinically significant or detectable level, rather than completely eliminating all effects associated with the disease at all levels.

[0083] "Patient" or "subject" refers to a living organism suffering from or likely to suffer from a disease, disorder, or condition treatable by administration of a compound or pharmaceutical composition provided herein. Non-limiting examples include humans, rats, mice, rabbits, hamsters, guinea pigs, hamsters, cats, dogs, non-human primates (e.g., monkeys), goats, pigs, sheep, cows, deer, horses, and other non-mammalian animals. Examples of mammals that can be treated by administering a compound or pharmaceutical composition provided herein include, for example, rodents (e.g., rats, mice, squirrels, guinea pigs, hamsters, etc.), lagomorphs (e.g., rabbits, hares, etc.), primates (e.g., monkeys, apes, etc.), bovine species (e.g., cattle), ungulates (e.g., horses), ungulates (e.g., bovine species such as cattle, ovine species such as sheep, caprine species such as goats, porcine species such as pigs, etc.), and marsupials (e.g., kangaroos, wallabies, wallaroos, sugar gliders, etc.). In some embodiments, the patient or subject is a human. In some embodiments, the patient or subject is a companion animal such as a cat or dog. In some embodiments, the patient or subject is a livestock animal such as a goat, sheep, cow, pig, or horse. In some embodiments, the patient or subject is a primate (e.g., monkey), marsupial (e.g., kangaroo, wallaby, wallaroo, sugar glider, etc.), or exotic animal such as a non-domesticated or hybrid cat or dog.

[0084] As used herein, "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0085] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of and absorption by a subject of an active agent. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are also useful in the present disclosure.

[0086] The term "prodrug" refers to a compound that is more active in vivo. Certain compounds disclosed herein may also exist as prodrugs. Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to yield the compounds. Furthermore, prodrugs can be converted to the compounds by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound or parent drug. For example, a prodrug may be bioavailable by oral administration even when the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0087] The compounds disclosed herein can exist as therapeutically acceptable salts (also referred to herein as "pharmaceutically acceptable salts"). The present disclosure includes compounds provided herein in the form of salts, including acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts are usually pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the compound in question. Base addition salts are also formed and are pharmaceutically acceptable.

[0088] As used herein, the terms "therapeutically acceptable salt" and "pharmaceutically acceptable salt" refer to water- or oil-soluble or dispersible, therapeutically acceptable salts or zwitterionic forms of the compounds disclosed herein, as defined herein. Salts can be prepared during the final isolation and purification of the compounds, or separately by reacting a suitable compound in its free base form with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, and malonate. Salts include, but are not limited to, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate), and undecanoate. In addition, the basic group of the compounds disclosed herein can be quaternized with, for example, methyl chloride, bromide, and iodide, ethyl chloride, bromide, and iodide, propyl chloride, bromide, and iodide, and butyl chloride, bromide, and iodide; dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; decyl chloride, bromide, and iodide, lauryl chloride, bromide, and iodide, myristyl chloride, bromide, and iodide, and steryl chloride, bromide, and iodide; and benzyl bromide and phenylethyl bromide. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.Salts can also be formed by coordination of the compounds with alkali metal or alkaline earth ions. Thus, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0089] Base addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine catylamine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

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

[0091] "KRAS G12C-positive cancer" refers to cancer characterized by the KRAS G12C mutation.

[0092] As used herein, a "combined therapeutically effective amount" refers to amounts of therapeutic agents that, when administered separately (chronologically staggered, especially sequentially) to a warm-blooded animal, especially a human being, exhibit an (additive, but preferably synergistic) interaction (combined therapeutic effect). Whether this is the case can be determined, inter alia, by following blood levels indicating that both compounds are present in the blood of the human being for at least a specified time interval.

[0093] As used herein, "synergistic effect" refers to the effect of at least two therapeutic agents, a KRAS G12C inhibitor as defined herein, and an additional agent, which may be an agent configured to treat a disease, disorder, or condition, or a symptom thereof. The effect may be, for example, slowing the progression of a symptom of a proliferative disease, such as cancer, particularly lung cancer, or a symptom thereof. Similarly, a "synergistically effective amount" refers to the amount required to achieve a synergistic effect.

[0094] "A," "an," or "a(n)," when used herein with respect to a group of substituents or "substituents," means at least one. For example, when a compound is substituted with "an" alkyl or aryl, the compound is unsubstituted or substituted with at least one alkyl and / or at least one aryl, where each alkyl and / or aryl is optionally different. In another example, when a compound is substituted with "a" substituents, the compound is substituted with at least one substituent, where each substituent is optionally different.

[0095] compound In one aspect, the present disclosure provides a compound represented by formula IA: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] and -OR 8 is selected from R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl is unsubstituted or has one or more R 13 is replaced by R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring; R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 6 But there is one or more R 15is a bicyclic heteroaryl substituted with R 7 But halogen, -OR 12 , —CN, and H; R 8 However, H and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 15 are independently halogen, -N(R 12 )2, -N(R 12 )C(O)(C 1-6 alkyl), -CN, -OR 12 , and C 1-6alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each E, independently, [ka] and -CN; R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R c But halogen, C 1-6 alkyl, and H; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0096] In some embodiments, the disclosure provides a compound of formula IA, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0097] In some embodiments, R 1 -OR 8 is.

[0098] In some embodiments, R 8 is H. In some embodiments, R 8 is C 1-6 alkyl and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R 8 is the unsubstituted C 1-6 It is alkyl.

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

[0100] In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R bis halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0101] In some embodiments, R 1 teeth, [ka] is selected from.

[0102] In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0103] In some embodiments, R 1 teeth, [ka] is selected from.

[0104] In some embodiments, R 1 is OH. In some embodiments, R 8 is -OCH3, -OCH2CH3, -OCH2CH2OH, or -OCH2CH2OCH3.

[0105] In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some such embodiments, each R 13 are independently -OR 22 (e.g., —OH) and —CN. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is C 1-2 In some embodiments, R 2 is selected from —CH, —CHCH, —CHCHOH, —CHCHCN, and —CH(CH). 2 is selected from 3- to 6-membered carbocyclic rings. 2 is cyclopropyl.

[0106] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R 12 )(E). In some embodiments, R 3 is a C2 alkyl substituted with -N(H)(E).

[0107] In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine has one or more E and one to two R 10 is replaced by R 10 But C 1-6 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is the unsubstituted C 1-6 It is alkyl (eg, methyl).

[0108] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally, two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally forming a piperazinyl ring substituted with two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E's and one or two R's, together with the atoms to which they are attached. 11 forming a piperazinyl ring substituted with R 11 is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 and optionally, two R g The groups, together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0109] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0110] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0111] In some embodiments, each R g is H.

[0112] In some embodiments, R 4 is H.

[0113] In some embodiments, R 5 is H.

[0114] In some embodiments, R 5 is -CN.

[0115] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0116] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0117] In some embodiments, R 5 -OR 12 Selected from R 12 is C 1-6 alkyl and H. In some embodiments, R 5 is -OCH3.

[0118] In some embodiments, R 5 is selected from 3- to 6-membered carbocycle, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocycle, and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is selected from 3- to 6-membered carbocyclic rings and 3- to 6-membered heterocyclic rings, and any carbocyclic or heterocyclic ring is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 (e.g., one or more —CN). In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R is a 5- to 6-membered heteroaryl or phenyl substituted with alkyl. 5 is pyridyl, furanyl, or imidazolyl, each of which is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R 5 is furanyl. In some embodiments, R 5 is phenyl.

[0119] In some embodiments, R 6 may independently be one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur substituted with 6 may independently be one or more R 15 In some such embodiments, at least one R 15 is -N(R 12 )2 (e.g., —NH2). In some embodiments, at least one R 15 is halogen (e.g., F). In some embodiments, each R 15 are independently selected from halogen, -CN, and -N(R 12 In some embodiments, R 6 is at least two R 15 (e.g., at least halogen and -NH2).

[0120] In some embodiments, R 6 has the following structure: [ka] wherein X is selected from N and C-CN, Y is selected from O and S, and R 23 is -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 22 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R13 is replaced by

[0121] In some embodiments, R 6 teeth, [ka] is selected from Any of them has one or more R 15 is replaced by

[0122] In some embodiments, R 6 teeth, [ka] is selected from.

[0123] In some embodiments, R 6 teeth, [ka] is selected from.

[0124] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] is.

[0125] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0126] In some embodiments, R 7 -OR 12 In some embodiments, R 7-OR 12 and R 12 is C 1-6 It is alkyl.

[0127] In some embodiments, R 7 is -CN.

[0128] In some embodiments, R 7 is H.

[0129] In some embodiments, each E is independently: [ka] is selected from.

[0130] In some embodiments, each E is [ka] is. In some embodiments, each R d and R e is H. In some embodiments, the compound has a single E.

[0131] In some embodiments, R 4 is H and R 7 is a halogen and R 1 is OH. In some embodiments, R 7 is F. In some embodiments, R 5 is H. In some embodiments, R 5 is -CF3.

[0132] In some embodiments, R 4 is H and R 7 is a halogen (e.g., F), and R 1 teeth, [ka] is selected from. In some embodiments, Ra and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from. In some embodiments, R 1 teeth, [ka] is selected from. In some embodiments, R7 is F. In some embodiments, R 5 is H. In some embodiments, R 5 is -CF3. In some embodiments, R 5 is Cl.

[0133] In some embodiments, R 4 is H and R 7 is a halogen and R 1 teeth, [ka] is selected from. In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from. In some embodiments, R 7 is F. In some embodiments, R 5 is H. In some embodiments, R 5 is -CF3.

[0134] In some embodiments, the present disclosure provides a compound represented by formula IA1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] is selected from R 2 is unsubstituted or contains one or more R 13 C replaced by 1-6 is alkyl, R 3But one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR 12 , —CN, and H; Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each E, independently, [ka] and -CN; R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 alkyl and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0135] In some embodiments, the disclosure provides a compound of formula IA1, or a salt thereof (eg, a pharmaceutically acceptable salt):

[0136] In some embodiments of the compound of formula IA1, R 2 is C 1-2 In some embodiments, R 2 is methyl.

[0137] In some embodiments of the compound of formula IA1, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E;g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is the unsubstituted C 1-6 It is alkyl (eg, methyl).

[0138] In some embodiments, the present disclosure provides a compound represented by formula IA2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] is selected from R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR 12 , —CN, and H; Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 20 Independently, -OH, -OC1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each E, independently, [ka] and -CN; R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 alkyl and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25, and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0139] In some embodiments, the disclosure provides a compound of formula IA2, or a salt thereof (eg, a pharmaceutically acceptable salt):

[0140] In some embodiments of the compound of formula IA2, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally, two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally forming a piperazinyl ring substituted with two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 and optionally, two Rg The groups, together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0141] In some embodiments of the compound of formula IA1 or IA2, R 1 teeth, [ka] In the formula, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0142] In some embodiments of the compound of formula IA1 or IA2, R 5 is C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is -CN or C substituted with one or more halogens 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is phenyl. In some embodiments, R 5is furanyl. In some embodiments, R 5 is H. In some embodiments, R 5 is a halogen (e.g., F or Cl).

[0143] In some embodiments of the compound of formula IA1 or IA2, R 7 is halogen (e.g., F). In some embodiments, R 7 is -CN. In some embodiments, R 7 is H.

[0144] In some embodiments of the compound of formula IA1 or IA2, X is N and Y is O. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S. In some embodiments, R 23 is -NH. In some embodiments, R 24 is F. In some embodiments, R 25 and R 26 is H. In some embodiments, [ka] teeth, [ka] is selected from.

[0145] In some embodiments of the compound of formula IA1 or IA2, [ka] In some embodiments, [ka] is.

[0146] In some embodiments of the compound of formula IA1 or IA2, each E is [ka] is. In some embodiments, each R d and R e is H. In some embodiments, the compound has a single E.

[0147] In some embodiments of the compound of formula IA1 or IA2, R 7 is H and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is -CF3. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is S.

[0148] In some embodiments of the compound of formula IA1 or IA2, R 7 is a halogen and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 7 is F. In some embodiments, R 5 is -CF3. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is S.

[0149] In some embodiments of the compound of formula IA1 or IA2, R 7 is a halogen and R 5 is H. In some embodiments, R 7 is F. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0150] In some embodiments of the compound of formula IA1 or IA2, R 7 is a halogen and R5 is halogen. In some embodiments, R 7 is F. In some embodiments, R 5 In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0151] In another aspect, the present disclosure provides a compound represented by formula IB: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by A, [ka] is selected from R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 6 But there is one or more R 15 is a bicyclic heteroaryl substituted with R 7 But halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 15 are independently halogen, -N(R 12 )2, -CN, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R g But independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6is selected from alkyl and H.

[0152] In some embodiments, the disclosure provides a compound of formula IB, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0153] In some embodiments, A is [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, A is substituted with [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H.

[0154] In some embodiments, A is [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, A is substituted with [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H.

[0155] In some embodiments, R 1 -OR 8 Selected from R 8 is selected from heterocycle and alkylheterocycle, any heterocycle containing 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is C 1-6 In some embodiments, R 8 is a heterocycle or alkylheterocycle, any heterocycle containing 4 to 8 members and containing one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a and / or R bIn some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and / or R b and one or more R a and / or R b is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and / or R b and one or more R a and / or R b is C 1-6 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and / or R b and one or more R a and / or R b -OR 12 (e.g., -OCH3).

[0156] In some embodiments, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R ais unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0157] In some embodiments, R 1 teeth, [ka] is selected from.

[0158] In some embodiments, R 1 teeth, [ka] is selected from.

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

[0160] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

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

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

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

[0164] In some embodiments, R 4 is H.

[0165] In some embodiments, R 5 is H.

[0166] In some embodiments, R 5 is -CN.

[0167] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0168] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0169] In some embodiments, R 5 -OR 12 Selected from R 12 is C 1-6 alkyl and H. In some embodiments, R 5 is -OCH3.

[0170] In some embodiments, R 5is selected from 3- to 6-membered carbocycle, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocycle, and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is selected from 3- to 6-membered carbocyclic rings and 3- to 6-membered heterocyclic rings, and any carbocyclic or heterocyclic ring is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 (e.g., one or more —CN). In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R is a 5- to 6-membered heteroaryl or phenyl substituted with alkyl. 5 is pyridyl, furanyl, or imidazolyl, each of which is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R 5 is furanyl. In some embodiments, R 5 is phenyl.

[0171] In some embodiments, R 6 may independently be one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur substituted with 6 may independently be one or more R 15 In some such embodiments, at least one R 15 is -N(R 12)2 (e.g., —NH2). In some embodiments, at least one R 15 is halogen (e.g., F). In some embodiments, each R 15 are independently selected from halogen, -CN, and -N(R 12 In some embodiments, R 6 is at least two R 15 (e.g., at least halogen and -NH2).

[0172] In some embodiments, R 6 has the following structure: [ka] wherein X is selected from N and C-CN, Y is selected from O and S, and R 23 is -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 22 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0173] In some embodiments, R 6 teeth, [ka] is selected from Any of them has one or more R 15 is replaced by

[0174] In some embodiments, R 6 teeth, [ka] is selected from.

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

[0176] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] is.

[0177] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F.

[0178] In some embodiments, R 7 -OR 12 In some embodiments, R 7 -OR 12 and R 12 is C 1-6 It is alkyl.

[0179] In some embodiments, R 7 is -CN.

[0180] In some embodiments, R 7 is H.

[0181] In some embodiments, each E is independently: [ka] is selected from.

[0182] In some embodiments, each E is [ka] is.

[0183] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0184] In some embodiments, R 4 is H and R 7 is a halogen and A is [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, A is substituted with [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, R 7 is F.

[0185] In some embodiments, R 4 is H and R 7 is a halogen and A is [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, A is substituted with [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, R 7 is F.

[0186] In another aspect, the present disclosure provides a compound according to formula IC: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 6 But there is one or more R 15 is a bicyclic heteroaryl substituted with R 7 But halogen, -OR x , —CN, and H; R 8 But C 1-6 and alkyl, heterocyclic, and alkylheterocyclic, any heterocyclic ring containing 4 to 8 members and unsubstituted or containing one or more R a and / or R b is replaced by R 8 Any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 15 are independently halogen, -N(R 12 )2, -OR 12 , -CN, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0187] In some embodiments, the disclosure provides a compound of formula IC, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0188] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R 2is unsubstituted or contains one or more R 13 C replaced by 1-6 In some such embodiments, each R 13 are independently -OR 22 (e.g., —OH) and —CN. In some embodiments, R 2 is methyl. In some embodiments, R 2 is selected from —CH3, —CH2CH3, —CH2CH2OH, —CH2CH2CN, and —CH(CH3)2.

[0189] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R 12 )(E). In some embodiments, R 3 is a C2 alkyl substituted with -N(H)(E).

[0190] In some embodiments, R 3 is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is selected from 4-6 membered heterocycles, the heterocycle containing a single heteroatom which is N, the heterocycle containing one or more E and 0-4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3is selected from 4-6 membered heterocycles, the heterocycle containing a single heteroatom which is N, the heterocycle containing one or more E and 0-4 R 10 In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine has one or more E and one to two R 10 is replaced by R 10 But C 1-6 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0191] In some embodiments, R 1 is H.

[0192] In some embodiments, R 1 -OR 8 Selected from R 8 is selected from heterocycle and alkylheterocycle, any heterocycle containing 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is C 1-6 In some embodiments, R 8is a heterocycle or alkylheterocycle, any heterocycle containing 4 to 8 members and containing one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a and / or R b In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and / or R b and one or more R a and / or R b is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and / or R b and one or more R a and / or R b is C 1-6 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and / or R b and one or more R a and / or R b -OR 12 (e.g., -OCH3).

[0193] In some embodiments, R 1 teeth, [ka] In the formula, R a and R b are each independently a halogen, -OR 12 and H. In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0194] In some embodiments, R 1 teeth, [ka] is selected from.

[0195] In some embodiments, R 1 teeth, [ka] In the formula, each R a are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0196] In some embodiments, R 1 teeth, [ka] is selected from.

[0197] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H. In some embodiments, one or more R a and / or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0198] In some embodiments, R 1 teeth, [ka] is selected from.

[0199] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is.

[0200] In some embodiments, R 4 is H. In some embodiments, R 4 is -OCH3.

[0201] In some embodiments, R 5 is H.

[0202] In some embodiments, R 5 is -CN.

[0203] In some embodiments, R 5 is halogen. In some embodiments, R 5 is F. In some embodiments, R 5 is Cl.

[0204] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0205] In some embodiments, R 5 -OR 12 Selected from R 12 is C 1-6 alkyl and H. In some embodiments, R 5 is -OCH3.

[0206] In some embodiments, R 5 is selected from a 3- to 6-membered heterocycle, a 5- to 6-membered heteroaryl, a phenyl, and a 3- to 6-membered carbocycle, and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is selected from a 3- to 6-membered heterocycle and a 3- to 6-membered carbocycle, and any carbocycle or heterocycle is unsubstituted or contains one or more R 14 In some embodiments, R 5is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 (e.g., one or more —CN). In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R is a 5- to 6-membered heteroaryl or phenyl substituted with alkyl. 5 is pyridyl, furanyl, or imidazolyl, each of which is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R 5 is furanyl. In some embodiments, R 5 is phenyl.

[0207] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0208] In some embodiments, R 7 -OR x In some embodiments, R 7 -OR x and R x is C 1-6 In some embodiments, R 7 is -OH.

[0209] In some embodiments, R 7 is -CN.

[0210] In some embodiments, R 7 is H.

[0211] In some embodiments, R 7teeth, [ka] is.

[0212] In some embodiments, R 6 may independently be one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur substituted with 6 may independently be one or more R 15 In some such embodiments, at least one R 15 is -N(R 12 )2 (e.g., —NH2). In some embodiments, at least one R 15 is halogen (e.g., F). In some embodiments, each R 15 are independently selected from halogen, -CN, and -N(R 12 In some embodiments, R 6 is at least two R 15 (e.g., at least halogen and -NH2).

[0213] In some embodiments, R 6 has the following structure: [ka] wherein X is selected from N and C-CN, Y is selected from O and S, and R 23 is -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 22 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0214] In some embodiments, R 6 teeth, [ka] is selected from Any of them has one or more R 15 is replaced by

[0215] In some embodiments, R 6 teeth, [ka] is selected from.

[0216] In some embodiments, R 6 teeth, [ka] is selected from.

[0217] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] is.

[0218] In some embodiments, each E is independently: [ka] is selected from.

[0219] In some embodiments, each E is [ka] is.

[0220] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0221] In some embodiments, R 4 is H and R 7 is a halogen and R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R 12 )(E). In some embodiments, R 3 is a C alkyl substituted with —N(H)(E). In some embodiments, R 7 is F. In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is methyl.

[0222] In some embodiments, R 4 is H and R 7 is a halogen and R 3 is selected from 4-6 membered heterocycles, the heterocycle containing a single heteroatom which is N, the heterocycle containing one or more E and 0-4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 In some embodiments, R 7 is F. In some embodiments, R 2 is H. In some embodiments, R 2 is C1-6 In some embodiments, R 2 is methyl.

[0223] In some embodiments, the compound is a compound according to formula IC1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 and R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 3 But one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR x , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more Ra and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0224] In some embodiments, the disclosure provides a compound of formula IC1, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0225] In some embodiments of the compound of formula IC1, R 2 is C 1-2 In some embodiments, R 2 is methyl.

[0226] In some embodiments of the compound of formula IC1, R 3is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one Rg is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl.

[0227] In some embodiments, the compound is a compound according to formula IC2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 and R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR x , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 12But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 alkyl and H; Each R g But independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by

[0228] In some embodiments, the disclosure provides a compound of formula IC2, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0229] In some embodiments, the compound is a compound according to formula IC3, IC4, or IC5, [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 and R 2 But H, C 1-6alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR x , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R x But independently, C 1-6selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R fBut independently, C 1-6 alkyl and H; Each R g But independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by

[0230] In some embodiments, the disclosure provides a compound of formula IC3, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the disclosure provides a compound of formula IC4, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the disclosure provides a compound of formula IC5, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0231] In some embodiments, the compound is a compound according to formula IC6: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 3 But one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR x , —CN, and H; Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 , a 3- to 6-membered carbocyclic ring, and H; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0232] In some embodiments, the disclosure provides a compound of formula IC6, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0233] In some embodiments of the compound of formula IC6, R a is halogen. In some embodiments, R ais F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of is methyl.

[0234] In some embodiments of the compound of formula IC6, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl.

[0235] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 2 is C 1-2 In some embodiments, R 2 is methyl. In some embodiments, R 2 is methyl.

[0236] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0237] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 5 is C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is -CN or C substituted with one or more halogens 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is phenyl. In some embodiments, R 5 is furanyl. In some embodiments, R 5 is H. In some embodiments, R 5 is a halogen (e.g., F or Cl).

[0238] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 7 is halogen (e.g., F). In some embodiments, R 7 is -CN. In some embodiments, R 7 is H.

[0239] In some embodiments of a compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, X is N and Y is O. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S. In some embodiments, R 23 is -NH. In some embodiments, R 24is F. In some embodiments, R 25 and R 26 is H. In some embodiments, [ka] is selected from.

[0240] In some embodiments of a compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, [ka] In some embodiments, [ka] is.

[0241] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, each E is [ka] is. In some embodiments, each R d and R e is H. In some embodiments, the compound has a single E.

[0242] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 7 is H and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is -CF3. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is S.

[0243] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 7is a halogen and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 7 is F. In some embodiments, R 5 is -CF3. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is S.

[0244] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 7 is a halogen and R 5 is H. In some embodiments, R 7 is F. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0245] In some embodiments of the compound of formula IC1, IC2, IC3, IC4, IC5, or IC6, R 7 is a halogen and R 5 is halogen. In some embodiments, R 7 is F. In some embodiments, R 5 In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0246] In another aspect, the present disclosure provides a compound according to formula ID: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl is unsubstituted or has one or more R 13 is replaced by R 3 is a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 But -CN, C 2-6 Alkynyl, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 6 But there is one or more R 15 is a bicyclic heteroaryl substituted with R 7 But halogen, -OR x, —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 15 are independently halogen, -N(R 12 )2, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , -CN, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a are independently halogens, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0247] In some embodiments, the disclosure provides a compound of formula ID, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0248] In some embodiments, R 5 is -CN.

[0249] In some embodiments, R 5 is C 2-6 In some embodiments, R is selected from alkynyl. 5 is a C2 alkynyl.

[0250] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is replaced by -CN 1-6 In some embodiments, R 5 is -CN and one or more R 13 C replaced by 1-6 In some embodiments, R 5 is -CN and one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is —CHCN. In some embodiments, R 5 is C substituted with one or more halogens 1-6 In some embodiments, R 5 is -CF3.

[0251] In some embodiments, R 5 is unsubstituted or contains one or more R14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 5- to 6-membered heterocycle or heteroaryl substituted with 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0252] In some embodiments, R 5 teeth, [ka] is.

[0253] In some embodiments, R 1 is H.

[0254] In some embodiments, R 1 -OR 8 Selected from R 8 is selected from heterocycle and alkylheterocycle, any heterocycle containing 4 to 8 members and is unsubstituted or contains one or more R a and the alkyl portion of any alkyl heterocycle is C 1-6 In some embodiments, R 8 is a heterocycle or alkylheterocycle, any heterocycle containing 4 to 8 members and containing one or more R a In some embodiments, R 8 is unsubstituted or contains one or more R a In some embodiments, R 8 is unsubstituted or contains one or more R a In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and one or more R a is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and one or more R a is C 1-6 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and one or more R a -OR 12 (e.g., -OCH3).

[0255] In some embodiments, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, -OR 12 and H. In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl.1 teeth, [ka] is selected from.

[0256] In some embodiments, R 1 teeth, [ka] is selected from.

[0257] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0258] In some embodiments, R 1 teeth, [ka] is selected from.

[0259] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0260] In some embodiments, R1 teeth, [ka] is selected from.

[0261] In some embodiments, R 1 teeth, [ka] is selected from.

[0262] In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some such embodiments, each R 13 are independently -OR 22 (e.g., —OH) and —CN. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is selected from —CH, —CHCH, —CHCHOH, —CHCHCN, and —CH(CH). 2 is selected from 3- to 6-membered carbocyclic rings.

[0263] In some embodiments, R 3 is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 and optionally, two R 10 In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0264] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally, two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0265] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

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

[0267] In some embodiments, R 6 may independently be one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur substituted with 6 may independently be one or more R 15 In some such embodiments, at least one R 15 is -N(R 12 )2 (e.g., —NH2). In some embodiments, at least one R 15 is halogen (e.g., F). In some embodiments, each R 15 are independently selected from halogen, -CN, and -N(R 12 In some embodiments, R 6 is at least two R 15(e.g., at least halogen and -NH2).

[0268] In some embodiments, R 6 has the following structure: [ka] wherein X is selected from N and C-CN, Y is selected from O and S, and R 23 is -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 22 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0269] In some embodiments, R 6 teeth, [ka] is selected from Any of them has one or more R 15 is replaced by

[0270] In some embodiments, R 6 teeth, [ka] is selected from.

[0271] In some embodiments, R 6 teeth, [ka] is selected from.

[0272] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] is.

[0273] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0274] In some embodiments, R 7 -OR x In some embodiments, R 7 -OR x and R x is C 1-6 It is alkyl.

[0275] In some embodiments, R 7 is -CN.

[0276] In some embodiments, R 7 is H.

[0277] In some embodiments, each E is independently: [ka] is selected from.

[0278] In some embodiments, each E is [ka] is.

[0279] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0280] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is C 2-6 In some embodiments, R is selected from alkynyl. 5 is C alkynyl. In some embodiments, R 7 is F.

[0281] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is —CHCN. In some embodiments, R 7 is F.

[0282] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14In some embodiments, R 7 is F.

[0283] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 is selected from 5- to 6-membered heterocycles substituted with

[0284] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0285] In some embodiments, R 5 teeth, [ka] is.

[0286] In some embodiments, R 7 is F.

[0287] In some embodiments, R 4 is H and R 7 is a halogen and R5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 7 is F. In some embodiments, R 5 is -CF3.

[0288] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is H. In some embodiments, R 7 is F.

[0289] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is halogen. In some embodiments, R 7 is F. In some embodiments, R 5 is Cl.

[0290] In some embodiments, the compound is a compound according to formula ID1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 and R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl is unsubstituted or has one or more R 13 is replaced by R 3 is a 4- to 6-membered heterocyclic ring, and the heterocyclic ring is 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 is H, R 5 But C 2-6 Alkynyl, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl is substituted with -CN and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR x , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a are independently halogens, C 1-6Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0291] In some embodiments, the disclosure provides a compound of formula ID1, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0292] In some embodiments of the compound of formula ID1, R 2 is C 1-2 In some embodiments, R 2 is methyl. In some embodiments, R 2 is methyl.

[0293] In some embodiments of the compound of formula ID, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0294] In some embodiments of the compound of formula ID1, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally, two R 11The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally forming a piperazinyl ring substituted with two R 11 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 and optionally, two R g The groups, together with the atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0295] In some embodiments of the compound of formula ID1, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R bEach of R is methyl. b is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0296] In some embodiments of the compound of formula ID1, R 5 is replaced by -CN 1-6 In some embodiments, R 5 is selected from 3- to 6-membered carbocycles and phenyl, and any carbocycle or phenyl is unsubstituted or has one or more R 14 In some embodiments, R 5 is phenyl. In some embodiments, R 5 is selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocycle, and any heteroaryl or heterocycle is unsubstituted or contains one or more R 14 In some embodiments, R 5 is furanyl.

[0297] In some embodiments of the compound of formula ID1, R 7 is halogen (e.g., F or Cl). In some embodiments, R 7 is -CN. In some embodiments, R 7 is H.

[0298] In some embodiments of the compound of formula ID1, X is N and Y is O. In some embodiments, X is N and Y is S. In some embodiments, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S. In some embodiments, R 23 is -NH. In some embodiments, R 24 is F. In some embodiments, R 25 and R 26is H. In some embodiments, [ka] teeth, [ka] is selected from.

[0299] In some embodiments, [ka] In some embodiments, [ka] is.

[0300] In some embodiments of the compound of formula ID1, each E is [ka] is. In some embodiments, each R d and R e is H. In some embodiments, the compound has a single E.

[0301] In some embodiments of the compound of formula ID1, R 7 is H and R 5 is replaced by -CN 1-6 In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0302] In some embodiments of the compound of formula ID1, R 7 is a halogen and R 5 is replaced by -CN 1-6 In some embodiments, R 7is F. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0303] In some embodiments of the compound of formula ID1, R 7 is H and R 5 is selected from 3- to 6-membered carbocycles and phenyl, and any carbocycle or phenyl is unsubstituted or has one or more R 14 In some embodiments, R 5 is phenyl. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0304] In some embodiments of the compound of formula ID1, R 7 is a halogen and R 5 is selected from 3- to 6-membered carbocycles and phenyl, and any carbocycle or phenyl is unsubstituted or has one or more R 14 In some embodiments, R 5 is phenyl. In some embodiments, R 7 is F. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0305] In some embodiments of the compound of formula ID1, R 7 is H and R 5 is selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocycle, and any heteroaryl or heterocycle is unsubstituted or contains one or more R 14 In some embodiments, R 5 is furanyl. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0306] In some embodiments of the compound of formula ID1, R 7 is a halogen and R 5is selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocycle, and any heteroaryl or heterocycle is unsubstituted or contains one or more R 14 In some embodiments, R 5 is furanyl. In some embodiments, R 7 is F. In some embodiments, X is N and Y is S. In some embodiments, X is C—CN and Y is S.

[0307] In another aspect, the present disclosure provides a compound according to formula IE: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 selected from alkyl, and 3- to 6-membered carbocyclic ring; R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 is replaced by or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 forming a 4- to 8-membered heterocyclic ring substituted with R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 6 But there is one or more R 15 is a bicyclic heteroaryl substituted with R 7 is -OH, R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R22 )2, and halogen; Each R 14 are independently halogen, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 15 are independently halogen, -N(R 12 )2, -OR 12 , -CN, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a are independently halogens, C 1-6 Alkyl, -OR 12, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0308] In some embodiments, the disclosure provides a compound of formula IE, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0309] In some embodiments, R 1 is H.

[0310] In some embodiments, R 1 -OR 8 Selected from R 8 is selected from heterocycle and alkylheterocycle, any heterocycle containing 4 to 8 members and is unsubstituted or contains one or more R a and the alkyl portion of any alkyl heterocycle is C 1-6 In some embodiments, R 8 is a heterocycle or alkylheterocycle, any heterocycle containing 4 to 8 members and containing one or more R a b In some embodiments, R 8 is unsubstituted or contains one or more R a In some embodiments, R 8 is unsubstituted or contains one or more R a In some embodiments, R 8is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and one or more R a is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and one or more R a is C 1-6 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and one or more R a -OR 12 (e.g., -OCH3).

[0311] In some embodiments, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, -OR 12 and H. In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, Ra is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. 1 teeth, [ka] is selected from.

[0312] In some embodiments, R 1 teeth, [ka] is selected from.

[0313] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a are independently halogen, C 1-6 Alkyl, -OR 12 and H;c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0314] In some embodiments, R 1 teeth, [ka] is selected from.

[0315] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and Rb is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0316] In some embodiments, R 1 teeth, [ka] is selected from.

[0317] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is selected from.

[0318] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R2 is C 1-2 In some embodiments, R 2 is selected from -CH3, -CH2CH3, and -CH(CH3)2. In some embodiments, R 2 is selected from 3- to 6-membered carbocyclic rings. 2 is cyclopropyl.

[0319] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R 12 )(E). In some embodiments, R 3 is selected from C2 alkyl substituted with -N(H)(E).

[0320] In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, at least one R 10 is halogen (e.g., F). In some embodiments, at least one R 10 is C1-6 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0321] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0322] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0323] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0324] In some embodiments, each R g is H.

[0325] In some embodiments, R 4 is H.

[0326] In some embodiments, R 5 is H.

[0327] In some embodiments, R5 is -CN.

[0328] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0329] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0330] In some embodiments, R 5 -OR 12 Selected from R12 is C 1-6 alkyl and H. In some embodiments, R 5 is -OCH3.

[0331] In some embodiments, R 5 is selected from 3- to 6-membered carbocycle, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocycle, and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R is a 5- to 6-membered heteroaryl or phenyl substituted with alkyl. 5 is pyridyl, furanyl, or imidazolyl, each of which is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R 5 is furanyl. In some embodiments, R 5 is phenyl.

[0332] In some embodiments, R 6 may independently be one or more R 15 In some embodiments, R is a 9-10 membered heteroaryl having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur substituted with 6 may independently be one or more R 15 In some such embodiments, at least one R 15 is -N(R 12)2 (e.g., —NH2). In some embodiments, at least one R 15 is halogen (e.g., F). In some embodiments, each R 15 are independently selected from halogen, -CN, and -N(R 12 In some embodiments, R 6 is at least two R 15 (e.g., at least halogen and -NH2).

[0333] In some embodiments, R 6 has the following structure: [ka] wherein X is selected from N and C-CN, Y is selected from O and S, and R 23 is -N(R 12 )2, C 1-6 Alkyl, and C 1-6 Alkyl-N(R 22 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by

[0334] In some embodiments, R 6 teeth, [ka] is selected from Any of them has one or more R 15 is replaced by

[0335] In some embodiments, R 6 teeth, [ka] is selected from.

[0336] In some embodiments, R 6 teeth, [ka] is selected from.

[0337] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] is.

[0338] In some embodiments, each E is independently: [ka] is selected from.

[0339] In some embodiments, each E is [ka] is.

[0340] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0341] In some embodiments, R 4 is H and R 5 is halogen. In some embodiments, R 5 is Cl.

[0342] In some embodiments, R 1 is H and R 4 is H and R 5 is halogen. In some embodiments, R 5 is Cl.

[0343] In another aspect, the present disclosure provides a compound according to formula II: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] -OR 8 , a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl is unsubstituted or has one or more R 13 is replaced by R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring; R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR X , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 and H, or R bonded to the same atom a and R b But together with the atoms to which they are bonded, C 3-6 forming a carbocyclic ring, R c But C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0344] In some embodiments, the disclosure provides a compound of Formula II, or a salt thereof (eg, a pharmaceutically acceptable salt):

[0345] In another aspect, the present disclosure provides a compound according to formula IIA: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] and a 4- to 6-membered heterocycle containing a nitrogen atom, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl is unsubstituted or has one or more R 13 is replaced by R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring; R 4 But, H, -OR12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR X , —CN, and H; Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 and H, or R bonded to the same atom a and R b But together with the atoms to which they are bonded, C 3-6 forming a carbocyclic ring, R c But C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0346] In some embodiments, the disclosure provides a compound of formula IIA, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0347] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H, or R bonded to the same atom a and R b But together with the atoms to which they are bonded, C 3-6 forms a carbocyclic ring, R cis C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0348] In some embodiments, R 1 teeth, [ka] is.

[0349] In some embodiments, R 1 teeth, [ka] is selected from.

[0350] In some embodiments, R 1 teeth, [ka] is selected from.

[0351] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is.

[0352] In some embodiments, R 2 is H, C 1-6 alkyl, and 3- to 6-membered carbocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R 2 is H, C 1-6 In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some such embodiments, each R 13 are independently -OR 22 (e.g., —OH) and —CN. In some embodiments, R 2 is C 1-6 In some embodiments, R 2is selected from —CH, —CHCH, —CHCHOH, —CHCHCN, and —CH(CH). 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0353] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is replaced by -N(H)(E) 1-6 alkyl.

[0354] In some embodiments, R 3 is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 and a 4- to 6-membered heterocycle substituted with a single heteroatom that is N, and optionally two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0355] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally, two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally forming a piperazinyl ring substituted with two R 11 Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0356] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0357] In some embodiments, R 4 is H.

[0358] In some embodiments, R 5 is H.

[0359] In some embodiments, R 5 is -CN.

[0360] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0361] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-2 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CFH, -CF, -CHCN, and -CHCH. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0362] In some embodiments, R 5 -OR 12 In some embodiments, R 5 -OR 12 Selected from R 12 is C 1-6 alkyl and H. In some embodiments, R 5 is —OCH. In some embodiments, R 5 is -OCF3.

[0363] In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is phenyl.

[0364] In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 3- to 6-membered heterocycle or a 5- to 6-membered heteroaryl substituted with 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl substituted with 5contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0365] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0366] In some embodiments, R 7 -OR X In some embodiments, R 7 -OR X and R X is C 1-6 It is alkyl.

[0367] In some embodiments, R 7 is -CN.

[0368] In some embodiments, R 7 is H.

[0369] In some embodiments, R 7 teeth, [ka] is.

[0370] In some embodiments, X is N. In some embodiments, X is N and Y is O. In some embodiments, X is N and Y is S.

[0371] In some embodiments, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S. In some embodiments, Y is S.

[0372] In some embodiments, R 23 is -N(R 12 In some embodiments, R 23 is -NH2.

[0373] In some embodiments, R 24 is halogen. In some embodiments, R 24 is F.

[0374] In some embodiments, R 25 and R 26 is H.

[0375] In some embodiments, each E is independently: [ka] is selected from.

[0376] In some embodiments, each E is [ka] is. In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0377] In some embodiments, R 4 is H and R 7 is a halogen and R 1 teeth, [ka] is. In some embodiments, R 1 teeth, [ka] is selected from. In some embodiments, R 1 teeth, [ka] is selected from. In some embodiments, R 7 is F.

[0378] In some embodiments, R 4 is H and R 7 is a halogen and R 1 teeth, [ka] is. In some embodiments, R 1 teeth, [ka] is. In some embodiments, R 7 is F.

[0379] In some embodiments, R 4 is H and R 7 is a halogen and R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is. In some embodiments, R 7 is F.

[0380] In another aspect, the present disclosure provides a compound according to formula IIA1: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] is selected from R 2 But H, C 1-6 alkyl, and 3- to 6-membered carbocyclic rings, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 3 But one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR X , —CN, and H; Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 and H, or R bonded to the same atom a and R b But together with the atoms to which they are bonded, C 3-6 forming a carbocyclic ring, R c But C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0381] In some embodiments, the disclosure provides a compound of formula IIA1, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0382] In some embodiments, R 2 is H. In some embodiments, R 2 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some such embodiments, each R 13 are independently -OR 22(e.g., —OH) and —CN. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is selected from —CH, —CHCH, —CHCHOH, —CHCHCN, and —CH(CH). 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0383] In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 and optionally, two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 and a 4- to 6-membered heterocycle substituted with a single heteroatom that is N, and optionally two R 10 The groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0384] In another aspect, the present disclosure provides a compound according to formula IIA2: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 but, [ka] is selected from R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring; R 4 is H, R 5 H, -CN, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR X , —CN, and H; Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; Each R x But independently, C 1-6 selected from alkyl, 3- to 6-membered carbocyclic ring, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, C 1-6 Alkyl, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R a and R b are independently halogens, C 1-6 Alkyl, -OR 12 and H, or R bonded to the same atom a and R b But together with the atoms to which they are bonded, C 3-6 forming a carbocyclic ring, R c But C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0385] In some embodiments, the disclosure provides a compound of formula IIA2, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0386] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 and optionally forming a piperazinyl ring substituted with two R 11Groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0387] In some embodiments of the compound of formula IIA1 or IIA2, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R b The group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R bis halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0388] In some embodiments of the compound of Formula IIA1 or IIA2, R 1 teeth, [ka] is selected from.

[0389] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is H.

[0390] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is -CN.

[0391] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0392] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-2 In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CFH, -CF, -CHCN, and -CHCH. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0393] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 -OR 12 In some embodiments, R 5 -OR 12 Selected from R 12is C 1-6 alkyl and H. In some embodiments, R 5 is —OCH. In some embodiments, R 5 is -OCF3.

[0394] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is phenyl.

[0395] In some embodiments of the compound of Formula IIA1 or IIA2, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 3- to 6-membered heterocycle or a 5- to 6-membered heteroaryl substituted with 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl substituted with 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5is unsubstituted or contains one or more R 14 The group is selected from furanyl, pyridinyl, and pyrazolyl substituted with

[0396] In some embodiments of the compound of Formula IIA1 or IIA2, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0397] In some embodiments of the compound of Formula IIA1 or IIA2, R 7 -OR X , for example, —OH. In some embodiments, R 7 -OR X and R X is C 1-6 It is alkyl.

[0398] In some embodiments of the compound of Formula IIA1 or IIA2, R 7 is -CN.

[0399] In some embodiments of the compound of Formula IIA1 or IIA2, R 7 is H.

[0400] In some embodiments of the compound of formula IIA1 or IIA2, X is N. In some embodiments, X is N and Y is O. In some embodiments, X is N and Y is S.

[0401] In some embodiments of the compound of formula IIA1 or IIA2, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S. In some embodiments, Y is S.

[0402] In some embodiments of the compound of Formula IIA1 or IIA2, R 23 is -N(R 12 In some embodiments, R23 is -NH2.

[0403] In some embodiments of the compound of Formula IIA1 or IIA2, R 24 is halogen. In some embodiments, R 24 is F.

[0404] In some embodiments of the compound of Formula IIA1 or IIA2, R 25 and R 26 is H.

[0405] In some embodiments of compounds of formula IIA1 or IIA2, each E is independently: [ka] is selected from.

[0406] In some embodiments of the compound of formula IIA1 or IIA2, each E is [ka] is.

[0407] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0408] In a further aspect, the present disclosure provides a compound according to formula IIB: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by A, [ka] is selected from R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 H, -CN, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22, -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 is selected, R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R g But independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R h But independently, C 1-6 alkyl and H; R i But -N(R 12 )(E), E, ​​and -(C 1-6 alkyl)E; R a and R b each independently represents a halogen, -OR 12 , C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0409] In some embodiments, the disclosure provides a compound of formula IIB, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0410] In some embodiments, A is [ka] is selected from.

[0411] In some embodiments, one R g Only A is E. In some embodiments, A is [ka] is selected from.

[0412] In some embodiments, A is [ka] is selected from.

[0413] In some embodiments, one R g Only A is E. In some embodiments, A is [ka] is selected from.

[0414] In some embodiments, A is [ka] is.

[0415] In some embodiments, A is [ka] is selected from.

[0416] In some embodiments, A is [ka] is selected from.

[0417] In some embodiments, A is [ka] is selected from.

[0418] In some embodiments, R 1 is H.

[0419] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a and / or R b In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and / or R b and one or more R a and / or R b is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and / or R b and one or more R a and / or R b is C 1-6In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and / or R b and one or more R a and / or R b -OR 12 (e.g., -OCH3).

[0420] In some embodiments, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, -OR 12 , C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, Rb is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. b is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0421] In some embodiments, R 1 teeth, [ka] is selected from.

[0422] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R ais H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0423] In some embodiments, R 1 teeth, [ka] is.

[0424] In some embodiments, R 1 teeth, [ka] is selected from.

[0425] In some embodiments, R 1 teeth, [ka] is selected from.

[0426] In some embodiments, R 1 teeth, [ka] is selected from.

[0427] In some embodiments, R 1 teeth, [ka] is selected from.

[0428] In some embodiments, R 4 is H.

[0429] In some embodiments, R 5 is H.

[0430] In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0431] In some embodiments, R 5 is -CN.

[0432] In some embodiments, R 5 is C 2-6 In some embodiments, R is selected from alkynyl. 5 is a C2 alkynyl.

[0433] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0434] In some embodiments, R 5 -OR 12 Selected from R 12 is C 1-6 alkyl and H. In some embodiments, R 5 is -OCH3.

[0435] In some embodiments, R 5 is selected from 3- to 6-membered carbocycle, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocycle, and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14In some embodiments, R 5 is unsubstituted or contains one or more R 14 (e.g., one or more —CN). In some embodiments, R 5 is unsubstituted or contains one or more R 14 (For example, C 1-6 In some embodiments, R5 is a 5-6 membered heteroaryl or phenyl substituted with one or more R 14 (For example, C 1-6 In some embodiments, R 5 is furanyl. In some embodiments, R 5 is phenyl.

[0436] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0437] In some embodiments, R 7 -OR 12 In some embodiments, R 7 -OR 12 and R 12 is C 1-6 It is alkyl.

[0438] In some embodiments, R 7 is -CN.

[0439] In some embodiments, R 7 is H.

[0440] In some embodiments, X is N and Y is O. In some embodiments, X is N and Y is S.

[0441] In some embodiments, X is C—CN and Y is O. In some embodiments, X is C—CN and Y is S.

[0442] In some embodiments, X is N.

[0443] In some embodiments, Y is S.

[0444] In some embodiments, R 23 is -N(R 12 In some embodiments, R 23 is -NH2.

[0445] In some embodiments, R 24 is halogen. In some embodiments, R 24 is F.

[0446] In some embodiments, R 25 and R 26 is H.

[0447] In some embodiments, each E is independently: [ka] is selected from.

[0448] In some embodiments, each E is [ka] is.

[0449] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0450] In another aspect, the present disclosure provides a compound according to formula IIC: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 selected from alkyl, and 3- to 6-membered carbocyclic ring; R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 is replaced by or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R 11 forming a 4- to 8-membered heterocyclic ring substituted with R 4 But, -OR Y and R Y But C 1-6 alkyl, R 5 is selected from halogen and H; R 7 But halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, -N(R 12 )C(O)(C 1-6alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 is selected, R 24 , R 25 , and R 26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; R a and R b each independently represents a halogen, -OR 12 , C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0451] In some embodiments, the disclosure provides a compound of formula IIC, or a salt thereof (eg, a pharmaceutically acceptable salt):

[0452] In some embodiments, R 4 is -OCH3.

[0453] In some embodiments, R 1 is H.

[0454] In some embodiments, R 1 -OR 8 Selected from R 8 is selected from heterocycle and alkylheterocycle, any heterocycle containing 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is C 1-6 In some embodiments, R 8 is a heterocycle or alkylheterocycle, any heterocycle containing 4 to 8 members and containing one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a and / or R b In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and / or R b and one or more R a and / or R bis halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and / or R b and one or more R a and / or R b is C 1-6 In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and / or R b and one or more R a and / or R b -OR 12 (e.g., -OCH3).

[0455] In some embodiments, R 1 teeth, [ka] is selected from In the formula, R a and R b are each independently a halogen, -OR 12 and H. In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, Rb is H. In some embodiments, R b is halogen. In some embodiments, R b is F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0456] In some embodiments, R 1 teeth, [ka] is selected from.

[0457] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R c is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0458] In some embodiments, R 1 teeth, [ka] is selected from.

[0459] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a’ group, two R b’ or R a and R b is C 1-6 alkyl (e.g., F). In some embodiments, R cis selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0460] In some embodiments, R 1 teeth, [ka] is selected from.

[0461] In some embodiments, R 1 is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is selected from.

[0462] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is C 1-2 In some embodiments, R 2 is selected from -CH3, -CH2CH3, and -CH(CH3)2. In some embodiments, R 2 is selected from 3- to 6-membered carbocyclic rings. 2 is cyclopropyl.

[0463] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R12 )(E). In some embodiments, R 3 is selected from C2 alkyl substituted with -N(H)(E).

[0464] In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, halogen, H, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0465] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R 2 and R3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0466] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0467] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each Rg independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0468] In some embodiments, each R g is H.

[0469] In some embodiments, R 5 is H. In some embodiments, R 5 is halogen. In some embodiments, R 5 is Cl. In some embodiments, R 5 is F.

[0470] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0471] In some embodiments, R 7 -OR 12 In some embodiments, R 7 -OR 12 and R 12 is C 1-6 It is alkyl.

[0472] In some embodiments, R 7 is -CN.

[0473] In some embodiments, R 7 is H.

[0474] In some embodiments, X is N and Y is O. In some embodiments, X is N and Y is S.

[0475] In some embodiments, X is C-CN and Y is O. In some embodiments, X is C-CN and Y is S.

[0476] In some embodiments, X is N.

[0477] In some embodiments, Y is S.

[0478] In some embodiments, R 23 is -N(R 12 In some embodiments, R 23 is -NH2.

[0479] In some embodiments, R 24 is halogen. In some embodiments, R 24 is F.

[0480] In some embodiments, R 25 and R 26 is H.

[0481] In some embodiments, each E is independently: [ka] is selected from.

[0482] In some embodiments, each E is [ka] is.

[0483] In some embodiments, each R d and R e is H. In some embodiments, the compound contains a single E.

[0484] In some embodiments, R 4 is -OCH3, and R 1 is H.

[0485] In some embodiments, R 4 is -OCH3, and R 1 is H and R 5 is H and R 7 is halogen. In some embodiments, R 7 is F.

[0486] In a further aspect, the present disclosure provides a compound according to formula IID: [ka] or a salt (e.g., a pharmaceutically acceptable salt), ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, wherein: R 1 But, -OR 8 , [ka] a 4- to 6-membered heterocycle containing a nitrogen atom, and H, wherein the heterocycle is unsubstituted or contains one or more R 16 is replaced by R 2 But H, C 1-6 selected from alkyl, and 3- to 6-membered carbocyclic ring; R 3 But C 1-6 alkyl and 4- to 6-membered heterocycle, 1-6 The alkyl is -N(R 12 )(E), and the heterocycle is substituted with one or more E and 0 to 4 R 10 and optionally, two R 10 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring, or or R 2 and R 3 together with the atoms to which they are attached, one or more E and 0 to 4 R11 and optionally, two R 11 groups, together with the atom or atoms to which they are attached, form a 3- to 6-membered carbocyclic ring; R 4 But, H, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 5 But -CN, C 1-6 Alkyl, -OR 12 , 3- to 6-membered carbocyclic ring, 5- to 6-membered heteroaryl, phenyl, and 3- to 6-membered heterocyclic ring; 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R 14 is replaced by R 7 But halogen, -OR 12 , —CN, and H; R 8 is selected from heterocycle and alkylheterocycle, and any heterocycle contains 4 to 8 members and is unsubstituted or contains one or more R a and / or R b and the alkyl portion of any alkyl heterocycle is substituted with C 1-6 alkyl, Each R 10 But independently, C 1-6 alkyl and halogen, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 11 But independently, C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 is replaced by Each R 12 But independently, C 1-6 Alkyl, C 2-6alkenyl, and H, and any C 1-6 Alkyl or C 2-6 The alkenyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 13 but independently, -OR 22 , -CN, -N(R 22 )2, and halogen; Each R 14 are independently halogen, -CN, -N(R 12 )2, and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each R 16 are independently halogen, -N(R 12 )2, C 1-6 Alkyl, -OR 12 and 3- to 6-membered heterocycles, 1-6 The alkyl may be unsubstituted or may contain one or more R 13 and any heterocycle is unsubstituted or substituted with one or more R 20 is replaced by Each R 20 Independently, -OH, -OC 1-6 Alkyl, -CN, -NH2, -NHC 1-6 alkyl, and halogen; Each R 22 But independently, C 1-6 Alkyl, C 2-6 alkenyl, and H; X is selected from N and C-CN; Y is selected from O and S; R 23 But -N(R 12 )2, -N(R 12 )C(O)(C 1-6 alkyl), -OR 12 , and C 1-6 Alkyl-N(R 12 )2 is selected, R 24 , R 25 , and R26 are independently H, halogen, -OR 12 , and C 1-6 alkyl, any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by R 27 is a 3- to 6-membered heterocycle containing one or more heteroatoms selected from N, O, and S, and the heterocycle is unsubstituted or contains one or more R 28 is replaced by Each R 28 But independently, C 1-6 selected from alkyl and halogen; Each R a and R b each independently represents a halogen, -OR 12 , C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 is replaced by Each E, independently, [ka] and -CN; Each R d and R e are independently halogens, C 1-6 alkyl, and H; Each R f But independently, C 1-6 is selected from alkyl and H.

[0487] In some embodiments, the disclosure provides a compound of formula IID, or a salt thereof (eg, a pharmaceutically acceptable salt).

[0488] In some embodiments, R 5 is -CN.

[0489] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6In some embodiments, R 5 is unsubstituted, such as methyl or ethyl 1-6 In some embodiments, R 5 is C substituted with one or more halogens or -CN 1-6 In some embodiments, R 5 is replaced by -CN 1-6 In some embodiments, R 5 is a C substituted with one or more halogens, such as one or more fluorines 1-6 In some embodiments, R 5 is selected from -CF and -CFH. In some embodiments, R 5 is selected from -CF, -CFH, and -CHCN. In some embodiments, R 5 is selected from —CH, —CHCH, —CFH, —CF, —CFCH, and —CHCN. In some embodiments, R 5 is one or more R 13 C replaced by 1-6 alkyl, and each R 13 are independently -OR 22 , -CN, and -N(R 22 In some embodiments, R 5 is -CHCN.

[0490] In some embodiments, R 5 -OR 12 Selected from R 12 is unsubstituted or substituted with one or more halogens; 1-6 In some embodiments, R 5 is selected from —OCF3 and —OCH3.

[0491] In some embodiments, R 5 is unsubstituted or contains one or more R 14In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from cyclopropyl and cyclobutyl substituted with 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is phenyl.

[0492] In some embodiments, R 5 is selected from a 3- to 6-membered heterocycle and a 5- to 6-membered heteroaryl, wherein the heterocycle or heteroaryl is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R is selected from a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl substituted with 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0493] In some embodiments, R 5 teeth, [ka] is.

[0494] In some embodiments, R 1 is H.

[0495] In some embodiments, R 1 -OR 8 In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is unsubstituted or contains one or more R a and / or R b In some embodiments, R 8 is —CH2 (heterocycle), the heterocycle is unsubstituted or contains one or more R a and / or R b In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is a 4-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is an 8 membered bicyclic heterocycle having 1-2 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocycle of a heterocycle or alkylheterocycle is substituted with one or more R a and / or R b and one or more R a and / or R b is halogen (e.g., F). In some embodiments, the heterocycle or heterocycle of an alkylheterocycle is selected from the group consisting of one or more R a and / or R b and one or more R a and / or R b is C 1-6In some embodiments, the heterocycle or heterocycle of the alkylheterocycle is selected from one or more R a and / or R b and one or more R a and / or R b -OR 12 (e.g., -OCH3).

[0496] In some embodiments, R 1 is selected from [ka] In the formula, R a and R b are each independently a halogen, -OR 12 , C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a and R b are each independently a halogen, C 1-6 Alkyl, -OR 12 , and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, R a is halogen. In some embodiments, R a is F. In some embodiments, R a is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R a is methyl. In some embodiments, R a -OC 1-6 In some embodiments, R a is H. In some embodiments, R b is H. In some embodiments, R b is halogen. In some embodiments, R bis F. In some embodiments, R b is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R b is methyl. In some embodiments, R a and R b Each of R is F. In some embodiments, R a and R b Each of R is methyl. b is methyl. In some embodiments, R 1 teeth, [ka] is selected from.

[0497] In some embodiments, R 1 teeth, [ka] is selected from.

[0498] In some embodiments, R 1 teeth, [ka] is selected from In the formula, each R a and R b are independently halogen, C 1-6 Alkyl, -OR 12 and H; c is C 1-6 alkyl, C 1-6 The alkyl may be unsubstituted or may contain one or more R 13 In some embodiments, one R a or R b is a halogen, C 1-6 Alkyl, and -OR 12 Selected from other R a and R bThe group is H. In some embodiments, one R a or R b is halogen (e.g., F). In some embodiments, two R a group, two R b group, or R a and R b is halogen (e.g., F). In some embodiments, one R a or R b -OR 12 (e.g., —OCH or —CHF). In some embodiments, one R a or R b is C 1-6 In some embodiments, two R a group, two R b group, or R a and R b is C 1-6 In some embodiments, R c is selected from -CH, -CHCHF, -CHCHF, and -CHCHCN. 1 teeth, [ka] is selected from.

[0499] In some embodiments, R 1 teeth, [ka] is selected from.

[0500] In some embodiments, R 1 teeth, [ka] is selected from.

[0501] In some embodiments, R 1is a 4- to 6-membered heterocyclic ring containing a nitrogen atom, the heterocyclic ring being unsubstituted or containing one or more R 16 In some embodiments, R 1 teeth, [ka] is.

[0502] In some embodiments, R 2 is H. In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is C 1-6 In some embodiments, R 2 is C 1-2 In some embodiments, R 2 is selected from -CH3, -CH2CH3, and -CH(CH3)2. In some embodiments, R 2 is a 3- to 6-membered carbocyclic ring. In some embodiments, R 2 is cyclopropyl.

[0503] In some embodiments, R 3 is -N(R 12 )(E) replaced by C 1-6 In some embodiments, R 3 is -N(R 12 )(E). In some embodiments, R 3 is selected from C2 alkyl substituted with -N(H)(E).

[0504] In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10and wherein the heterocycle contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 3 is one or more E and 0 to 4 R 10 wherein the heterocycle contains a single heteroatom that is N. In some embodiments, R 3 is azetidine, pyrrolidine, or piperidine, and the azetidine, pyrrolidine, or piperidine is one or more E and 0 to 4 R 10 In some embodiments, R 3 is one or more E and 0 to 4 R 10 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 at least one R selected from alkyl, H, halogen, and E; g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 3 teeth, [ka] is selected from In the formula, each R g independently, C 1-6 alkyl, halogen, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R gindependently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, at least one R g is halogen. In some embodiments, at least one R g is F. In some embodiments, at least one R g is unsubstituted or contains one or more R 20 C replaced by 1-6 In some embodiments, at least one R g is C 1-6 It is alkyl (eg, methyl).

[0505] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Forming In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, each R g is H. In some embodiments, one or two R g The group is C 1-6 In some embodiments, R2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0506] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0507] In some embodiments, R 2 and R 3 consists of one or more E and 0-4 R, together with the atoms to which they are attached. 11 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, H, and E, and at least one R g is E and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 together with the atoms to which they are attached, [ka] forming a structure selected from In the formula, each R g independently, C 1-6 alkyl, and H, and any C 1-6 The alkyl may be unsubstituted or may contain one or more R 20 In some embodiments, R 2 and R 3 are the structures, along with the atoms to which they are attached. [ka] Form.

[0508] In some embodiments, each R g is H.

[0509] In some embodiments, R 4 is H.

[0510] In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-2 In some embodiments, R 5 is selected from -CF2H, -CF3, -CH2CN, and -CH2CH3.

[0511] In some embodiments, R 5 -OR 12 In some embodiments, R 5 is -OCF3 or -OCH3.

[0512] In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14In some embodiments, R 5 is unsubstituted or contains one or more R 14 phenyl substituted with

[0513] In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0514] In some embodiments, R 7 is halogen. In some embodiments, R 7 is F. In some embodiments, R 7 is Cl.

[0515] In some embodiments, R 7 -OR 12 In some embodiments, R 7 -OR 12 and R 12 is C 1-6 It is alkyl.

[0516] In some embodiments, R 7 is -CN.

[0517] In some embodiments, R 7 is H.

[0518] In some embodiments, X is N and Y is O. In some embodiments, X is N and Y is S.

[0519] In some embodiments, X is C—CN and Y is O. In some embodiments, X is C—CN and Y is S.

[0520] In some embodiments, X is N.

[0521] In some embodiments, Y is S.

[0522] In some embodiments, R 23 is -N(R 12 In some embodiments, R 23 is -NH2.

[0523] In some embodiments, R 24 is halogen. In some embodiments, R 24 is F.

[0524] In some embodiments, R 25 and R 26 is H.

[0525] In some embodiments, each E is independently: [ka] is selected from.

[0526] In some embodiments, each E is [ka] is. In some embodiments, each Rd and R e is H. In some embodiments, the compound contains a single E.

[0527] In some embodiments, R 4 is H and R 7 is halogen. In some embodiments, R 7 is F.

[0528] In some embodiments, R 4 is H and R 7 is a halogen and R 1 is H. In some embodiments, R 7 is F.

[0529] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 13 C replaced by 1-6 In some embodiments, R 5 is unsubstituted or contains one or more R 13 C replaced by 1-2 In some embodiments, R 5 is selected from -CFH, -CF, -CHCN, and -CHCH. In some embodiments, R 7 is F.

[0530] In some embodiments, R 4 is H and R 7 is a halogen and R 5 -OR 12 In some embodiments, R 5 is —OCF or —OCH. In some embodiments, R 7 is F.

[0531] In some embodiments, R 4 is H and R 7is a halogen and R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 7 is F.

[0532] In some embodiments, R 4 is H and R 7 is a halogen and R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 7 is F. In some embodiments, R 5 contains one or two heteroatoms selected from O and N and is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R 5 is unsubstituted or contains one or more R 14 In some embodiments, R is selected from furanyl, pyridinyl, and pyrazolyl substituted with 5 teeth, [ka] is selected from.

[0533] Also provided herein are embodiments in which any embodiment described herein can be combined with any one or more of these embodiments, unless the combinations are mutually exclusive.As used herein, two embodiments are "mutually exclusive" when one is defined as being different from the other.For example, an embodiment in which two groups are bonded to form a ring is mutually exclusive with an embodiment in which one group is ethyl and the other group is hydrogen.Similarly, an embodiment in which one group is CH2 is mutually exclusive with an embodiment in which the same group is NH.

[0534] In some embodiments of any of the preceding aspects, the compound is a compound included in Table 2, 3, 4, or 5, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 2, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 3, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 4, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the compound is a compound included in Table 5, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof.

[0535] Also provided herein is a compound selected from Tables 2, 3, 4, or 5, or any of the Examples provided herein, or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the present disclosure provides a compound selected from Tables 2, 3, 4, or 5, or any of the Examples provided herein, or a salt thereof.

[0536] In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, comprises an electrophilic moiety E provided herein. In some embodiments of any of the preceding aspects, the compound comprises multiple electrophilic moieties. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can covalently interact with a cysteine ​​(C) at position 12 of a KRAS protein (e.g., a G12C mutation) (e.g., via an electrophilic moiety E). In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can reversibly interact with a cysteine ​​(C) at position 12 of a KRAS protein (e.g., a G12C mutation) (e.g., via an electrophilic moiety E). In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can irreversibly interact with cysteine ​​(C) at position 12 of a KRAS protein (e.g., a G12C mutation) (e.g., via electrophilic moiety E). In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, selectively binds to KRAS having a G12C mutation compared to KRAS having other residues at position 12 of the P loop, e.g., glycine (G), valine (V), serine (S), alanine (A), aspartic acid (D). For example, in some embodiments, the compounds provided herein, or salts, esters, tautomers, zwitterionic forms, or stereoisomers thereof, exhibit at least 1.5, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more selectivity for KRAS having a G12C mutation compared to KRAS having other residues at position 12 of the P loop, e.g., glycine (G), valine (V), serine (S), alanine (A), aspartic acid (D).In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, selectively binds to KRAS having a G12C mutation compared to wild-type KRAS. For example, in some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, exhibits at least 1.5, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or more times binding selectivity for KRAS having a G12C mutation compared to wild-type KRAS. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, selectively binds to KRAS having a G12C mutation compared to other forms of RAS (e.g., HRAS and NRAS). For example, in some embodiments, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, exhibits at least 1.5, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100-fold or more binding selectivity for KRAS having a G12C mutation compared to another form of RAS (e.g., HRAS or NRAS), e.g., an HRAS or NRAS protein having a G12C mutation. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can bind to a KRAS protein having a G12C mutation and one or more additional mutations, e.g., a mutation at codon 13 (e.g., to D or C) or codon 61.

[0537] In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can selectively bind to KRAS protein in its active (GTP-bound) conformation. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can selectively bind to KRAS protein in its inactive (GDP-bound) conformation. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, can selectively bind to KRAS protein in both its active (GTP-bound) and inactive (GDP-bound) conformations. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, has greater selectivity for KRAS protein in its active (GTP-bound) conformation than in its inactive (GDP-bound) conformation. In some embodiments of any of the preceding aspects, a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, has greater selectivity for KRAS protein in its inactive (GDP-bound) conformation than in its active (GTP-bound) conformation.

[0538] composition The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. In some embodiments, the provided compositions comprise a compound provided herein, or a pharmaceutically acceptable salt thereof. For example, the present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, together with a pharmaceutically acceptable carrier. In some embodiments, the provided pharmaceutical compositions comprise a compound provided herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0539] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the oral pharmaceutical formulation is selected from a tablet and a capsule.

[0540] 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.

[0541] While it may be possible for the compounds provided herein (e.g., compounds of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or salts, esters, tautomers, prodrugs, zwitterionic forms, or stereoisomers thereof, to be administered as the raw chemical, the compounds may additionally or alternatively be provided in a pharmaceutical formulation. Thus, provided herein are pharmaceutical formulations comprising one or more compounds disclosed herein (e.g., compounds of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Appropriate formulation will depend upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as appropriate and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any well-known, suitable manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0542] The pharmaceutical formulations provided herein may be suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including cutaneous, buccal, sublingual, and intraocular) administration. The most suitable route may depend, for example, on the condition and disorder of the subject to whom the pharmaceutical formulation is to be administered. The pharmaceutical formulations may be provided in unit dosage form. The pharmaceutical formulations may be prepared by any suitable method. The method for preparing a pharmaceutical formulation may include contacting a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof ("active ingredient") with one or more pharmaceutically acceptable carriers (e.g., auxiliary ingredients). In general, the formulations are prepared by uniformly and intimately bringing into contact the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0543] Pharmaceutical formulations of the compounds provided herein (e.g., compounds of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID 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, cachets, and / or tablets containing a predetermined amount of the compound (e.g., active ingredient) in any suitable form; as a solution or suspension in a solvent (e.g., an aqueous or non-aqueous solvent); as an emulsion (oil-in-water emulsion or water-in-oil emulsion); or as a powder or granules. Additionally or alternatively, the active ingredient may be provided as a bolus, electuary, or paste.

[0544] Pharmaceutical formulations suitable for oral administration include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be prepared, for example, by compression or molding, optionally with one or more accessory ingredients, such as one or more pharmaceutically acceptable excipients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating surfactant, or dispersing agent. Molded tablets can be prepared by molding, in a suitable machine, a mixture of powdered compounds moistened with an inert liquid diluent. Tablets may be coated or scored as needed and can be formulated for sustained or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules may contain the active ingredient mixed with one or more fillers, such as lactose, one or more binders, such as starches, and / or one or more lubricants, such as talc or magnesium stearate, and optionally one or more stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers and other ingredients may also be added. Dragee cores may be provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gums, gelling agents, polymers, solvents, or combinations thereof. Dyes or pigments may be added to tablets or dragee coatings for identification purposes or to characterize different combinations of active compound doses.

[0545] Pharmaceutical compositions comprising a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.), can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage form, e.g., in ampoules, vials, or multi-dose containers, with added preservatives. The compositions can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. The formulations may also be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder or freeze-dried (lyophilized) form requiring only the addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, prior to (e.g., immediately before) use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0546] Pharmaceutical compositions containing compounds provided herein (e.g., compounds of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), may be formulated as injectable solutions, which may be aqueous or non-aqueous (oily) sterile solutions and may contain one or more antioxidants, thickeners, suspending agents, buffers, solutes, and / or bacteriostatic agents. The addition of one or more such additives can make the formulation isotonic with the blood of the intended recipient (e.g., a subject or patient). Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0547] In addition to the formulations described elsewhere herein, the compounds provided herein (e.g., compounds of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID in any suitable form (e.g., salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.)) can also be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., a sparingly soluble salt.

[0548] Pharmaceutical compositions containing a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) suitable for buccal or sublingual administration, can take the form of a tablet, lozenge, pastille, or gel. Such compositions can include the active ingredient in a flavored base such as sucrose and acacia, or tragacanth. Pharmaceutical compositions containing a compound provided herein or a predetermined form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) suitable for rectal administration can be formulated as a suppository or retention enema and can include a vehicle such as cocoa butter, polyethylene glycol, or other glycerides.

[0549] Certain compounds provided herein (e.g., compounds of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), can be formulated for non-systemic administration, such as topical administration. This includes applying a compound or a form thereof disclosed herein to the epidermis or externally to the buccal cavity, and instilling such a compound or a form thereof into the ear, eye, and nose, such that the compound or a form thereof does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0550] Formulations suitable for topical administration 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, as well as drops suitable for administration to the eye, ear, or nose. For topical administration, the active ingredient can comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient can comprise 10% w / w. In other embodiments, the active ingredient can comprise less than 5% w / w. In certain embodiments, the active ingredient can comprise 2% to 5% w / w. In other embodiments, the active ingredient can comprise 0.1% to 1% w / w of the formulation.

[0551] For administration by inhalation, a compound (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be conveniently delivered from an inhaler, a nebulizer pressurized pack, or other convenient means of delivering an aerosol spray. Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds provided herein can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition may be presented in unit dosage form, for example, in capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0552] Preferred unit dosage formulations are those containing an effective dose, as described herein, or an appropriate fraction thereof, of the active ingredient (e.g., a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof).

[0553] It will be understood that, in addition to the ingredients described in detail elsewhere herein, the formulations described herein may include other useful agents having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0554] A compound (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) can be administered orally or via injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other presentation forms provided in discrete units can conveniently contain units containing an effective amount of one or more compounds in that dose or multiple thereof, e.g., 5 mg to 500 mg, usually about 10 mg to 200 mg.

[0555] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0556] method The present disclosure also provides methods for modulating KRAS (e.g., KRAS having a G12C mutation), comprising contacting KRAS with a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure can provide methods for altering cell phenotype, cell proliferation, KRAS activity, biochemical output produced by active or inactive KRAS, KRAS expression, and / or KRAS binding to a natural binding partner. Any such characteristic can be monitored and altered by contacting KRAS with a compound provided herein, or a predetermined form thereof. The method of modulating KRAS (e.g., KRAS having a G12C mutation) can be a treatment modality for a disease, disorder, or condition (e.g., cancer), a biological assay, a cellular assay, a biochemical assay, etc. In some embodiments, the method of modulating KRAS (e.g., KRAS having a G12C mutation) comprises contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, wherein the KRAS protein is in an active (GTP-bound) conformation. In some embodiments, the method of modulating KRAS (e.g., KRAS having a G12C mutation) comprises contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, wherein the KRAS protein is in an inactive (GDP-bound) conformation. In some embodiments, contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof comprises incubating the KRAS protein with the compound or a form thereof.In some embodiments, contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, comprises contacting a cell containing a KRAS protein with the compound or a form thereof. In some embodiments, the cell is in a subject. In some embodiments, the subject is a human. In some embodiments, the subject is a human with a disease, disorder, or condition, such as cancer, for example, a cancer characterized by a KRAS protein having a G12C mutation.

[0557] The present disclosure also provides a method of treating a disease, disorder, or condition in a subject in need thereof using a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure provides a method comprising providing (e.g., administering) an effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject (e.g., a patient) in need thereof. The present disclosure also provides a method of treating a disease, disorder, or condition in a subject in need thereof using a pharmaceutical composition comprising a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof. For example, the present disclosure provides a method comprising providing (e.g., administering) a pharmaceutical composition comprising an effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject (e.g., a patient) in need thereof. In some embodiments, the subject is known to have (e.g., has previously been diagnosed with) a disease, disorder, or condition, such as cancer.The disease, disorder, or condition can be a KRAS-mediated disease, such as cancer characterized by a G12C mutation in KRAS. In some embodiments, the compound administered to a subject in need thereof according to the methods described herein is a compound described in an embodiment, example, figure, or table herein, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0558] The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for use as a medicament, such as a medicament for the treatment of a disease, disorder, or condition (e.g., cancer). The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for use in the manufacture of a medicament for the treatment of a disease, disorder, or condition (e.g., cancer) in a subject in need of treatment.

[0559] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for the treatment of a disease, disorder, or condition (e.g., a cancer described herein, e.g., a cancer characterized by a KRAS protein having a G12C mutation) in a subject in need of treatment.

[0560] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, in the manufacture of a medicament for treating a disease, disorder, or condition (e.g., a cancer described herein, e.g., a cancer characterized by a KRAS protein having a G12C mutation) in a subject in need of treatment.

[0561] The present disclosure also provides a method of inhibiting KRAS (e.g., KRAS having a G12C mutation) (e.g., in a subject in need thereof), comprising contacting KRAS with a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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. In some embodiments, the method of inhibiting KRAS (e.g., KRAS having a G12C mutation) comprises contacting KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, wherein the KRAS protein is in an active (GTP-bound) conformation. In some embodiments, a method for inhibiting KRAS (e.g., KRAS having a G12C mutation) comprises contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, wherein the KRAS protein is in an inactive (GDP-bound) conformation. In some embodiments, contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, comprises incubating the KRAS protein with the compound or a form thereof. In some embodiments, contacting a KRAS protein with a compound provided herein, or a salt, ester, tautomer, zwitterionic form, or stereoisomer thereof, comprises contacting a cell comprising the KRAS protein with the compound or a form thereof. In some embodiments, the cell is within a subject. In some embodiments, the subject is a human. In some embodiments, the subject is a human with a disease, disorder, or condition, such as, for example, cancer, e.g., cancer characterized by a KRAS protein having a G12C mutation.

[0562] The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for use in inhibiting KRAS (e.g., KRAS having a G12C mutation) (e.g., in a subject in need thereof). The present disclosure also provides a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for use in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0563] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0564] The present disclosure also provides the use of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), 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, in the manufacture of a medicament for inhibiting KRAS (e.g., KRAS having a G12C mutation) in a subject in need thereof.

[0565] The present disclosure also includes administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, to a subject (e.g., a patient) (e.g., a subject in need thereof), thereby alleviating, reducing, eliminating, delaying, or ameliorating one or more symptoms of the subject, such as one or more symptoms of a disease, disorder, or condition (e.g., cancer). In some embodiments, the subject has cancer characterized by mutant KRAS (e.g., KRAS with a G12C mutation).

[0566] In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, delays or prevents tumor growth. In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, results in tumor shrinkage (e.g., tumor regression). In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, can be used to treat a range of conditions, e.g., for a period of one week or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, or more), a period of one month or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more), or a period of one year or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more), or a period of one year or more (e.g., at least about 1, 2, 3 years or more).In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof, stabilizes a tumor. In some embodiments, administering a therapeutically effective amount of a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a salt, ester, tautomer, prodrug, zwitterionic form, or stereoisomer thereof stabilizes a tumor, for example, for a period of one week or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 weeks or more), a period of one month or more (e.g., at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more), or a period of one year or more (e.g., at least about 1, 2, 3 years or more). In some embodiments, the subject has a cancer characterized by mutated KRAS (eg, KRAS with a G12C mutation).

[0567] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder, or condition is cancer. In some embodiments of any of the methods, uses, and medicaments provided herein, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung cancer), colorectal cancer (CRC), endometrial cancer, uterine carcinosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma, Wilm's tumor, retinoblastoma, skin cancer, breast cancer, prostate cancer, head and neck cancer, or ovarian cancer. In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), lung cancer (e.g., non-small cell lung adenocarcinoma), or colorectal cancer (CRC). In some embodiments, the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). In some embodiments, the cancer is non-small cell lung adenocarcinoma. In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the cancer is or comprises a solid tumor.

[0568] In some embodiments of any of the methods, uses, and medicaments provided herein, the disease, disorder, or condition is associated with KRAS, such as a disorder associated with a mutation in KRAS or a dysregulation of KRAS. In some embodiments, the disease, disorder, or condition is associated with the KRAS gene, such as a disease, disorder, or condition associated with a mutation in the KRAS gene or a dysregulation of the KRAS gene. The mutation or dysregulation of KRAS or KRAS may include a mutation or dysregulation of human K-Ras4a and / or human K-Ras4b. In some embodiments, the disease, disorder, or condition is associated with KRAS (e.g., human K-Ras4a or K-Ras4b) signaling pathway activity, such as a disease, disorder, or condition associated with aberrant KRAS signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with a mutation or dysregulation of human K-Ras4b. In some embodiments, the disease, disorder, or condition is associated with aberrant K-Ras4b signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with mutations or dysregulation of human K-Ras4a. In some embodiments, the disease, disorder, or condition is associated with aberrant K-Ras4a signaling pathway activity.

[0569] Administration and Combination Therapy Certain compounds provided herein (e.g., compounds of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID) and forms thereof (e.g., salts, esters, tautomers, prodrugs, zwitterionic forms, stereoisomers, etc.), or compositions (e.g., pharmaceutical compositions) comprising them, can be administered in various ways (e.g., orally, topically, or by injection). The amount of active ingredient (e.g., a compound provided herein in any suitable form thereof) administered to a subject (e.g., a patient) is the responsibility of the attending healthcare provider. The specific dosage level for a particular subject (e.g., patient) will depend on a variety of factors, including, for example, the activity of the active ingredient being administered; the subject's physical attributes (e.g., age, weight, height, BMI, general health, co-morbidities, sex, etc.); other characteristics of the subject (e.g., diet, activity level, country of origin, ethnicity, etc.); time of administration; route of administration; rate of excretion; concomitant medications; the disease, disorder, or condition being treated; and the severity of the disease, disorder, or condition being treated.

[0570] In some embodiments, a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) is administered in combination with an additional agent, such as an additional therapeutic agent. For example, if a subject experiences side effects, such as high blood pressure, when administered a compound provided herein or a certain form thereof, it may be appropriate to administer an additional agent effective in managing the side effects, such as an antihypertensive agent. In another example, the therapeutic effectiveness of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof, can be enhanced by administration of an adjuvant, which may itself have minimal therapeutic benefit but may be combined with another therapeutic agent to provide an enhanced overall therapeutic benefit to the subject. In a further example, the therapeutic benefit of a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof, can be enhanced by administration of the compound or a form thereof and an additional agent (which may include an additional treatment regimen) that also provides a therapeutic benefit. For example, a compound provided herein (e.g., a compound of any one of formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof, can be administered in combination with an additional agent that may be effective in treating a disease, disorder, or condition, such as cancer.Generally, the combination of a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof, and one or more additional agents (e.g., therapeutic agents) can enhance the overall benefit a subject experiences from either component individually. In some embodiments, the effect can be additive. In some embodiments, the effect can be synergistic.

[0571] In some embodiments, a compound provided herein (e.g., a compound of any one of Formulas IA, IA1, IA2, IB, IC, IC1, IC2, IC3, IC4, IC5, IC6, ID, ID1, IE, II, IIA, IIA1, IIA2, IIB, IIC, and IID), or a form thereof (e.g., a salt, ester, tautomer, prodrug, zwitterionic form, stereoisomer, etc.) is administered in combination with an anti-cancer agent (e.g., a chemotherapeutic agent). The anti-cancer agent can be, for example, an alkylating agent, a mitotic inhibitor, a checkpoint inhibitor, an antimetabolite, a plant alkaloid, a terpenoid, a cytotoxic agent, an antibiotic, a topoisomerase inhibitor, an aromatase inhibitor, an angiogenesis inhibitor, an anti-steroid, an anti-androgen, an mTOR inhibitor, a monoclonal antibody, or a tyrosine kinase inhibitor. The alkylating agent can be, for example, almustine, chlorambucil (LEUKERAN), cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN), dacarbazine, ifosfamide, lomustine (CCNU), melphalan (ALKERAN)...

Claims

1. A compound represented by formula IA2, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein, R １ is 【Chemical 2】 selected from, R ２ and R ３ together with the atoms to which they are attached form a 4- to 8-membered heterocyclic ring substituted with one or more E and 0 to 4 R １１ optionally, two R １１ groups together with the one or more atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring, R ４ is H, and R ５ is selected from H, -CN, halogen, C １－６ alkyl, -OR １２ , a 3- to 6-membered carbocycle, a 5- to 6-membered heteroaryl, phenyl, and a 3- to 6-membered heterocycle, wherein the C １－６ alkyl is unsubstituted or substituted with one or more R １３ , and the carbocycle, heteroaryl, phenyl, or heterocycle is unsubstituted or substituted with one or more R １４ . R ６ is a bicyclic heteroaryl substituted with one or more R １５ and is represented by the formula: R ７ is selected from halogen, -OR １２ , -CN, and H, Each R １１ is independently selected from C １－６ alkyl, and any C １－６ alkyl is is unsubstituted or substituted with one or more R ２０ and is substituted with Each R １２ is independently selected from C １－６ alkyl, C ２－６ alkenyl, and H, and any C １－６ alkyl or C ２－６ alkenyl is unsubstituted or substituted with one or more R １３ and Each R １３ is independently selected from -OR ２２ , -CN, -N(R ２２ ), ２ and halogen, Each R １４ is independently selected from halogen, -CN, -N(R １２ ), ２ and C １－６ alkyl, and any C １－６ alkyl is unsubstituted or substituted with one or more R １３ s, Each R ２０ is independently selected from -OH, -OC １－６ alkyl, -CN, -NH ２ , -NHC １－６ alkyl, and halogen, Each R ２２ is independently selected from C １－６ alkyl, C ２－６ alkenyl, and H R ２７ is a 3- to 6-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, and the heterocyclic ring is unsubstituted or substituted with one or more R ２８ substituted with, Each R ２８ is independently selected from C １－６ alkyl and halogen, each E is independently, 【Chemical Formula 3】 selected from and -CN, R ａ and R ｂ each independently represents halogen, C １－６ alkyl, -OR １２ , and H, and the C １－６ alkyl is unsubstituted or substituted with one or more R １３ . Each R ｄ and R ｅ is independently selected from halogen, C １－６ alkyl, and H Each R ｆ is independently selected from C １－６ alkyl and H, X is selected from N and C-CN, Y is selected from O and S, R 23 is selected from -N(R 12 ) 2, C 1-6 alkyl, and C 1-6 alkyl-N(R 12 ) 2, and any C 1-6 alkyl is unsubstituted or substituted with one or more R 13, R 24, R 25, and R 26 are independently selected from H, halogen, -OR 12, and C 1-6 alkyl, and the C 1-6 alkyl is unsubstituted or substituted with one or more R 13, said compound, or a salt thereof.

2. R １ is 【Chemical Formula 4】 selected from, the compound according to claim 1.

3. R ａ is halogen and / or R ｂ is halogen, the compound according to claim 2.

4. R １ is [Chemical Formula 5] selected from, the compound according to claim 2.

5. R １ is 【Chemical Formula 6】 selected from, the compound according to claim 1.

6. R ２ and R ３ together with the atoms to which they are attached form a piperazinyl ring substituted with one or more E and zero to four R １１ groups, and optionally two R １１ groups together with one or more atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring, the compound according to claim 1.

7. R ２ and R ３ together with the atoms to which they are attached form a piperazinyl ring substituted with one or more E and 1-2 R １１ and R １１ is C １－６ alkyl, the compound according to claim 1.

8. R ２ and R ３ together with the atoms to which they are attached form a structure 【Chemical Formula 7】 is formed, wherein each R ｇ is independently selected from C １－６ alkyl and H, and said C １－６ alkyl is unsubstituted or substituted with one or more R ２０ and optionally two R ｇ groups together with the atoms to which they are attached form a 3- to 6-membered carbocyclic or heterocyclic ring, the compound according to claim 1.

9. At least one R ｇ is unsubstituted or C ２０ substituted with one or more R １－６ is alkyl, the compound according to claim 8.

10. One or two Rs ｇ The compound according to claim 9, wherein one or two R groups are methyl.

11. R ２ and R ３ together with the atoms to which they are attached form a structure 【Chemical 8】 forming, the compound according to claim 1.

12. R ２ and R ３ together with the atoms to which they are attached form a crosslinked piperazinyl ring substituted with one or more E and from 0 to 4 R １１ The compound according to claim 1, wherein

13. R ２ and R ３ together with the atoms to which they are attached form a structure 【Chemical Formula 9】 forming, the compound according to claim 12.

14. R ２ and R ３ together with the atoms to which they are attached form a 4- to 8-membered bicyclic heterocyclic ring containing a fused ring system substituted with one or more E and 0 to 4 R １１ The compound according to claim 1, wherein

15. R ２ and R ３ together with the atoms to which they are attached ​ forms a structure selected from, wherein each R ｇ is independently selected from C １－６ alkyl, H, and E, and at least one R ｇ is E, and any C １－６ alkyl is unsubstituted or substituted with one or more R ２０ The compound according to claim 14, wherein

16. R ５ The compound according to claim 1, wherein R is a halogen.

17. R ５ The compound according to claim 16, wherein R is Cl.

18. R ５ is unsubstituted or C １３ substituted with one or more R １－６ alkyl, the compound according to claim 1.

19. R ５ is C substituted with one or more halogens １－６ alkyl, the compound according to claim 18

20. R ５ is -CHF ２ or -CF ３ and the compound according to claim 19

21. R ５ is -CF ３ The compound according to claim 20, wherein

22. R ７ The compound according to claim 1, wherein R is a halogen.

23. R ７ The compound according to claim 22, wherein R is F.

24. each E is independently, 【Chemical 11】 selected from, the compound according to claim 1.

25. each E is, 【Chemical 12】 is, the compound according to claim 24.

26. Each R ｄ and R ｅ is H, the compound according to claim 25.

27. R １ is 【Chemical 13】 is, and R ２ and R ３ together with the atoms to which they are attached form a 4- to 8-membered heterocyclic ring which is substituted with one or more E and 0 to 4 R １１ and form a 4- to 8-membered heterocyclic ring which is substituted with one or more E and 0 to 4 R R ５ is selected from halogen and C １－６ alkyl, and said C １－６ alkyl is unsubstituted or substituted with one or more R １３ The compound according to claim 1, wherein the compound is substituted with

28. a compound selected from the compounds of Table 2, Table 3, Table 4 and Table 5, or a pharmaceutically acceptable salt thereof.

29. The following structure: 【Chemical 14】 A compound having or a pharmaceutically acceptable salt thereof.

30. The following structure: 【Chemical 15】 A compound having or a pharmaceutically acceptable salt thereof.

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

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

33. The composition according to claim 32, wherein the medicament is useful in the prevention or treatment of a disease, disorder, or condition ameliorated by inhibition of KRAS having a G12C mutation. A composition comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

35. The composition according to claim 34, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, and lung cancer. A composition comprising the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof for use in a method comprising contacting a KRAS protein having a G12C mutation with the compound.

37. The method according to any one of claims 36, wherein the KRAS protein is in an active (GTP-bound) state or an inactive (GDP-bound) state.

38. The composition according to claim 36, wherein the KRAS protein is located intracellularly. A composition according to claim 36, wherein the method comprises inhibiting the function of a KRAS protein having a G12C mutation.

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